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Volume 15 - Number 11 November 2011

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The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in

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It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more

traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology,

and educational items in the various related topics for students in Medicine and in Sciences.

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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11)







Editor

Jean-Loup Huret

(Poitiers, France)

Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section

Alessandro Beghini (Milan, Italy) Genes Section

Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections

Judith Bovée (Leiden, The Netherlands) Solid Tumours Section

Vasantha Brito-Babapulle (London, UK) Leukaemia Section

Charles Buys (Groningen, The Netherlands) Deep Insights Section

Anne Marie Capodano (Marseille, France) Solid Tumours Section

Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections

Antonio Cuneo (Ferrara, Italy) Leukaemia Section

Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section

Louis Dallaire (Montreal, Canada) Education Section

Brigitte Debuire (Villejuif, France) Deep Insights Section

François Desangles (Paris, France) Leukaemia / Solid Tumours Sections

Enric Domingo-Villanueva (London, UK) Solid Tumours Section

Ayse Erson (Ankara, Turkey) Solid Tumours Section

Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections

Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section

Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections

Anne Hagemeijer (Leuven, Belgium) Deep Insights Section

Nyla Heerema (Colombus, Ohio) Leukaemia Section

Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections

Sakari Knuutila (Helsinki, Finland) Deep Insights Section

Lidia Larizza (Milano, Italy) Solid Tumours Section

Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section

Edmond Ma (Hong Kong, China) Leukaemia Section

Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections

Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections

Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section

Fredrik Mertens (Lund, Sweden) Solid Tumours Section

Konstantin Miller (Hannover, Germany) Education Section

Felix Mitelman (Lund, Sweden) Deep Insights Section

Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section

Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections

Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections

Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section

Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section

Mariano Rocchi (Bari, Italy) Genes Section

Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section

Albert Schinzel (Schwerzenbach, Switzerland) Education Section

Clelia Storlazzi (Bari, Italy) Genes Section

Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections

Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections

Dan Van Dyke (Rochester, Minnesota) Education Section

Roberta Vanni (Montserrato, Italy) Solid Tumours Section

Franck Viguié (Paris, France) Leukaemia Section

José Luis Vizmanos (Pamplona, Spain) Leukaemia Section

Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections




Volume 15, Number 11, November 2011

Table of contents

Gene Section

CTCF (CCCTC-binding factor (zinc finger protein)) 914 Jacques Piette

EPS8 (epidermal growth factor receptor pathway substrate 8) 921 Anna A Bulysheva, W Andrew Yeudall

FAM107A (family with sequence similarity 107, member A) 925 Kenji Kadomatsu, Ping Mu

GAST (gastrin) 928 Celia Chao, Mark R Hellmich

PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) 935 Yuan-Hao Hsu

TGFBRAP1 (transforming growth factor, beta receptor associated protein 1) 938 Jens U Wurthner

AXIN1 (axin 1) 940 Nives Pecina-Slaus, Tamara Nikuseva Martic, Tomislav Kokotovic

CCR2 (chemokine (C-C motif) receptor 2) 945 Jérôme Moreaux

DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) 949 Dimitra Florou, Andreas Scorilas, Dido Vassilacopoulou, Emmanuel G Fragoulis

DDR1 (discoidin domain receptor tyrosine kinase 1) 958 Barbara Roig, Elisabet Vilella

ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) 963 Luca Braccioli, Marilena V Iorio, Patrizia Casalini

KIAA0101 (KIAA0101) 972 Shannon Joseph, Lingbo Hu, Fiona Simpson

PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) 975 Nikki Minnebo, Nele Van Dessel, Monique Beullens, Aleyde van Eynde, Mathieu Bollen

SMYD2 (SET and MYND domain containing 2) 979 Hitoshi Tsuda, Shuhei Komatsu

Leukaemia Section

t(1;9)(p34;q34) 981 Jean-Loup Huret

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




Deep Insight Section

Understanding the structure and function of ASH2L 983 Paul F South, Scott D Briggs

Case Report Section

A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature 989 Sarah M Heaton, Frederick Koppitch, Anwar N Mohamed

Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M. 992 Kavita S Reddy

Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M. 994 Kavita S Reddy

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 914



CTCF (CCCTC-binding factor (zinc finger protein)) Jacques Piette

Institut de Genetique Moleculaire de Montpellier (CNRS-Université de Montpellier I-II UMR5535),

1919 Route de Mende, 34293, Montpellier-Cedex 5, France (JP)

Published in Atlas Database: April 2011

Online updated version : http://AtlasGeneticsOncology.org/Genes/CTCFID40187ch16q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CTCFID40187ch16q22.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

HGNC (Hugo): CTCF

Location: 16q22.1

Local order: AGRP, FAM65A, CTCF, RLTPR,

ACD, PARD6A.

DNA/RNA

Note

See figure 1.

Description

76776 bp gene (Ensembl).

Transcription

Ubiquitously highly expressed gene (GeneCards),

12 exons, 11 introns with at least 5 differentially

spliced transcripts (Ensembl).

Pseudogene

No.

Figure 1. Schematic representation of CTCF location on chromosome 16, gene structure and transcripts. Chromosome 16 is represented with the characteristic banding pattern. The region surrounding the CTCF gene is enlarged. Genes are

represented by arrows pointing in the direction of transcription. Transcripts are represented with exons as vertical bars and introns as lines. Distances are in kilo bases (NCBI Map Viewer).

CTCF (CCCTC-binding factor (zinc finger protein)) Piette J


Figure 2. Schematic representation of the CTCF protein. Protein sequences encoded by exons are boxed. 11 ring fingers are indicated by green boxes as also putative AT-hooks by blue boxes (Ensembl). Phosphorylated residues are in black

(PhosphoSitePlus), those sensitive to rapamycin are indicated by R (Chen et al., 2009) and those phosphorylated by CKII by CKII (El-Kady et al., 2005; Klenova et al., 2001), sumoylated residues are in red (Kitchen et al., 2010; MacPherson et al., 2009),

acetylated residue is indicated by Ac (Choudhary et al., 2009). The domain containing poly(ADPribosyl)ation sites (PAR) is boxed in red (Farrar et al., 2010). Residues mutated in tumors are indicated (see further), BT = breast tumor, PT = prostate

tumor and WT = Wilms tumor.

Protein

Description

CTCF was originally described as a c-myc activator

(Klenova et al., 1993). It is a 727 aa protein with a

MW of 82.8 kD, a charge of 8.5 and an iso electric

point of 6.95 (Ensembl). The central domain with

11 zinc fingers of the C2H2 type is highly

conserved.

Expression

CTCF is an abundant and ubiquitously expressed

protein, yet absent in primary spermatocytes

(Loukinov et al., 2002). It is downregulated during

differentiation of human myeloid leukemia cells

(Delgado et al., 1999; Torrano et al., 2005). Post-

traductional modifications include acetylation

(Choudhary et al., 2009), sumoylation (Kitchen et

al., 2010; MacPherson et al., 2009),

phosphorylation, in particular ser604-612 by CKII

(El-Kady et al., 2005; Klenova et al., 2001), and

poly(ADPribo)sylation (see figure 2). The latter

modification is lost or decreased in proliferating

cells and in BT (Docquier et al., 2009) (for sites and

role see Farrar et al., 2010 and Yu et al., 2004).

CTCF is a downstream target protein of growth

factor-induced pathways and is regulated by EGF

and insulin through activation of ERK and AKT

signaling cascades (Gao et al., 2007). It was

recently shown to be regulated by NF-kB (Lu et al.,

2010).

Localisation

CTCF is localized in the nucleoplasm of

proliferating cells with exclusion from the

nucleolus. It was detected at the centrosomes and

midbody during mitosis (Zhang et al., 2004). It is

associated with the nuclear matrix (Dunn et al.,

2003; Yusufzai et al., 2004a) and the Lamina

(Guelen et al., 2008; Ottaviani et al., 2009).

Nucleolar translocation after growth arrest is

accompanied by inhibition of nucleolar

transcription (Torrano et al., 2006). Cytoplasmic

expression was described in sporadic breast tumors

(Rakha et al., 2004).

Function

CTCF is an essential protein, since KO mice die

before ED 9.5 (Heath et al., 2008) (reviewed in

Filippova, 2008 and Phillips et al., 2009). It

interacts with up to 39609 genomic sites (in ES

cells) (Chen et al., 2008; Bao et al., 2007; Barski et

al., 2007; Kim et al., 2007). The 11 Zn fingers

would provide flexibility in DNA recognition

(Filippova et al., 1996), the central 4 bind to a

consensus DNA sequence (Filippova et al., 1998;

Renda et al., 2007). Multiple interacting proteins

were described including RNA polymerase II

(Chernukhin et al., 2007), cohesin (Parelho et al.,

2008; Rubio et al., 2008; Wendt et al., 2008), Suz12

(Li et al., 2008), CHD8 (Ishihara et al., 2006), YY1

(Donohoe et al., 2007), nucleophosmin (Yusufzai et

al., 2004b), Kaiso (Defossez et al., 2005) and

Sin3A (Lutz et al., 2000).



Mediating DNA looping (Splinter et al., 2006)

could be at the basis of most functions of CTCF.

Long range interactions are cell type specific (Hou

et al., 2010) and would depend on the chromosomal

environment of the CTCF-binding sites, in

particular its interaction with other factors (see

concept of modular insulators in Weth et al., 2010).

One thoroughly studied factor is the thyroid

receptor (Awad et al., 1999; Lutz et al., 2003). Its

chromosomal environment could also explain the

multiple (not necessarily exclusive) functions that

were described for CTCF, including chromatin

barrier (Cuddapah et al., 2008; Witcher et al.,

2009), promoter insulation from enhancer (Bell et

al., 1999) or silencer (Hou et al., 2008),

transcriptional activation (Gombert et al., 2009) (for

instance of the tumour suppressor genes

INK4A/ARF (Rodriguez et al., 2010) and p53

(Soto-Reyes et al., 2010)), repression (for instance

hTERT (Renaud et al., 2005)), nucleosome

positioning (Fu et al., 2008b), protection from DNA

methylation (Mukhopadhyay et al., 2004;

Schoenherr et al., 2003; Guastafierro et al., 2008),

preservation of triplet-repeat stability (Cho et al.,

2005; Filippova et al., 2001; Libby et al., 2008),

imprinting (Fedoriw et al., 2004; Fitzpatrick et al.,

2007), X chromosome inactivation (Chao et al.,

2002), chromosome "kissing" (Ling et al., 2006),

transvection (Liu et al., 2008), death signaling

(Docquier et al., 2005; Gomes et al., 2010; Li et al.,

2007), replication timing (Bergstrom et al., 2007),

mitotic bookmarking (Burke et al., 2005) or MHC

class II gene expression (Majumder et al., 2008).

Homology

49 orthologues were described including D.

melanogaster (Smith et al., 2009) and C. elegans

proteins (Moon et al., 2005), 3 paralogues: CTCFL

or BORIS, originating from a gene duplication in

reptiles (Hore et al., 2008; Loukinov et al., 2002),

and possibly ZFP64 (Mack et al., 1997) and the

Histone H4 transcription factor HINF-P (van

Wijnen et al., 1991).

Mutations

Note

SNP at AA 630 /K /E 90 /D /G 447 fR (NCBI).

Germinal

Non-coding mutations only.

Somatic

Mutations are rare and include point mutations of

Zn-fingers in breast (BT) (Aulmann et al., 2003),

prostate (PT) and Wilms tumor (WT) (Filippova et

al., 2002) and insertion in BT (Aulmann et al.,

2003) (see figure 2).

Implicated in

Various cancers

Note

LOH of CTCF was described in many cancers

together with potential tumor suppressor genes

(TSG), including E-Cad, since it is part of a larger

deletion (Cancer Chromosomes; Sanger institute).

In addition to WT (Yeh et al., 2002; Mummert et

al., 2005), BT (Rakha et al., 2004), PT (Filippova et

al., 1998), LOH was found in laryngeal squamous

cell carcinoma (Grbesa et al., 2008), however, there

is no evidence that CTCF is the TSG at 16q22.1

(Rakha et al., 2005), except possibly in lobular

carcinoma in situ of the breast (Green et al., 2009).

CTCF was also described to be overexpressed in

BT (Docquier et al., 2005). An indirect role of

CTCF in tumor progression is mainly suggested by

mutation or aberrant methylation of its bindings

sites (reviewed by Recillas-Targa et al., 2006).

Interestingly, a causal link between LOH of CTCF

and hypermethylation was proposed by Mummert

et al. in 2005, although no real correlation was

found by Yeh et al. in 2002. Methylation of CTCF

sites was first described in the IGF2 imprinting

control region in WT (Cui et al., 2001). Aberrant

methylation of this region was also found in PT (Fu

et al., 2008a; Paradowska et al., 2009), HNSCC (De

Castro Valente Esteves et al., 2006; Esteves et al.,

2005), colorectal cancer (Nakagawa et al., 2001),

osteosarcoma (Ulaner et al., 2003), ovarian

carcinoma (Dammann et al., 2010) and laryngeal

squamous cell carcinoma (Grbesa et al., 2008).

Hypomethylation was described in bladder cancer

(Takai et al., 2001). Microdeletions were described

in Beckwith-Wiedemann syndrome and WT

(Prawitt et al., 2005; Sparago et al., 2007). Other

methylated CTCF targets were found in the genes

AWT1 or WT1-AS in WT (Hancock et al., 2007),

Bcl6 in B cell lymphomas (Lai et al., 2010), p53,

pRb (De La Rosa-Velazquez et al., 2007), ARF

(Tam et al., 2003; Rodriguez et al., 2010), INK4B,

BRCA1 (Butcher et al., 2004; Butcher et al., 2007;

Xu et al., 2010) and Rasgrf1 (Yoon et al., 2005).

We describe below the rare cases of point mutations

affecting the CTCF protein.

Invasive ductal breast carcinoma, grade 2

Note

G2 grade tumor, no protein detected (Aulmann et

al., 2003).

Cytogenetics

14 bp insertion at AA D91, see figure 2.

Invasive ductal breast carcinoma, grade 3

Note

G3 grade tumor (Aulmann et al., 2003).

Cytogenetics

LOH and Q72H, figure 2.



Breast cancer

Note

Zinc finger mutation (Filippova et al., 2002).

Cytogenetics

LOH and K343E, figure 2.

Prostate cancer

Note


Cytogenetics

LOH and H344E, figure 2.

Wilms tumor

Note


Cytogenetics

LOH and R339W or R448Q, figure 2.

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This article should be referenced as such:

Piette J. CTCF (CCCTC-binding factor (zinc finger protein)). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):914-920.

Gene Section Review




EPS8 (epidermal growth factor receptor pathway substrate 8) Anna A Bulysheva, W Andrew Yeudall

VCU Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth

University, Richmond, VA 23298, USA (AAB, WAY)


Online updated version : http://AtlasGeneticsOncology.org/Genes/EPS8ID40476ch12p12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI EPS8ID40476ch12p12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

HGNC (Hugo): EPS8

Location: 12p12.3

DNA/RNA

Description

The EPS8 gene can be found on chromosome 12 at

12p12.3, starting at position 15664342 bp and

ending at 15833601 bp from pter on the reverse

strand. It contains 21 exons.

Transcription

The transcript consists of 4.1 kb and translates to a

822 residue protein.

Protein

Description

822 amino acids; contains pleckstrin homology

(PH) domain at amino acids 69-129 and 381-414;

contains Src homology (SH3) domain at amino

acids 531-590; intertwined dimer.

Expression

Ubiquitous in adult; temporal expression in

developing mouse embryo, in frontonasal neural

crest cells, branchial arches, liver primordium,

central nervous system and submandibular glands.

Localisation

Plasma membrane; cytoplasm; perinuclear; possibly

nuclear.

Function

Scaffolding protein; participates in signal

transduction downstream of receptor tyrosine

kinases (incl. EGFR, CSF1R, PDGFR); receptor

endocytosis; cell motility; actin reorganization.

Homology

45 orthologues identified (Ensembl).

3 paralogues: EPS8L1; EPS8L2; EPS8L3.

Schematic representation of Homo sapiens EPS8.

EPS8 (epidermal growth factor receptor pathway substrate 8) Bulysheva AA, Yeudall WA


Implicated in

Cancer

Note

Eps8 is reported to be expressed at elevated levels

in a range of human malignancies, including breast

cancer, pancreatic cancer, colon cancer and head

and neck squamous cell carcinoma.

Oncogenesis

Overexpression of EPS8 has been reported to be

sufficient to transform non-tumorigenic human

cells to a tumorigenic phenotype. In a model system

using murine fibroblasts, EPS8 overexpression led

to enhanced mitogenic signaling and growth factor-

dependent cellular transformation. Constitutive

tyrosine phosphorylation of EPS8 has been

documented in human tumor cell lines, although the

significance of this for tumorigenesis remains to be

established.

Breast cancer

Oncogenesis

EPS8 overexpression has been shown via integrated

cDNA array comparative genomic hybridization

and serial analyses of gene expression in a number

of human breast cancer cell lines such as ductal

carcinoma in situ cell lines, invasive ductal

carcinomas and lymph node metastases, as novel

candidate breast cancer oncogenes.

Pancreatic cancer

Oncogenesis

EPS8 was found to be overexpressed in multiple

pancreatic tumors, with elevated levels primarily

found in pancreatic ductal cells, cell lines derived

from malignancies and ascites compared to lower

levels in primary tumors and normal pancreatic

tissues. EPS8 was reported to localize to the tips of

F-actin filaments, filopodia, and the leading edge of

the cells, and was therefore correlated with the

migratory potential of tumor cells.

Colon cancer

Oncogenesis

EPS8 was found to be overexpressed in the

majority of colorectal tumors compared to their

normal counterparts. It was also found to modulate

FAK expression and together, EPS8 and FAK were

found to play an important role in cell locomotion.

Head and neck squamous cell carcinoma

Oncogenesis

Greater expression of EPS8 was found in malignant

head and neck squamous cell carcinoma cell lines

(HN12) compared to the primary tumor derived

cells (HN4) from the same patient. Ectopic

overexpression of EPS8 in HN4 cells led to

increased cell proliferation and migration in vitro

and tumorgenicity in vivo.

Signaling processes involving EPS8. Dashed lines, direct protein interactions; blue circles, effector proteins.



Knockdown of EPS8 in HN12 cells led to reduced

migration in vitro and reduced tumorgenicity in

vivo. EPS8 was found to mediate alphavbeta6 and

alpha5beta1 integrin dependent activation of Rac1

and resulting cell migration. Suppression of either

EPS8 or Rac1 resulted in reduced cell motility of

the same tumor cells, however constitutive

expression of Rac1 rescued reduced cell migration

in EPS8 knockdown cells. Therefore EPS8 and

Rac1 likely modulate integrin-dependent tumor cell

motility. FOXM1, a cell cycle related transcription

factor, was found to be upregulated in tumor cells

with elevated EPS8. Further studies showed cell

proliferation and migration due to EPS8 occurs in

part by FOXM1 deregulation and induction of

CXC-chemokine expression, which is mediated by

PI3K and AKT-dependent mechanisms.

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Croce A, Cassata G, Disanza A, Gagliani MC, Tacchetti C, Malabarba MG, Carlier MF, Scita G, Baumeister R, Di Fiore PP. A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans. Nat Cell Biol. 2004 Dec;6(12):1173-9

Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G. Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol. 2004 Dec;6(12):1180-8

Funato Y, Terabayashi T, Suenaga N, Seiki M, Takenawa T, Miki H. IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer Res. 2004 Aug 1;64(15):5237-44

Leu TH, Yeh HH, Huang CC, Chuang YC, Su SL, Maa MC. Participation of p97Eps8 in Src-mediated transformation. J Biol Chem. 2004 Mar 12;279(11):9875-81

Offenhäuser N, Borgonovo A, Disanza A, Romano P, Ponzanelli I, Iannolo G, Di Fiore PP, Scita G. The eps8



family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway. Mol Biol Cell. 2004 Jan;15(1):91-8

Wunsch A, Strothmann K, Simoni M, Gromoll J, Nieschlag E, Luetjens CM. Epidermal growth factor receptor pathway substrate 8 (Eps8) expression in maturing testis. Asian J Androl. 2004 Sep;6(3):195-203

Roffers-Agarwal J, Xanthos JB, Miller JR. Regulation of actin cytoskeleton architecture by Eps8 and Abi1. BMC Cell Biol. 2005 Oct 14;6:36

Disanza A, Mantoani S, Hertzog M, Gerboth S, Frittoli E, Steffen A, Berhoerster K, Kreienkamp HJ, Milanesi F, Di Fiore PP, Ciliberto A, Stradal TE, Scita G. Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. Nat Cell Biol. 2006 Dec;8(12):1337-47

Khanday FA, Santhanam L, Kasuno K, Yamamori T, Naqvi A, Dericco J, Bugayenko A, Mattagajasingh I, Disanza A, Scita G, Irani K. Sos-mediated activation of rac1 by p66shc. J Cell Biol. 2006 Mar 13;172(6):817-22

Yao J, Weremowicz S, Feng B, Gentleman RC, Marks JR, Gelman R, Brennan C, Polyak K. Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression. Cancer Res. 2006 Apr 15;66(8):4065-78

Maa MC, Lee JC, Chen YJ, Chen YJ, Lee YC, Wang ST, Huang CC, Chow NH, Leu TH. Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase. J Biol Chem. 2007 Jul 6;282(27):19399-409

Welsch T, Endlich K, Giese T, Büchler MW, Schmidt J. Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization. Cancer Lett. 2007 Oct 8;255(2):205-18

Chen YJ, Shen MR, Chen YJ, Maa MC, Leu TH. Eps8 decreases chemosensitivity and affects survival of cervical cancer patients. Mol Cancer Ther. 2008 Jun;7(6):1376-85

Wang H, Patel V, Miyazaki H, Gutkind JS, Yeudall WA. Role for EPS8 in squamous carcinogenesis. Carcinogenesis. 2009 Jan;30(1):165-74

Xu M, Shorts-Cary L, Knox AJ, Kleinsmidt-DeMasters B, Lillehei K, Wierman ME. Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival. Endocrinology. 2009 May;150(5):2064-71

Yap LF, Jenei V, Robinson CM, Moutasim K, Benn TM, Threadgold SP, Lopes V, Wei W, Thomas GJ, Paterson IC. Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation. Oncogene. 2009 Jul 9;28(27):2524-34

Zhang W, Wang L, Liu Y, Xu J, Zhu G, Cang H, Li X, Bartlam M, Hensley K, Li G, Rao Z, Zhang XC. Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione. Genes Dev. 2009 Jun 15;23(12):1387-92

Liu PS, Jong TH, Maa MC, Leu TH. The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation. Oncogene. 2010 Jul 8;29(27):3977-89

Wang H, Teh MT, Ji Y, Patel V, Firouzabadian S, Patel AA, Gutkind JS, Yeudall WA. EPS8 upregulates FOXM1 expression, enhancing cell growth and motility. Carcinogenesis. 2010 Jun;31(6):1132-41

Welsch T, Younsi A, Disanza A, Rodriguez JA, Cuervo AM, Scita G, Schmidt J. Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells. Exp Cell Res. 2010 Jul 15;316(12):1914-24

Yang TP, Chiou HL, Maa MC, Wang CJ. Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6


Bulysheva AA, Yeudall WA. EPS8 (epidermal growth factor receptor pathway substrate 8). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):921-924.

Gene Section Mini Review




FAM107A (family with sequence similarity 107, member A) Kenji Kadomatsu, Ping Mu

Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho,

Showa-ku, Nagoya 466-8550, Japan (KK, PM)


Online updated version : http://AtlasGeneticsOncology.org/Genes/FAM107AID42728ch3p14.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI FAM107AID42728ch3p14.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: DRR1; FLJ30158; FLJ45473;

TU3A

HGNC (Hugo): FAM107A

Location: 3p14.3

Note: The FAM107A protein is encoded by

FAM107A gene.

DNA/RNA

Description

FAM107A DNA contains 17742 bps (genomic

size), on negative strand.

Transcription

FAM107A has two transcript variants. FAM107A

transcript variant 1 mRNA contains 3465 bps and 5

exons. FAM107A transcript variant 2 mRNA

contains 3367 bps and 4 exons. These two

transcript variants encode for the same protein.

Protein

Description

144 amino acids, 17,5 kDa.

FAM107A protein includes a nuclear localization

signal (NLS) and a coiled domain (Yamato et al.,

1999; Wang et al., 2000).

Expression

FAM107A protein is expressed in a wide variety of

normal tissues. High expression is found in the

brain and heart (Wang et al., 2000; Zhao et al.,

2007).

Localisation

Nucleus and cytoplasm (Wang et al., 2000; Zhao et

al., 2007; Le et al., 2010).

Function

FAM107A is a candidate tumor suppressor gene.

FAM107A protein is downregulated in several

tumor cell lines and primary tumors.

Overexpression of FAM107A can suppress tumor

cell growth (Yamato et al., 1999; Wang et al., 2000;

Kholodnyuk et al., 2006; van den Boom et al.,

2006; Liu et al., 2009; Asano et al., 2010; Le et al.,

2010).

FAM107A protein is also involved in neuronal cell

survival. Downregulation of FAM107A protein in

primary cultured cortical neurons decrease cell

number (Asano et al., 2010).

FAM107A protein probably plays important roles

in embryo development (Zhao et al., 2007).

FAM107A protein is a cytoskeletal crosslinker that

regulates FA dynamics and cell movement.

FAM107A protein is an important molecular in cell

invasion (Le et al., 2010).

Homology

No proteins with significant homology with

FAM107A protein were found (Wang et al., 2000).

FAM107A (family with sequence similarity 107, member A) Kadomatsu K, Mu P


Mutations

Note

Up to now, no point mutations were identified.

Implicated in

Renal cell carcimoma

Disease

Loss of FAM107A gene was found on 3p21.1 in

renal cell carcinoma. Reduced expression was

found in renal cell carcinoma cell lines and primary

renal cell carcinomas. Overexpression of

FAM107A in renal cell carcinoma cell line resulted

in growth suppression of these cells (Yamato et al.,

1999; Wang et al., 2000). Also, FAM107A

hypermethylation was detected in renal cell

carcimomas and significantly associated with

advanced tumor stage (Awakura et al., 2008).

Astrocytomas

Disease

FAM107A was expressed at significantly lower

levels in secondary glioblastomas as compared to

diffuse astrocytomas (Van den Boom et al., 2006).

Lung cancer

Disease

Loss of expression of FAM107A was found in non-

small cell lung cancer and primary lung cancers.

Overexpression of FAM107A in non-small cell

lung cancer cell line reduced cell proliferation

activity and induced apoptosis (Liu et al., 2009).

Neuroblastoma

Disease

FAM107A protein was detected in the normal

ganglions and the ganglions exhibiting neuroblast

hyperplasia from 2 weeks hemizygote MYCN

transgenic mice. However, the expression of

FAM107A completely disappeared in the tumors

from 8 weeks hemizygote MYCN transgenic mice

(Asano et al., 2010).

Brain tumor

Disease

FAM107A is not expressed in normal glial cells, it

is highly expressed in the invasive component of

gliomas. It was found that FAM107A associates

with and organizes the actin and microtubular

cytoskeletons. FAM107A regulates focal adhesion

disassembly and cell invasion (Le et al., 2010).

Embryo development

Note

The expression level of FAM107A gene increases

gradually with embryo development in the early

stages (Zhao et al., 2007).

Schizophrenia and bipolar disorder

Note

High expression level of FAM107A was found in

the dorsolateral prefrontal cortex from

schizophrenia and bipolar disorder patient (Shao et

al., 2007).

Neuronal cell survival

Note

FAM107A protein was mainly localized in the

neurites of the primary culture of cerebral cortical

neurons. Downregulation of FAM107A expression

with siRNA decreased neuron cell number. These

data suggest that FAM107A plays a critical role in

neuronal cell survival (Asano et al., 2010).

References Yamato T, Orikasa K, Fukushige S, Orikasa S, Horii A. Isolation and characterization of the novel gene, TU3A, in a commonly deleted region on 3p14.3-->p14.2 in renal cell carcinoma. Cytogenet Cell Genet. 1999;87(3-4):291-5

Wang L, Darling J, Zhang JS, Liu W, Qian J, Bostwick D, et al. Loss of expression of the DRR 1 gene at chromosomal segment 3p21.1 in renal cell carcinoma. Genes Chromosomes Cancer. 2000 Jan;27(1):1-10

Kholodnyuk ID, Kozireva S, Kost-Alimova M, Kashuba V, Klein G, Imreh S. Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3-mouse fibrosarcoma hybrids in severe combined immunodeficiency mice. Int J Cancer. 2006 Jul 1;119(1):99-107

van den Boom J, Wolter M, Blaschke B, Knobbe CB, Reifenberger G. Identification of novel genes associated with astrocytoma progression using suppression subtractive hybridization and real-time reverse transcription-polymerase chain reaction. Int J Cancer. 2006 Nov 15;119(10):2330-8

Zhao XY, Liang SF, Yao SH, Ma FX, Hu ZG, Yan F, Yuan Z, Ruan XZ, Yang HS, Zhou Q, Wei YQ. Identification and preliminary function study of Xenopus laevis DRR1 gene. Biochem Biophys Res Commun. 2007 Sep 14;361(1):74-8

Awakura Y, Nakamura E, Ito N, Kamoto T, Ogawa O. Methylation-associated silencing of TU3A in human cancers. Int J Oncol. 2008 Oct;33(4):893-9

Shao L, Vawter MP. Shared gene expression alterations in schizophrenia and bipolar disorder. Biol Psychiatry. 2008 Jul 15;64(2):89-97

Zhao XY, Li HX, Liang SF, Yuan Z, Yan F, Ruan XZ, You J, Xiong SQ, Tang MH, Wei YQ. Soluble expression of human DRR1 (down-regulated in renal cell carcinoma 1) in Escherichia coli and preparation of its polyclonal antibodies. Biotechnol Appl Biochem. 2008 Jan;49(Pt 1):17-23

Liu Q, Zhao XY, Bai RZ, Liang SF, Nie CL, Yuan Z, Wang CT, Wu Y, Chen LJ, Wei YQ. Induction of tumor inhibition and apoptosis by a candidate tumor suppressor gene DRR1 on 3p21.1. Oncol Rep. 2009 Nov;22(5):1069-75

Asano Y, Kishida S, Mu P, Sakamoto K, Murohara T, Kadomatsu K. DRR1 is expressed in the developing nervous system and downregulated during neuroblastoma carcinogenesis. Biochem Biophys Res Commun. 2010 Apr 9;394(3):829-35

Frijters R, Fleuren W, Toonen EJ, Tuckermann JP, et al Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor. BMC Genomics. 2010 Jun 5;11:359

FAM107A (family with sequence similarity 107, member A) Kadomatsu K, Mu P


Le PU, Angers-Loustau A, de Oliveira RM, Ajlan A, Brassard CL, Dudley A, Brent H, Siu V, Trinh G, Mölenkamp G, Wang J, Seyed Sadr M, Bedell B, Del Maestro RF, Petrecca K. DRR drives brain cancer invasion by regulating cytoskeletal-focal adhesion dynamics. Oncogene. 2010 Aug 19;29(33):4636-47


Kadomatsu K, Mu P. FAM107A (family with sequence similarity 107, member A). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):925-927.

Gene Section Review




GAST (gastrin) Celia Chao, Mark R Hellmich

Department of Surgery, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch,

Galveston, TX 77555, USA (CC, MRH)


Online updated version : http://AtlasGeneticsOncology.org/Genes/GASTID44214ch17q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI GASTID44214ch17q21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: GAS

HGNC (Hugo): GAST

Location: 17q21.2

DNA/RNA

Note

The 4.3 kb gene for human gastrin contains two

introns and 3 exons that encode preprogastrin, the

gastrin precursor. It is located on chromosome

17(q21), and consists of three exons that contain the

code sequence for a prepropeptide of 101 amino

acid residues with a calculated molecular mass of

11.4 kDa (see diagram below). The primary

structure of human preprogastrin protein consists of

an N-terminal 21-amino acid signal sequence

followed by a spacer peptide, a bioactive domain,

and finally a hexapeptide C-terminal flanking

peptide (CTFP). Upon initiation of translation, the

signal sequence facilitates the translocation of the

elongating polypeptide into the endoplasmic

reticulum (ER), where it is subsequently removed

by a membrane-bound signal peptidase that cleaves

the growing polypeptide chain between alanine

residue 21 and serine 22 to generate the 80 amino

acid peptide, progastrin. Progastrin is further

processed (see protein section below) into the two

principal C-terminal alpha-amidated forms of

circulating gastrin generated from the proteolytic

cleavage of progastrin are gastrin-17 (G17) and

gastrin-34 (G34).

Protein

Note

It should be noted that the numbering system of

critical amino acid residues involved in peptide

cleavage and post-translational modifications of

gastrin varies within the scientific literature. This is

due to the fact that the numbering system of some

authors is based on the sequence of preprogastrin,

which includes the 21 amino acids of the signal

peptide sequence, whereas the numbering system of

others is based on the sequence of progastrin. Our

description of prohormone processing will be based

on the 80 amino acid peptide sequence of

progastrin.

After signal peptide cleavage, progastrin undergoes

additional post-translational modifications as it

transits from the ER through the Golgi to the trans-

Golgi network before it is sorted into immature

secretory vesicles of the regulated exocytosis

(secretory) pathway. The modifications include O-

sulfation at tyrosine residue 66 of the propeptide by

tyrosylprotein sulfotransferases and/or

phosphorylation at serine 75 by a calcium-

dependent casein-like kinase. Although O-sulfation

is thought to occur primarily in the trans-Golgi

network, a recent study provides evidence

suggesting that it may continue through later

compartments of the regulated secretory pathway.

Chromosome 17 - NC_000017.10.

GAST (gastrin) Chao C, Hellmich MR


Schematic representation of the preprogastrin gene, its mRNA, and the peptide precursor preprogastrin. The gene is transcribed as a 303 nucleotide RNA transcript and the mRNA is processed into a 101 amino acid (aa) preprohormone. The

preprogastrin peptide consists of a 21-aa signal sequence, which is co-translationally cleaved, a N-terminal spacer, the active peptide and the C-terminal flanking peptide (CTFP). Progastrin is formed after removal of the signal peptide.

The extent of gastrin O-sulfation varies with

species and cellular localization of peptide

synthesis within the GI tract as well as the

developmental stage of the tissues. For example, in

adult humans, approximately half of the gastrin

peptide synthesized in G cells of the antrum and

duodenum, and released into the circulation are

sulfated, whereas all of the gastrin peptide produced

by the fetal pancreas appears to be sulfated.

Functionally, sulfation of gastrin enhances

endoproteolytic processing of progastrin, and may

promote protein-protein interactions and peptide

sorting between secretory pathways. However,

unlike sulfation of the related peptide,

cholecystokinin (CCK), sulfation of gastrin does

not significantly affect its affinity for its

physiologic receptor.

Phosphorylation of serine 75 of progastrin may

promote proteolytic processing at the upstream

arginine residues at positions 73 and 74 (arginine

73-arginine 74) releasing the C-terminal flanking

peptide, and may affect the conversion of glycine-

extended gastrin intermediates to mature C-terminal

alpha-amidated peptides. However, since

phosphorylation is not essential for progastrin

processing, its biological significance remains an

enigma.

Following sulfation and/or phosphorylation,

progastrin exits the trans-Golgi network and enters

immature granules of the regulated secretory

pathway. The major proteolytic processing of

progastrin to its biologically active peptides occurs

in the maturing dense core secretory granules of the

regulated pathway. Progastrin is cleaved by two

types of proteases: endo- and exopeptidases.

Endopeptidases, also known as prohormone

convertases (PC), typically cleave polypeptides

downstream of two adjacent basic amino acid

residues at the general motif (lysine/arginine)-(X)n-

(lysine/arginine), where n=0, 2, 4, or 6 and X is any

amino acid, but usually not a Cysteine. PC1/3 and

PC2 are involved in progastrin processing.

The two principal biologically active forms of

circulating gastrin are gastrin-17 (G17) and gastrin-

34 (G34). In rodent and human G cells of antrum

and proximal duodenum, approximately 95% of the

progastrin is processed to partially sulfated G17

(85%) and G34 (10%). Although G17 is the

predominant product, G34 is the major circulating

form of gastrin due to its slower rate of clearance.

In both humans, the half-life of circulating G34 is

approximately five times longer than that of G17.

The proteolytic processing of progastrin involves

convertase-specific cleavage at three dibasic

consensus sites. PC1/3 is active early in the

secretory pathway in granules with a neutral pH

(i.e., pH ≈ 7) and cleaves the prohormone after the

arginine 36-arginine 37 and arginine 73-arginine 74

sequences, releasing the C-terminal flanking

peptide, and generating G34. The post-cleavage

residual basic residues are then removed by

carboxypeptidase E, generating what are commonly

referred to as the glycine-extended gastrins (i.e.,

G34-Glycine). In contrast to PC1/3, PC2 is mainly

active in mature granules at an acidic pH (i.e., pH ≈

5). Cleavage of G34-glycine by PC2 after the

dibasic amino acid sequence lysine 53-lysine 54

produces G17-glycine. These glycine-extended

peptides are substrates for the peptidyl-glycine

alpha-amidating monooxygenase (PAM) that

utilizes the glycyl residue as an amide donor to

alpha-amidate the carboxyl group of the C-terminus

of the peptide. The ratio of amidated gastrins to

processing intermediates varies considerably across

tissues and cell types. Processing intermediates are

quite scarce in the gastric antrum, making up only

about 1-5% of gastrin gene products, while in the

duodenum the value has been reported to be as high



Processing of gastrin. The numbering system of critical amino acid residues involved in peptide cleavage and post-translational modifications of gastrin varies within the scientific literature. This is due to the fact that the numbering system of some authors is

based on the sequence of preprogastrin, which includes the 21 amino acids of the signal peptide sequence, whereas the numbering system of others is based on the sequence of progastrin. The numbers at the top of the diagram represents the

amino acid (aa) sequence for preprogastrin; the numbers at the bottom of the diagram represents the aa sequence for progastrin. The signal peptide is cleaved co-translationally in the rough ER by signal peptidase. In the Trans-Golgi-Network

(TGN), progastrin is modified by sulfation at Tyr 66 and phosphorylation of Ser 75 by a casein-like kinase. Prohormone convertases (PC) and carboxypeptidase E (CPE) sequentially convert the prohormone to the glycine-extended forms (G71-Gly,

G34-Gly, G17-Gly). Abbreviations: CTFP: C-terminal flanking peptide, TPST: tyrosyl-protein sulfotransferase, PAM: peptidyl-alpha-amidating-monooxygenase.

as 20%. Carboxyl-terminus alpha-amidation is a

prerequisite for high affinity binding of gastrin to

its cognate receptor, CCK2 receptor.

Mutations

Note

There are no known mutations in the gastrin gene

causing a pathologic entity. Overexpression of

gastrin, or aberrant expression of gastrin, have both

been associated with gastric, colorectal, esophageal

and pancreatic cancers.

Implicated in

Gastrinomas

Note

Gastrinomas are neuroendocrine tumors that can

arise from the stomach, duodenum or pancreas.

Patients with multiple endocrine neoplasia type 1

(MEN1) have a mutation in the menin gene and are

at very high risk for developing gastrinomas. In

patients with hypergastrinemia due to pernicious

anemia or MEN1, tissue and plasma levels of PAI-2

are elevated. Gastrin directly regulates PAI-2

expression in CCK2 receptor-positive cells, and in

neighboring receptor-negative cells, by way of

paracrine mediators released from the CCK2

receptor-expressing cells. Direct regulation involves

cell automous activation of CRE and AP-1

transcription factors via a PKC, Ras, Raf, RhoA,

and the NFkappaB signaling pathways in CCK2

receptor-expressing cells by gastrin. The CRE and

AP-1 transcription factors, in turn, regulate

expression of the genes for IL-8 and COX2. IL-8

acts through a GACAGA site via the activating

signal cointegrator 1 (ASC-1) complex, whereas

prostaglandins, resulting from the activation of

COX2, target the Myc-associated zinc finger

protein (MAZ site via the small GTPase RhoA to

stimulate PAI-2 expression in adjacent CCK2

receptor-negative cells.

Inflammation-associated carcinomas

Note

In a rat intestinal epithelial cell model, MAPKs

mediate CCK2 receptor regulation of cyclooxgenase

2 (COX-2). COX-2 is an inducible enzyme

catalyzing the rate-limiting step in prostaglandin

synthesis, converting arachidonic acid to

prostaglandin H2. A large body of genetic and

biochemical evidence support the important role of



COX-2 and the subsequent synthesis of

prostaglandins in the regulation of inflammation

and promotion of tumorigenesis. Gastrin has been

shown to increase COX-2 expression in colorectal,

gastric, and esophageal cancers.

Gastric cancer

Note

Gastric carcinogenesis is a multistep process that

arises from superficial gastritis, chronic atrophic

gastritis, progressing to intestinal metaplasia,

dysplasia, and finally carcinoma. H. pylori is the

most common known cause of chronic gastritis in

humans, secretes urease, which converts urea to

ammonia, and neutralizes the acid in the stomach.

H. pylori initiates a host inflammatory response that

is associated with the recruitment of mononuclear

and polymorphonuclear leukocytes, and bone

marrow-derived cells. Specific inflammatory

cytokines from immune cells are required for the

initiation and promotion of carcinogenesis. In

addition to local inflammation, H. pylori induces

the systemic elevation of serum gastrin

(hypergastrinemia). The combination of

achlorhydria and hypergastrinemia, induced by H.

pylori infection, results in gastric bacterial

overgrowth, lack of parietal cell differentiation,

development of gastric metaplasia, and eventual

progression to gastric carcinoma.

Colorectal cancer

Note

Gastrin and gastrin-like peptides are upregulated

locally in 78% of premalignant adenomatous

polyps, before the appearance of invasive

carcinoma, and gastrin expression has been linked

to key mutations in the initiation of colorectal

carcinogenesis. When the APCmin-/+

mouse was

crossed with a gastrin gene knockout mouse, the

hybrid developed fewer intestinal polyps. Gastrin

transcription is linked to the Wnt/beta-catenin

pathway by a binding site for the transcription

factor TCF4 in the gastrin promoter. Induction of

the wild-type APC decreased gastrin mRNA

expression, while transfection of constitutively

active beta-catenin increased gastrin promoter

activity.

References GREGORY RA, TRACY HJ. THE CONSTITUTION AND PROPERTIES OF TWO GASTRINS EXTRACTED FROM HOG ANTRAL MUCOSA. Gut. 1964 Apr;5:103-14

Korman MG, John DJ, Hansky J. Studies on serum gastrin levels in pernicious anaemia. Gut. 1970 Nov;11(11):981

Rehfeld JF, Stadil F. Gel filtration studies on immunoreactive gastrin in serum from Zollinger-Ellison patients. Gut. 1973 May;14(5):369-73

Stadil F, Rehfeld JF. Release of gastrin by epinephrine in man. Gastroenterology. 1973 Aug;65(2):210-5

Walsh JH, Debas HT, Grossman MI. Pure human big gastrin. Immunochemical properties, disappearance half time, and acid-stimulating action in dogs. J Clin Invest. 1974 Aug;54(2):477-85

Dockray GJ, Taylor IL. Heptadecapeptide gastrin: measurement in blood by specific radioimmunoassay. Gastroenterology. 1976 Dec;71(6):971-7

Larsson LI, Rehfeld JF, Sundler F, Håkanson R. Pancreatic gastrin in foetal and neonatal rats. Nature. 1976 Aug 12;262(5569):609-10

Walsh JH, Isenberg JI, Ansfield J, Maxwell V. Clearance and acid-stimulating action of human big and little gastrins in duodenal ulcer subjects. J Clin Invest. 1976 May;57(5):1125-31

Feldman M, Walsh JH, Wong HC, Richardson CT. Role of gastrin heptadecapeptide in the acid secretory response to amino acids in man. J Clin Invest. 1978 Feb;61(2):308-13

Thompson JC, Lowder WS, Peurifoy JT, Swierczek JS, Rayford PL. Effect of selective proximal vagotomy and truncal vagotomy on gastric acid and serum gastrin responses to a meal in duodenal ulcer patients. Ann Surg. 1978 Oct;188(4):431-8

Hirschowitz BI, Helman CA. Effects of fundic vagotomy and cholinergic replacement on pentagastrin dose responsive gastric acid and pepsin secretion in man. Gut. 1982 Aug;23(8):675-82

Taylor IL, Byrne WJ, Christie DL, Ament ME, Walsh JH. Effect of individual l-amino acids on gastric acid secretion and serum gastrin and pancreatic polypeptide release in humans. Gastroenterology. 1982 Jul;83(1 Pt 2):273-8

Boel E, Vuust J, Norris F, Norris K, Wind A, Rehfeld JF, Marcker KA. Molecular cloning of human gastrin cDNA: evidence for evolution of gastrin by gene duplication. Proc Natl Acad Sci U S A. 1983 May;80(10):2866-9

Andersen BN. Measurement and occurrence of sulfated gastrins. Scand J Clin Lab Invest Suppl. 1984;168:5-24

Brand SJ, Andersen BN, Rehfeld JF. Complete tyrosine-O-sulphation of gastrin in neonatal rat pancreas. Nature. 1984 May 31-Jun 6;309(5967):456-8

Brand SJ, Klarlund J, Schwartz TW, Rehfeld JF. Biosynthesis of tyrosine O-sulfated gastrins in rat antral mucosa. J Biol Chem. 1984 Nov 10;259(21):13246-52

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Chao C, Hellmich MR. GAST (gastrin). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):928-934.





PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Yuan-Hao Hsu

Department of Chemistry and Biochemistry and Pharmacology, School of Medicine, San Diego, La

Jolla, California 92093-0601, USA (YHH)


Online updated version : http://AtlasGeneticsOncology.org/Genes/PAK2ID41634ch3q29.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI PAK2ID41634ch3q29.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: PAK65; PAKgamma

HGNC (Hugo): PAK2

Location: 3q29

DNA/RNA

Description

Pak2 gene at 193763319 to 193859670 bp from pter

contains 96352 bases and 34 exons. Pak2 gene at

the alternative location starts at 196466728 and

ends at 196559518 bp from pter. The PAK2 gene in

this location contains 20 exons.

Protein

Description

Pak2 has an N-terminal regulatory domain and a C-

terminal catalytic domain. In the regulatory domain,

Pak2 have several conserved regions, including an

autoinhibitory domain (AID), a p21-binding

domain (PBD), dimerization domain, proline-rich

regions, and an acidic region. The schematic

structure of Pak2 is shown in figure above. The

catalytic domain of Pak is a conserved bilobal

structure in most of the protein kinases.

Expression

Pak2 is 58.8 kDa (524 residues) and expressed

ubiquitously in mammalian cells.

Function

PAK activation is through disruption of

autoinhibition, followed by autophosphorylation. In

the inactive state, the AID interacts with the

catalytic domain to inhibit its kinase activity. GTP-

bound Cdc42 can disrupt autoinhibition, which, in

turn, leads to autophosphorylation and activation of

PAK. Pak2's basal autophosphorylation activity is

observed and Pak2 is autophosphorylated at 5 sites,

serines 19, 20, 55, 192 and 197. Additional three

phosphorylation sites (serines 141 and 165 and

threonine 402) are autophosphorylated in the

presence of Cdc42(GTP) and ATP.

Autophosphorylation of Thr402 in the activation

loop is required for the kinase activity of Pak2.

Pak2 can be activated in response to a lot of

stresses. Moderate stresses, like hyperosmolarity,

ionizing radiation, DNA-damaging agents and

serum-deprivation, induce Pak2 activation in cells

and lead to cell cycle arrest at G2/M. Activated

Pak2 inhibits translation by phosphorylation of

various substrates. Pak2 has specific protein

substrates, e.g. histone 4, myosin light chain

(MLC), prolactin, c-Abl, eukaryote translation

initiation factor 3 (eIF3), eIF4B, eIF4G, and Mnk1.

Pak2 recognizes the consensus sequence

(K/RRXS).

Pak2 is the only member of the PAK family that is

directly activated by caspase 3. When Pak2 is

cleaved and activated by caspase 3, Pak2 promotes

the morphological and biochemical changes of

apoptosis. The pro-apoptosis protease, caspase 3

cleaves Pak2 after Asp 212, and thus produces a

p27 fragment containing primarily the regulatory

domain, and a p34 fragment containing a small

piece of the regulatory domain and the entire

catalytic domain. Autophosphorylation results in a

constitutively active p34 kinase domain.

PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Hsu YH


The Linear schematic of Pak2. Functional domains, including proline rich regions (P), acidic region (A), p21-binding domain

(PBD), Cdc42 and Rac interaction and binding sequence (CRIB) and autoinhibitory domain (AID) are designated. Autophosphorylation sites (*) and caspase 3 cleavage site (v) are marked. The regulatory domain is blue; the protein kinase

domain is green; the overlapping region between PBD and AID is pink.

The nuclear import signal (245-251) is required for

nuclear localization. Disruption of the region (197-

246), containing nuclear export signal results in the

nuclear localization of the Pak2 p34 fragment.

Homology

Pak1, Pak2 and Pak3 are highly homologous. The

primary sequence of human Pak2 is 72 % identical

to Pak1 and 71 % identical to Pak3.

Mutations

Note

None is reported.

Implicated in

Tumors

Prognosis

Huang (2004) showed Pak2 is a negative regulator

of Myc and suggested Pak2 may be the product of a

tumor suppressor gene. Coniglio (2008) reported

Pak2 mediates tumor invasion in breast carcinoma

cells. Inhibition of RhoA in Pak2-depleted cells

decreases MLC phosphorylation and restores cell

invasion. Also, the NF2 tumor suppressor Merlin is

a substrate of Pak2. Wilkes (2009) showed that

Erbin regulates the function of Merlin through Pak2

binding to Merlin.

Immunodeficiency

Note

Human immunodeficiency virus type 1 HIV-1.

Prognosis

Human immunodeficiency virus type 1 Nef

associates with a active Pak2 independently of

binding to Nck or PIX. Nef recruits the GEF Vav1

to plasma membrane to associate with Pak2.

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Jakobi R, McCarthy CC, Koeppel MA, Stringer DK. Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation. J Biol Chem. 2003 Oct 3;278(40):38675-85

Huang Z, Traugh JA, Bishop JM. Negative control of the Myc protein by the stress-responsive kinase Pak2. Mol Cell Biol. 2004 Feb;24(4):1582-94

Orton KC, Ling J, Waskiewicz AJ, Cooper JA, Merrick WC, Korneeva NL, Rhoads RE, Sonenberg N, Traugh JA. Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. J Biol Chem. 2004 Sep 10;279(37):38649-57

Ling J, Morley SJ, Traugh JA. Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2. EMBO J. 2005 Dec 7;24(23):4094-105

Coniglio SJ, Zavarella S, Symons MH. Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms. Mol Cell Biol. 2008 Jun;28(12):4162-72

Hsu YH, Johnson DA, Traugh JA. Analysis of conformational changes during activation of protein kinase Pak2 by amide hydrogen/deuterium exchange. J Biol Chem. 2008 Dec 26;283(52):36397-405

PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Hsu YH


Wilkes MC, Repellin CE, Hong M, Bracamonte M, Penheiter SG, Borg JP, Leof EB. Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta. Dev Cell. 2009 Mar;16(3):433-44

Hsu YH, Traugh JA. Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis. PLoS One. 2010 Mar 1;5(3):e9455


Hsu YH. PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):935-937.





TGFBRAP1 (transforming growth factor, beta receptor associated protein 1) Jens U Wurthner

Translational Pharmacology and Discovery Medicine, GlaxoSmithKline, Gunnels Wood Road,

Stevenage, SG1 2NY, USA (JUW)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TGFBRAP1ID42542ch2q12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI TGFBRAP1ID42542ch2q12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: TRAP-1; TRAP1

HGNC (Hugo): TGFBRAP1

Location: 2q12.1

DNA/RNA

Description

Encoded on the minus strand. 12 exons, exon

number 1 is not depicted in the diagram and

appears to undergo differential splicing, according

to recent NCBI-AceView (accessed 17 Apr 2011).

Transcription

Work by the Wurthner lab in 2003-2005 identified

an 860 aa protein that could be matched with

genomic sequences. Recently predicted proteins

from mRNA variants describe translation products

of 896, 952, 161 and 30 aminino acids (NCBI

AceView, accessed 17 April 2011).

Protein

Description

A fragment of TGFBRAP1 was initially identified

in a Yeast-2-Hybrid screen as a TGF-beta type I

receptor interacting protein (Charng et al., 2002).

Further work by Wurthner et al. demonstrated

binding of the full-length molecule exclusively to

either TGF-beta receptor I and TGF-beta receptor

II, or to Smad4, suggesting TGFBRAP1 to be a

Smad4 chaperone (Wurthner et al., 2001).

Furthermore, receptor activated Smads were shown

to compete for binding of TRAP1 with Smad4,

suggesting only a transient association between

TRAP1 and Smad4. In addition, an interaction of

TRAP1 with 5-lipoxgenase in a yeast two-hybrid

system was described by a different group (Provost

et al., 1999). Gene inactivation of TGFBRAP1

through conventional targeting leads to early

developmental arrest of murine embryos around

day E 6.5 (Messler et al., 2010).

Generated by BlastAnalyser in 2005 (unpublished). Contig: NT_022171.13 (gi: 29789878).

TGFBRAP1 (transforming growth factor, beta receptor associated protein 1)

Wurthner JU


CNH: Citron Homology Domain; CLH: Clathrin Homology Domain; VPS39: Vesicle Protein Sorting Protein 39 Domain.

Expression

Ubiquitous.

Localisation

Punctate pattern suggestive of endosomal

localisation.

Function

Chaperone for Smad4 in the TGF-beta signal

transduction cascade (Wurthner et al., 2001).

Endosomal trafficking (circumstantial evidence:

domain structure and early embryonic lethality;

Messler et al., 2010).

Homology

hVPS39 (hVam6, hTrap-like-Protein).

References Charng MJ, Zhang D, Kinnunen P, Schneider MD. A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor. J Biol Chem. 1998 Apr 17;273(16):9365-8

Provost P, Samuelsson B, Rådmark O. Interaction of 5-lipoxygenase with cellular proteins. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1881-5

Wurthner JU, Frank DB, Felici A, Green HM, Cao Z, Schneider MD, McNally JG, Lechleider RJ, Roberts AB. Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone. J Biol Chem. 2001 Jun 1;276(22):19495-502

Felici A, Wurthner JU, Parks WT, Giam LR, Reiss M, Karpova TS, McNally JG, Roberts AB. TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling. EMBO J. 2003 Sep 1;22(17):4465-77

Messler S, Kropp S, Episkopou V, Felici A, Würthner J, Lemke R, Jerabek-Willemsen M, Willecke R, Scheu S, Pfeffer K, Wurthner JU. The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development. Immunobiology. 2011 Mar;216(3):343-50


Wurthner JU. TGFBRAP1 (transforming growth factor, beta receptor associated protein 1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):938-939.

Gene Section Review




AXIN1 (axin 1) Nives Pecina-Slaus, Tamara Nikuseva Martic, Tomislav Kokotovic

Department of Biology, Laboratory for Neurooncology, Croatian Institute for Brain Research,

Medical School University of Zagreb, Salata 12, Zagreb, Croatia (NPS, TN, TK)

Published in Atlas Database: May 2011

Online updated version : http://AtlasGeneticsOncology.org/Genes/AXIN1ID379ch16p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI AXIN1ID379ch16p13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: AXIN; MGC52315

HGNC (Hugo): AXIN1

Location: 16p13.3

Note

According to Entrez gene and Ensembl the isoform

a starts at 337440 and ends at 402464 bp with the

total lenght of 65025 bp. The isoform b starts at

338122 and ends at 397025 with the total lenght of

58904 bp. Zeng et al. (1997) renamed the gene that

was originally termed Fu to Axin in order to avoid

confusion with the unrelated Drosophila gene

fused.

DNA/RNA

Description

Axin 1 consists of 11 exons (isoform a). Full gene

transcript product length is 3675 bp. Isoform b

lacks an in-frame exon in the 3' coding region and

is shorter with sequence length of 3567 bp

(Salahshor and Woodgett, 2005) (Figure 1).

Transcription

There are two transcript variants. Variant 1

(encoding for isoform a) represents the longer

transcript (NM 003502.3). Variant 2 (encoding for

isoform b) is shorter compared to variant 1 (NM

181050.2). According to Ensembl there are six

transcripts of AXIN1 of which first two are well

known isoforms a and b and the remaining 4 are

still in research.

Protein

Note

Protein name: Axin 1, Axin, Axis inhibitor, Axis

inhibitor protein 1.

Description

At least two isoforms of protein axin are expressed.

Longer isoform has all eleven exons translated and

consists of 862 aminoacids while shorter has 826

aminoacids translated from ten exons. Axin 1

protein can be recognized primarily by two

domains, the N-terminal RGS domain (regulators of

G-protein signaling) and the C-terminal DIX

domain (dishevelled and axin) (Luo et al., 2005;

Shibata et al., 2007). RGS domain is needed for

APC binding while DIX domain for

homodimerization and heterodimerization

(Ehebauer and Arias, 2009; Noutsou et al., 2011).

There is also a central region of the protein that

binds GSK3beta and beta-catenin. Axin protein has

nuclear localization (NLS) and nuclear export

(NES) sequences as well. It is well known that axin

is a scaffold protein that can shuttle between the

cytoplasm and the nucleus.

Figure 1. Genomic structure of Axin 1. Axin 1 is composed of 10 exons and they encode isoform a, while in isoform b exon 8

is spliced out.

AXIN1 (axin 1) Pecina-Slaus N, et al.


Nucleo-cytoplasmatic shuttling under normal

circumstances suggests existence of possible

"salvage pathway" that would be activated by axin

translocation to the nucleus in order to reduce beta-

catenin oncogenic activity by exporting nuclear

beta-catenin and degrading it in the cytoplasm

(Wiechens et al., 2004). Axin can also undergo

posttranslational modifications. Phosphorilation by

casein kinase 1 (CK1) enhances binding of

GSK3beta and AXIN1. For activation of JNK

pathway axin needs to be SUMOylated (Kim et al.,

2008) (Figure 2).

Figure 2. Two crystallized domains of the Axin 1

protein are shown: (A) RGS and (B) DIX.

Expression

Axin is expressed ubiquitously.

Localisation

Axin is predominantlly expressed in the cytoplasm,

but periplasmic and nuclear localization are also

observed depending on the stimulation of the cells

(Cong and Varmus, 2004; Luo and Lin, 2004). In

nonstimulated cells, axin colocalizes with Smad3.

The subcellular location of axin is not well defined

in the literature. It has been reported that

physiological concentrations of axin is low in

Xenopus egg cells. It has also been shown that it is

located in cytoplasmic puncta in living mammalian

cells. Wang et al. (2009) report that axin 1 is highly

co-localized with beta-catenin in the cytoplasm of

human cumulus cells and that this localization

denotes intact wnt signaling. Pecina-Slaus et al.

(2011) showed the subcellular location of axin in

normal brain white matter and glioblastoma tissue.

The majority of glioblastomas (69.04%) had axin

localized in the cytoplasm. Nevertheless, 9.5% of

glioblastomas samples had axin localized in the

nucleus (Figure 3). Distribution of axin was

reported previously by Anderson et al. (2002) in

neoplastic colon. Altered nuclear expression of axin

seen in colon polyps and carcinomas may be a

consequence of the loss of full-length APC and the

advent of nuclear beta-catenin.

Figure 3. Glioblastoma samples

immunohistochemically stained for protein expression of axin. (A) Cytoplasmic localization of axin and (B) nuclear

localization of axin.

Function

Tumor suppressor protein Axin 1 is an inhibitor of

the Wnt signaling pathway (Polakis, 2000;

Salahshor and Woodgett, 2005). As a scaffold

protein, its main role is binding multiple members

of Wnt signaling and formation of the beta-catenin

destruction complex. It down-regulates beta-

catenin, wnt pathway's main effector signaling

molecule, by facilitating its phosphorylation by

GSK3-beta (Hart et al., 1998). It binds directly to

APC (adenomatous polyposis coli), beta-catenin,

GSK3-beta and dishevelled forming a so called

"beta-catenin destruction complex" in which

phosphorylated beta-catenin is targeted for quick

ubiquitinilation and degradation in the 26S

proteosome (Yamamoto et al., 1999; Logan and

Nusse, 2004). In response to wnt signaling, or

under the circumstances of mutated axin or APC,

beta-catenin is stabilized, accumulates in the



cytoplasm and enters the nucleus, where it finds a

partner, a member of the DNA binding protein

family LEF/TCF. Together they stimulate the

expression of target genes including c-myc, c-jun,

fra-1 and cyclin D1. In developement Axin controls

dorsoventral polarity axis formation (Zeng et al.,

1997; Wodarz and Nusse, 1998) by two

independent mechanisms: downregulation of beta-

catenin, but also by activation of Wnt-independent

JNK signaling activation. Axin has a role in

determining cell's fate upon damage, haematopoetic

stem cells differentiation (Reya et al., 2003) and

transforming growth factor beta signaling

(Furuhashi et al., 2001). Reports indicate that beta-

catenin and axin regulate critical developmental

processes of normal CNS development (Pecina-

Slaus, 2010).

Axin interacts with a number of proteins including:

APC, Axam, Axin, beta-catenin, Ccd1, CKI,

DAXX, DCAP, Diversin, Dvl, gamma-tubulin,

GSK3beta, HIPK2, I-mfa, LRP5/LRP6, MDFIC,

MEKK1, MEKK4, P53, PIAS, Pirh2, PP2A, Rnf11,

Zbed3, Tip60, Smad3, Smad6, and Smad7 (Cliffe et

al., 2003; Chen et al., 2009; Fumoto et al., 2009; Li

et al., 2009; Choi et al., 2010; Kim and Jho, 2010).

Homology

Homologs are found in: Pan troglodytes, Canis

lupus familiaris, Bos taurus, Mus musculus, Rattus

norvegicus, Gallus gallus, Danio rerio.

Mutations

Note

According to HGMD there are 3 missense

mutations reported for AXIN 1 in colorectal

carcinoma. Nikuseva Martic et al. (2010) identified

gross deletions (Loss of Heterozygosity) of AXIN 1

in 6.3% of glioblastomas, in one neuroepithelial

dysembrioplastic tumor and in one

medulloblastoma. In a primary hepatocellular

carcinoma 13 somatic events were reported by

OMIM, a 33-bp deletion in exon 3 of the AXIN1

gene, and 12 missense mutations. OMIM also

reports on hypermethylation of AXIN 1 promotor

region in caudal duplication anomaly.

Implicated in

Hepatocellular carcinoma

Note

In a primary hepatocellular carcinoma (HCC),

Satoh et al. (2000) found a 33-bp deletion in exon 3

of the AXIN1 gene, involving 2 glycogen synthase

kinase-3-beta phosphorylation sites. In addition to

this deletion they found 12 missense mutations, of

which 9 occurred in codons encoding serine or

threonine residues. They confirmed that all 13

mutations found in primary HCCs occurred as

somatic events. Taniguchi et al. (2002) found

AXIN1 mutations in seven (9.6%) HCCs. The

AXIN1 mutations included seven missense

mutations, a 1 bp deletion, and a 12 bp insertion.

Loss of heterozygosity at the AXIN1 locus was

present in four of five informative HCCs with

AXIN1 mutations, suggesting a tumor suppressor

function of this gene. Park et al. (2005) showed that

mutations of AXIN 1 are late events in

hepatocellular carcinogenesis.

Medulloblastoma

Note

To find out if Axin is also involved in the

pathogenesis of sporadic medulloblastomas,

Dahmen et al. (2001) analyzed 86 cases and 11

medulloblastoma cell lines for mutations in the

AXIN1 gene. Using single-strand conformation

polymorphism analysis, screening for large

deletions by reverse transcription-PCR, and

sequencing analysis, a single somatic point

mutation in exon 1 (Pro255Ser) and seven large

deletions (12%) of AXIN1 were detected. Baeza et

al. (2003) screened 39 sporadic cerebellar

medulloblastomas for alterations in the AXIN1

gene. The authors found missense AXIN1

mutations in two tumours, CCC-->TCC at codon

255 (exon 1, Pro-->Ser) and TCT-->TGT at codon

263 (exon 1, Ser-->Cys). Furthermore, the A allele

at the G/A polymorphism at nucleotide 16 in intron

4 was significantly over-represented in

medulloblastomas (39 cases; G 0.76 vs-A 0.24)

compared to healthy individuals (86 cases; G 0.91

vs A 0.09; P=0.0027). Yokota et al. (2002) showed

another AXIN1 mutation in exon 3, corresponding

to GSK-3beta binding site.

Colorectal carcinoma

Note

Hart et al. (1998) report on overexpression of

Axin1 in connection to the downregulation of wild-

type beta-catenin in colon cancer cells. In addition,

Axin1 dramatically facilitated the phosphorylation

of APC and beta-catenin by GSK3 beta in vitro.

Another group (Jin et al., 2003) analyzed 54

colorectal cancer tissues for mutations in AXIN1

gene. They found 3 silent mutations, 6 missense

point mutations in different functionally important

regions. The missense mutation rate was hence

11%, suggesting that Axin 1 deficiency may

contribute to the onset of colorectal tumorigenesis.

Segditsas and Tomlinson (2006) report on

mutations in AXIN1 in microsatellite-unstable

colon cancers. Three AXIN1 missense variants

P312T, R398H, and L445M were detected in 1 of

124 patients with multiple colorectal adenomas.

Three other missense mutations, D545E, G700S,

and R891Q, were found. The overall frequency of

the rare variants was significantly higher in the

patients as compared with the controls (Fearnhead

et al., 2004).



Brain tumors

Note

A sample of 72 neuroepithelial brain tumors was

investigated for AXIN-1 gene changes by Nikuseva

Martic et al. (2010). Polymorphic marker for

AXIN-1, showed loss of heterozygosity in 11.1% of

tumors. Down regulation of axin expression and up

regulation of beta-catenin were detected. Axin was

observed in the cytoplasm in 68.8% of samples, in

28.1% in both the cytoplasm and nucleus and 3.1%

had no expression. Comparison of mean values of

relative increase of axin and beta-catenin showed

that they were significantly reversely proportional

(P=0.014) in a set of neuroepithelial brain tumors.

Pecina-Slaus et al. (2011) also explored axin's

existence at the subcellular level in glioblastomas

and showed that the highest relative quantity of

axin was measured when the protein was in the

nucleus and the lowest relative quantity of axin

when the protein was localized in the cytoplasm.

Ovarian endometroid adenocarcinomas

Note

Wu et al. (2001) report on a nonsense mutation in

one ovarian endometroid adenocarcinoma (OEA).

They also found another missense AXIN1 sequence

alteration in OEA-derived cell lines.

Lung cancer

Note

In 105 lung SCC and adenocarcinoma tissue

samples, the cytoplasmic expression of Axin was

significantly lower than in normal lung tissues.

Western blot analysis also demonstrated that the

relative expression quantity of Axin was

significantly reduced in lung cancer tissues

compared with normal lung tissues. Nuclear

expression of Axin was observed in 21 cases (20%)

of lung cancers (Xu et al., 2011).

Oesophageal squamous cell carcinoma

Note

Nakajima et al. (2003) found reduced expression of

Axin1 in oesophageal squamous cell carcinoma.

Several mutations have also been reported in

oesophageal squamous cell carcinoma.

Cervical cancer

Note

Su et al. (2003) examined AXIN1 in cervical

cancer. Among the 30 tested cervical cancers

mutation analysis of AXIN1 revealed that one

specimen had a heterozygous mutation at codon

740. Six polymorphisms were also found.

Immunohistochemistry showed no relationship

between the protein expression patterns and

mutation of AXIN1.

Prostate cancer

Note

Yardy et al. (2009) reported on AXIN1 mutations

in advanced prostate cancer. They found 7

mutations in prostate cancer cases and 4

polymorphisms in prostate cancer cell lines.

Caudal duplication anomaly

Note

Hypermethylation of the AXIN1 promoter is

associated with the caudal duplication anomalies.

Oates et al. (2006) examined methylation at the

promoter region of the AXIN1 gene in

monozygotic twins. The promoter region of the

AXIN1 gene was significantly more methylated in

the twin with the caudal duplication than in the

unaffected twin.

References Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL 3rd, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell. 1997 Jul 11;90(1):181-92

Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol. 1998 May 7;8(10):573-81

Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol. 1998;14:59-88

Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem. 1999 Apr 16;274(16):10681-4

Polakis P. Wnt signaling and cancer. Genes Dev. 2000 Aug 1;14(15):1837-51

Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000 Mar;24(3):245-50

Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sörensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T. Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res. 2001 Oct 1;61(19):7039-43

Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, Kikuchi A, Miyazono K, Kato M. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Mol Cell Biol. 2001 Aug;21(15):5132-41

Wu R, Zhai Y, Fearon ER, Cho KR. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res. 2001 Nov 15;61(22):8247-55

Anderson CB, Neufeld KL, White RL. Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8683-8

Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002 Jul 18;21(31):4863-71



Yokota N, Nishizawa S, Ohta S, Date H, Sugimura H, Namba H, Maekawa M. Role of Wnt pathway in medulloblastoma oncogenesis. Int J Cancer. 2002 Sep 10;101(2):198-201

Baeza N, Masuoka J, Kleihues P, Ohgaki H. AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene. 2003 Jan 30;22(4):632-6

Cliffe A, Hamada F, Bienz M. A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling. Curr Biol. 2003 May 27;13(11):960-6

Jin LH, Shao QJ, Luo W, Ye ZY, Li Q, Lin SC. Detection of point mutations of the Axin1 gene in colorectal cancers. Int J Cancer. 2003 Dec 10;107(5):696-9

Nakajima M, Fukuchi M, Miyazaki T, Masuda N, Kato H, Kuwano H. Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma. Br J Cancer. 2003 Jun 2;88(11):1734-9

Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003 May 22;423(6938):409-14

Su TH, Chang JG, Yeh KT, Lin TH, Lee TP, Chen JC, Lin CC. Mutation analysis of CTNNB1 (beta-catenin) and AXIN1, the components of Wnt pathway, in cervical carcinomas. Oncol Rep. 2003 Sep-Oct;10(5):1195-200

Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2882-7

Fearnhead NS, Wilding JL, Winney B, Tonks S, Bartlett S, Bicknell DC, Tomlinson IP, Mortensen NJ, Bodmer WF. Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15992-7

Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781-810

Luo W, Lin SC. Axin: a master scaffold for multiple signaling pathways. Neurosignals. 2004 May-Jun;13(3):99-113

Wiechens N, Heinle K, Englmeier L, Schohl A, Fagotto F. Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin Pathway. J Biol Chem. 2004 Feb 13;279(7):5263-7

Luo W, Zou H, Jin L, Lin S, Li Q, Ye Z, Rui H, Lin SC. Axin contains three separable domains that confer intramolecular, homodimeric, and heterodimeric interactions involved in distinct functions. J Biol Chem. 2005 Feb 11;280(6):5054-60

Park JY, Park WS, Nam SW, Kim SY, Lee SH, Yoo NJ, Lee JY, Park CK. Mutations of beta-catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis. Liver Int. 2005 Feb;25(1):70-6

Salahshor S, Woodgett JR. The links between axin and carcinogenesis. J Clin Pathol. 2005 Mar;58(3):225-36

Oates NA, van Vliet J, Duffy DL, Kroes HY, Martin NG, Boomsma DI, Campbell M, Coulthard MG, Whitelaw E, Chong S. Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. Am J Hum Genet. 2006 Jul;79(1):155-62

Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene. 2006 Dec 4;25(57):7531-7

Shibata N, Tomimoto Y, Hanamura T, Yamamoto R, Ueda M, Ueda Y, Mizuno N, Ogata H, Komori H, Shomura Y, Kataoka M, Shimizu S, Kondo J, Yamamoto H, Kikuchi A, Higuchi Y. Crystallization and preliminary X-ray crystallographic studies of the axin DIX domain. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007 Jun 1;63(Pt 6):529-31

Kim MJ, Chia IV, Costantini F. SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability. FASEB J. 2008 Nov;22(11):3785-94

Chen T, Li M, Ding Y, Zhang LS, Xi Y, Pan WJ, Tao DL, Wang JY, Li L. Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling. J Biol Chem. 2009 Mar 13;284(11):6683-9

Ehebauer MT, Arias AM. The structural and functional determinants of the Axin and Dishevelled DIX domains. BMC Struct Biol. 2009 Nov 12;9:70

Fumoto K, Kadono M, Izumi N, Kikuchi A. Axin localizes to the centrosome and is involved in microtubule nucleation. EMBO Rep. 2009 Jun;10(6):606-13

Li Q, Lin S, Wang X, Lian G, Lu Z, Guo H, Ruan K, Wang Y, Ye Z, Han J, Lin SC. Axin determines cell fate by controlling the p53 activation threshold after DNA damage. Nat Cell Biol. 2009 Sep;11(9):1128-34

Wang HX, Tekpetey FR, Kidder GM. Identification of WNT/beta-CATENIN signaling pathway components in human cumulus cells. Mol Hum Reprod. 2009 Jan;15(1):11-7

Yardy GW, Bicknell DC, Wilding JL, Bartlett S, Liu Y, Winney B, Turner GD, Brewster SF, Bodmer WF. Mutations in the AXIN1 gene in advanced prostate cancer. Eur Urol. 2009 Sep;56(3):486-94

Choi SH, Choi KM, Ahn HJ. Coexpression and protein-protein complexing of DIX domains of human Dvl1 and Axin1 protein. BMB Rep. 2010 Sep;43(9):609-13

Kim S, Jho EH. The protein stability of Axin, a negative regulator of Wnt signaling, is regulated by Smad ubiquitination regulatory factor 2 (Smurf2). J Biol Chem. 2010 Nov 19;285(47):36420-6

Nikuseva Martić T, Pećina-Slaus N, Kusec V, Kokotović T, Musinović H, Tomas D, Zeljko M. Changes of AXIN-1 and beta-catenin in neuroepithelial brain tumors. Pathol Oncol Res. 2010 Mar;16(1):75-9

Pećina-Slaus N. Wnt signal transduction pathway and apoptosis: a review. Cancer Cell Int. 2010 Jun 30;10:22

Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, de Ridder I, Oikonomou C, Friedler A, Boelens R, Rüdiger SG, Maurice MM. Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded. J Mol Biol. 2011 Jan 21;405(3):773-86

Pećina-Slaus N, Martić TN, Kokotović T, Kusec V, Tomas D, Hrasćan R. AXIN-1 protein expression and localization in glioblastoma. Coll Antropol. 2011 Jan;35 Suppl 1:101-6

Xu HT, Yang LH, Li QC, Liu SL, Liu D, Xie XM, Wang EH. Disabled-2 and Axin are concurrently colocalized and underexpressed in lung cancers. Hum Pathol. 2011 Apr 13;


Pecina-Slaus N, Nikuseva Martic T, Kokotovic T. AXIN1 (axin 1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):940-944.





CCR2 (chemokine (C-C motif) receptor 2) Jérôme Moreaux

Institut de Recherche en Biotherapie, INSERM U847, Hopital Saint-Eloi, CHU de Montpellier, 80 av

Augustin Fliche, 34295 Montpellier Cedex 5, France (JM)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CCR2ID964ch3p21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CCR2ID964ch3p21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: CC-CKR-2; CCR2A; CCR2B;

CD192; CKR2; CKR2A; CKR2B; CMKBR2;

FLJ78302; MCP-1-R; MGC103828; MGC111760;

MGC168006

HGNC (Hugo): CCR2

Location: 3p21.31

DNA/RNA

Note

CCR2 is a member of the beta chemokine receptor

family. CCR2 is a seven transmembrane protein

similar to G protein-coupled receptors. This gene

encodes two isoforms of a receptor for monocyte

chemoattractant protein-1, a chemokine which

specifically mediates monocyte chemotaxis.

Monocyte chemoattractant protein-1 is involved in

monocyte infiltration in inflammatory diseases such

as rheumatoid arthritis as well as in the

inflammatory response against tumors. The

receptors encoded by this gene mediate agonist-

dependent calcium mobilization and inhibition of

adenylyl cyclase. This gene is located in the

chemokine receptor gene cluster region including

CCR1, CCRL2, CCR3, CCR5 and CCXCR1 on

chromosome 3p.

Description

Size: 7195 bases.

2 isoforms:

- C-C chemokine receptor type 2 isoform A.

CCDS43078.1

- C-C chemokine receptor type 2 isoform B.

CCDS46813.1

Transcription

Homo sapiens chemokine (C-C motif) receptor 2

(CCR2), transcript variant A, mRNA: 2689 bp.

Homo sapiens chemokine (C-C motif) receptor 2

(CCR2), transcript variant B, mRNA: 2335 bp.

Pseudogene

No pseudogenes have been reported for CCR2.

Protein

Note

Chemokine receptors are cytokine receptors found

on the surface of cells, which interact with a type of

cytokine called a chemokine. They have a 7

transmembrane structure and couple to G-protein

for signal transduction within a cell, making them

members of a large protein family of G protein-

coupled receptors. Following interaction with their

specific chemokine ligands, chemokine receptors

trigger a flux in intracellular calcium (Ca2+

) ions

(calcium signaling). This causes cell responses,

including the onset of a process known as

chemotaxis that traffics the cell to a desired location

within the organism.

CCR2 (chemokine (C-C motif) receptor 2) Moreaux J


Structure of CCR2. The typical serpentine structure is depicted with three extracellular (top) and three intracellular (bottom)

loops and seven transmembrane domains.

Chemokine receptors share many common

structural features; they are composed of about 350

amino acids that are divided into a short and acidic

N-terminal end, seven helical transmembrane

domains with three intracellular and three

extracellular hydrophilic loops, and an intracellular

C-terminus containing serine and threonine residues

that act as phosphorylation sites during receptor

regulation. The first two extracellular loops of

chemokine receptors are linked together by

disulfide bonding between two conserved cysteine

residues. The N-terminal end of a chemokine

receptor binds to chemokine(s) and is important for

ligand specificity. G-proteins couple to the C-

terminal end, which is important for receptor

signaling following ligand binding.

Description

374 amino acids; 41915 Da.

Expression

Peripheral blood monocytes, activated T cells, B

cells and immature dendritic cells.

Localisation

Cell membrane; multi-pass membrane protein.

Function

Receptor for the MCP-1/CCL2, MCP-3/CCL7 and

MCP-4/CCL13 chemokines. Transduces a signal by

increasing the intracellular calcium ions level.

Alternative coreceptor with CD4 for HIV-1

infection.

Homology

CCR2 proteins contains amino acid sequence

homology to other C-C chemokines. CCR1 (56%),

CCR5 (71%), CCR3 (78%), CCR4 (75%).

Implicated in

Multiple myeloma

Prognosis

In a cohort of 80 patients with Multiple Myeloma

(MM), patients with active disease showed

significant lower expression of CCR1, CCR2 and

CXCR4 than patients with non-active disease.

Oncogenesis

CCR1 and CCR2 are overexpressed in myeloma

cells compared to normal B cells. Osteoclasts

express genes coding for CCR2 chemokines

specifically (CCL2, CCL7, CCL8, and CCL13) and

high CCR2 gene expression in myeloma cells is

associated with increased bone lesions in MM

patients. CCR2 is significantly overexpressed in

MM cells compared to normal bone marrow plasma

cells. Osteoclasts can directly recruit MMC by

CCR2 chemokines production, promote MMC

survival, growth, and drug resistance by producing

various growth factors. MMC will promote

osteoclast progenitor recruitment and differentiation

producing CCL3, MIP-1beta, and CXCL12

chemokines, IGF-1, and increasing RANKL

production by stromal cells. Osteoclasts are the

main cells in the BM environment that produce



various CCR2 chemokines enabling malignant

plasma cells attraction.

Neuroblastoma

Oncogenesis

98 untreated primary neuroblastomas from patients

with metastatic disease were analyzed for tumor-

infiltrating iNKTs (Valpha24-Jalpha18-invariant

natural killer T cells) using RT-PCR and

immunofluorescent microscopy. 53% of tumors

contained iNKTs. CCR2 is more frequently

expressed by iNKT compared to T cells and natural

killer cells from blood. iNKTs migrate toward

neuroblastoma cells in a CCL2-dependent manner,

preferentially infiltrating MYCN nonamplified

proto-oncogene tumors that express CCL2.

Melanoma

Oncogenesis

MCP-1 may play a role in tumor angiogenesis and

early tumor growth of human malignant melanoma

by inducing VEGF and inflammatory cytokines

production (IL-1alpha and TNFalpha by the tumor-

associated macrophages (TAM) and

autocrine/paracrine effects on melanoma cells in a

mouse model.

Prostate cancer

Prognosis

The pleiotropic roles of CCL2 in the development

of prostate cancer are mediated through its receptor,

CCR2. An association between prostate cancer

progression and CCR2 expression was

demonstrated on tissue microarray specimens of

patients. CCR2 mRNA and protein were

significantly overexpressed within prostate cancer

metastatic tissues compared to localized prostate

cancer and benign prostate tissue. CCR2

overexpression was also associated with higher

Gleason score and higher clinical pathologic stages.

Oncogenesis

CCL2 support prostate cancer cell survival via

PI3K/AKT in vitro. CCL2 derived from human

bone marrow endothelial cells induces PC-3 cell

line transendothelial cell migration via activation of

the small GTPase Rac. In a cell co-culture system,

prostate cancer cell-conditioned medium induces

CCL2 overexpression in endothelial cells and

osteoblasts. In osteoblasts, this secretion is

mediated in part by parathyroid hormone-related

protein.

In mouse model, neutralizing antibody against

CCL2 inhibits prostate cancer PC-3 and VCaP

growth in bone. Same results were obtained with

CCL2 knockdown. CCL2 induces surviving

expression in prostate cancer cells and protect them

from autophagic death.

Breast cancer

Prognosis

Overexpression of the chemokine CCL2 is

frequently associated with advanced tumor stage

and metastatic relapse in breast cancer.

Oncogenesis

Overexpression of CCL2 promotes breast cancer

metastasis to both lung and bone in mice. Blocking

CCL2 with a neutralizing antibody reduced lung

and bone metastases. The enhancement of lung

metastases by CCL2 was associated with increased

macrophage infiltration. In bone, it was associated

with osteoclast differentiation. CCL2 produced by

breast tumor cells activates CCR2 positive stromal

cells of monocytic origin (including macrophages

and preosteoclasts) leading to metastases in lung

and bone.

Esophageal carcinoma

Oncogenesis

CCL2 is expressed by tumor cells of esophageal

squamous cell carcinoma. CCL2 produced by

tumor cell and CCR2 expressed on vascular

endothelial cells may participate in esophageal

carcinoma tumor angiogenesis.

Gastric cancer

Oncogenesis

CCL2 produced by human gastric carcinoma cells

is involved in angiogenesis via macrophage

recruitment and activation via CCR2. CCL2

produced by gastric carcinoma cells induces tumor

growth in ectopic xenografts and increased

tumorigenicity and induced lymph node metastases

and ascites in orthotopic xenografts.

References De Vos J, Couderc G, Tarte K, Jourdan M, Requirand G, Delteil MC, Rossi JF, Mechti N, Klein B. Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays. Blood. 2001 Aug 1;98(3):771-80

Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida N, Haruma K, Chayama K. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Int J Oncol. 2003 Apr;22(4):773-8

Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S. Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am J Gastroenterol. 2004 Sep;99(9):1667-74

Metelitsa LS, Wu HW, Wang H, Yang Y, Warsi Z, Asgharzadeh S, Groshen S, Wilson SB, Seeger RC. Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. J Exp Med. 2004 May 3;199(9):1213-21

Kuroda T, Kitadai Y, Tanaka S, Yang X, Mukaida N, Yoshihara M, Chayama K. Monocyte chemoattractant protein-1 transfection induces angiogenesis and tumorigenesis of gastric carcinoma in nude mice via macrophage recruitment. Clin Cancer Res. 2005 Nov 1;11(21):7629-36

Vande Broek I, Leleu X, Schots R, Facon T, Vanderkerken K, Van Camp B, Van Riet I. Clinical significance of



chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival. Haematologica. 2006 Feb;91(2):200-6

Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissière F, Laune D, Roques S, Lazennec G. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res. 2007;9(1):R15

Koga M, Kai H, Egami K, Murohara T, Ikeda A, Yasuoka S, Egashira K, Matsuishi T, Kai M, Kataoka Y, Kuwano M, Imaizumi T. Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice. Biochem Biophys Res Commun. 2008 Jan 11;365(2):279-84

Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008 Aug 28;267(2):271-85

Lu X, Kang Y. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast

cancer metastasis to lung and bone. J Biol Chem. 2009 Oct 16;284(42):29087-96

Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst. 2010 Apr 21;102(8):522-8

Zhang J, Patel L, Pienta KJ. CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev. 2010 Feb;21(1):41-8

Moreaux J, Hose D, Kassambara A, Reme T, Moine P, Requirand G, Goldschmidt H, Klein B. Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration. Blood. 2011 Jan 27;117(4):1280-90


Moreaux J. CCR2 (chemokine (C-C motif) receptor 2). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):945-948.

Gene Section Review




DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) Dimitra Florou, Andreas Scorilas, Dido Vassilacopoulou, Emmanuel G Fragoulis

Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens 15701,

Panepistimiopolis, Athens, Greece (DF, AS, DV, EGF)


Online updated version : http://AtlasGeneticsOncology.org/Genes/DDCID50590ch7p12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI DDCID50590ch7p12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: AADC

HGNC (Hugo): DDC

Location: 7p12.1

Local order: Centromere to telomere.

DNA/RNA

Note

The complete nucleotide structure of the human

DDC gene has been determined from tissues of

neural and non-neural origin (Sumi-Ichinose et al.,

1992; Ichinose et al., 1992). The full DDC cDNA

sequence has been cloned from human cells, such

as pheochromocytoma (Ichinose et al., 1989), liver

(Ichinose et al., 1992), hepatoma cells (Scherer et

al., 1992), placenta (Siaterli et al., 2003), peripheral

leukocytes (Kokkinou et al., 2009b), as well as

from several human cell lines, such as, U937

macrophage cells (Kokkinou et al., 2009a), SH-

SY5Y, HTB-14 and HeLa cells (Chalatsa et al.,

2011).

Description

The human DDC gene exists as a single-copy in the

haploid genome. It is composed of 15 exons and 14

introns, spanning for more than 85 kbs (Sumi-

Ichinose et al., 1992). The size of the exons was

found to range from 20 to 406 bps (Sumi-Ichinose

et al., 1992), whereas the size of the introns ranged

from 927 to 24077 bps (Sumi-Ichinose et al., 1992;

Yu et al., 2006). The DDC gene is located in close

proximity to the epidermal growth factor (EGF)

gene (Craig et al., 1992).

Transcription

Alternative splicing events are responsible for the

production of two distinct DDC mRNAs, termed

neural and non-neural, which differ in their 5'

untranslated region (UTR). The neural-type

transcript includes exon N1 (83 bps) that is located

17.8 kbs upstream of exon two. The non-neural

type DDC mRNA bears exon L1 (200 bps), which is

located 4.2 kbs upstream to the location of exon N1.

The second exon contains the translation start site

and is located 22 kbs downstream from the non-

neural (L1) exon (Ichinose et al., 1992). The

transcription of the gene starts at position -111

(Sumi-Ichinose et al., 1992).

It has been reported that the two alternative DDC

transcripts share identical coding regions and that

their production is a result of alternative splicing

and alternative promoter usage (Ichinose et al.,

1992; Sumi-Ichinose et al., 1995). Neural and non-

neural promoters have been identified 5' to the

flanking region of the respective exon 1 (Le Van

Thai et al., 1993; Sumi-Ichinose et al., 1995;

Chatelin et al., 2001; Dugast-Darzacq et al., 2004).

The generation of the two alternative DDC mRNAs

is not a mutually exclusive and tissue-specific event

as previously thought (Siaterli et al., 2003;

Vassilacopoulou et al., 2004; Kokkinou et al.,

2009a; Kokkinou et al., 2009b; Chalatsa et al.,

2011).

An alternative splicing event has been described

within the coding region of DDC mRNA, leading to

the formation of a shorter transcript lacking exon 3

(O'Malley et al., 1995; Chang et al., 1996).

DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))

Florou D, et al.


Table 1. Expression of DDC mRNA transcripts in human tissues, cells and cancer cell lines.

It must be noted that the above authors did not

specify the nature, neural or non-neural, of this

shorter transcript. Recent evidence have revealed

the neural nature of this alternative transcript in

humans (Kokkinou et al., 2009a; Kokkinou et al.,

2009b; Chalatsa et al., 2011).

A novel DDC mRNA coding region splice-variant,

resulting in the formation of a truncated DDC

mRNA has been also identified. This human DDC

mRNA (1.8 kbs), termed as Alt-DDC, lacks exons

10-15 of the full-length transcript, but includes an

alternative exon 10 (Vassilacopoulou et al., 2004).

The Alt-DDC exon 10 (358 bps) was found within

intron 9 of the DDC gene. Although Alt-DDC

mRNA was detected in human placenta, high

expression levels of this alternative transcript were

found in human kidney (Vassilacopoulou et al.,

2004).

The notion that transcription of the human DDC

gene leads to the production of multiple mRNA

isoforms, which are expressed in a non-mutually

exclusive and tissue-specific manner, underlines the

complexity of the expression patterns of this gene

(table 1).

Pseudogene

None has been identified yet.

Protein

Note

Although, it was initially suggested that the DDC

gene encoded for a single protein product (Sumi-

Ichinose et al., 1992), evidence that demonstrated

the expression of additional DDC protein isoforms

in humans, argue against it (O'Malley et al., 1995;

Chang et al., 1996; Vassilacopoulou et al., 2004).

Description

The DDC enzyme (EC 4.1.1.28) was initially

purified and characterized from pig kidney

(Christenson et al., 1970) as well as from the

insects Calliphora vicina (Fragoulis and Sekeris,

1975) and Ceratitis capitata (Mappouras and

Fragoulis, 1988; Bossinakou and Fragoulis, 1996).

DDC is a homodimer of 100-110 kDa, with a

subunit molecular mass of 50-55 kDa (Voltattorni

et al., 1979; Mappouras et al., 1990; Bossinakou

and Fragoulis, 1996). The full-length protein

molecule consists of 480 amino acids (Ichinose et

al., 1989). DDC is a pyridoxal-5-phosphate (PLP)-

dependent enzyme possessing a single binding-site

for PLP per subunit (Voltattorni et al., 1982;

Ichinose et al., 1989; Burkhard et al., 2001).

Expression of the DDC gene, in humans, results in

the production of additional protein isoforms

(O'Malley et al., 1995; Chang et al., 1996;

Vassilacopoulou et al., 2004). O'Malley et al.

(1995) identified of a new DDC protein isoform

(O'Malley et al., 1995). The truncated DDC protein

isoform (Mr; 50 kDa) consists of 442 amino acid

residues (DDC442). This isoform was found to be

inactive towards the decarboxylation of both L-

Dopa to Dopamine and 5-Hydroxytryptophan (5-

HTP) to serotonin (O'Malley et al., 1995). As

mentioned above, the translation of Alt-DDC

mRNA resulted in the synthesis of a truncated 338

amino acid long polypeptide, termed as Alt-DDC

(Mr; 37 kDa). This isoform was identical to the

full-length DDC protein up to amino acid residue

315. The remaining 23 amino acids of the C-

terminal sequence are encoded by the alternative

DDC exon 10 and are not incorporated in the full-

length DDC protein sequence (Vassilacopoulou et

al., 2004).

Although previous data had suggested that DDC

was a rather unregulated molecule, several findings

have indicated that DDC activity can be modulated

by many factors, such as D1, DA receptor

antagonists (Rossetti et al., 1990), a2-adrenergic

receptor antagonists (Rossetti et al., 1989), D1, D2

receptor antagonists (Zhu et al., 1992;

Hadjiconstantinou et al., 1993), DA receptor


Florou D, et al.


Table 2. Human DDC identity.

agonists (Zhu et al., 1993), PK-A and PK-C

mediated pathways (Young et al., 1993; Young et

al., 1994) and by endogenous inhibitors isolated

from human serum (Vassiliou et al., 2005) and

placenta (Vassiliou et al., 2009).

Expression

DDC has been detected throughout the length of the

gastrointestinal tract (Eisenhofer et al., 1997) and in

blood plasma (Boomsma et al., 1986). DDC is

expressed in normal human kidney and placenta

(Mappouras et al., 1990; Siaterli et al., 2003). DDC

expression was observed in normal peripheral

leukocytes and T-lymphocytes (Kokkinou et al.,

2009b). Furthermore, DDC is expressed in the

human cancer cell lines U937 (Kokkinou et al.,

2009a), SH-SY5Y, HeLa and HTB-14 (Chalatsa et

al., 2011). Interestingly, the expression of the

alternative DDC isoform (Alt-DDC) was also

demonstrated in peripheral leukocytes (Kokkinou et

al., 2009b), U937 (Kokkinou et al., 2009a), SH-

SY5Y and HeLa cell lines (Chalatsa et al., 2011).

In the central nervous system, increased DDC

enzymatic activity is detected in the hypothalamus,

epiphysis, striatum, locus ceruleus, olfactory bulb

and retina (Park et al., 1986). Elevated enzymatic

DDC activity is also detected in peripheral organs

such as liver, pancreas, kidney, lungs, spleen,

stomach, salivary glands, as well as in the

endothelial cells of blood vessels (Lovenberg et al.,

1962; Rahman et al., 1981; Lindström and Sehlin,

1983).

Localisation

DDC was considered to be a cytosolic molecule

(Lovenberg et al., 1962; Sims et al., 1973).

Nevertheless, additional experimental findings have

demonstrated that a population of enzymatically

active DDC molecules is associated with the

cellular membrane fraction in the mammalian CNS

(Poulikakos et al., 2001). Membrane-associated,

enzymatically active DDC subpopulations were

detected in the highly hydrophobic fractions of

normal human leukocytes and U937 cancer cells

(Kokkinou et al., 2009a; Kokkinou et al., 2009b).

Function

In terms of substrate specificity, the DDC molecule

purified from insects demonstrated a remarkably

high affinity towards the decarboxylation of L-

Dopa to dopamine (Fragoulis and Sekeris, 1975;

Mappouras and Fragoulis, 1988; Bossinakou and

Fragoulis, 1996). However, work by Mappouras et

al. (1990) in the normal human kidney has

suggested that the enzyme is capable of also

decarboxylating L-5-Hydroxytryptophan to

serotonin, although the decarboxylation activity

towards L-5-Hydroxytryptophan was found to be

considerably lower than the one observed for L-

Dopa (Mappouras et al., 1990). Since DDC

expression results in the production of multiple

protein isoforms, it is conceivable that these

different protein molecules could be responsible for

the decarboxylation of other aromatic L-amino

acids.

Homology

Comparison of the amino acid sequence of DDC

from different species, suggested that the enzyme is

an evolutionarily conserved molecule. The amino

acid sequence around the coenzyme binding lysine

is also evolutionarily conserved (Bossa et al., 1977;

Ichinose et al., 1989). The conserved amino acids

are residues 267-317, which surround the PLP-

binding site (Ichinose et al., 1989), as well as, the

extended regions of amino acids 64-155 and 182-

204, which according to Maras et al. (1991) are

important for the enzyme's catalytic function

(Maras et al., 1991). Table 2 shows the percentage

of human DDC amino acid identity to other species

(Maras et al., 1991; Mantzouridis et al., 1997).

Mutations

Table 3. The mutations of the DDC gene in the AADC

disorder.


Florou D, et al.


Germinal

Such mutations have not been identified so far.

Somatic

Aromatic L-amino acid decarboxylase (AADC)

deficiency, a rare autosomaly-recessive inherited

defect, is associated with mutations of the DDC

gene. This disorder leads to profound modifications

in the homeostasis of central and peripheral nervous

system (Hyland et al., 1992). In their majority, such

mutations are missense and are listed above (table

3). Other mutations of the human DDC gene that

are related to AADC-deficiency are also included

(Fiumara et al., 2002; Chang et al., 2004; Pons et

al., 2004; Tay et al., 2007; Lee et al., 2009).

Implicated in

Prostate cancer

Note

Neuroendocrine differentiation features have been

identified in prostatic adenocarcinoma.

Aggressiveness of the disease is increased as the

cells reach the androgen-independent phase

(Speights et al., 1997; Nelson et al., 2002). L-Dopa

decarboxylase has been identified as a novel

androgen receptor (AR) coactivator protein (Wafa

et al., 2003). Recent evidence have shown that the

expression of DDC mRNA could serve as a

potential novel biomarker in prostate cancer

(Avgeris et al., 2008). Wafa et al. (2007) have

indicated by immunohistochemistry that DDC was

found to be a putative neuroendocrine marker for

prostate cancer. In certain NE tumor cells of the

prostate gland, DDC was found to be co-expressed

with AR. DDC expression was increased after

hormone-ablation therapy, as well as, in metastatic

tumors that have progressed to the androgen-

independent phenotypes (Wafa et al., 2007).

Disease

Increased DDC mRNA and/or elevated protein

expression levels were detected in the LnCaP cell

line following synthetic androgen treatment. DDC

protein was found to be enzymatically active in the

androgen-treated LnCaP cells as compared to the

untreated controls. In treated LnCaP cells, DDC

was up-regulated during AR-activation, while DDC

expression was down-regulated following AR-

inhibition. These findings support a coactivator role

for DDC in AR activation (Shao et al., 2007). DDC

over-expression affects the gene expression profile

of the androgen-dependent prostate cancer cell line,

LnCaP, as revealed by microarray analysis

(Margiotti et al., 2007).

Prognosis

Statistically significant elevated DDC mRNA levels

were observed in prostate cancer tissue specimens

when compared to benign hyperplasia human

samples.

Multivariate survival analysis indicated that the

expression of the DDC gene could be used as an

independent marker for the differential diagnosis

between prostate cancer and benign hyperplasia

patients, using tissue biopsies. DDC mRNA

expression was also shown to be associated with

advanced tumor stage and higher Gleason score.

This finding suggested an unfavorable prognostic

value for DDC expression in patients with tumors

in their prostate glands (Avgeris et al., 2008).

Colorectal carcinoma

Note

High L-Dopa decarboxylase activity has been

detected in almost half of the original colorectal

carcinomas examined, as well as, in the majority of

cultured cell lines, established from human primary

and metastatic tumors (Park et al., 1987). Other

data have shown that most solid colorectal tumors

exhibited DDC activity at lower levels when

compared to the enzymatic DDC activity displayed

by the NE tumors (Gazdar et al., 1988). DDC

mRNA expression was found to be elevated in

well-differentiated (grade I) intestinal

adenocarcinomas as compared to more aggressive

tumors (Kontos et al., 2010).

Prognosis

Increased DDC mRNA levels were observed in

grade I colorectal adenocarcinomas. Survival

analysis revealed a significantly lower risk of

disease recurrence and longer overall survival for

patients with DDC-positive colorectal neoplasms.

These results indicate that DDC mRNA expression

might represent a possible future biomarker for the

prognosis of colorectal cancer patients (Kontos et

al., 2010).

Gastric cancer

Note

Advanced gastric cancer is characterized by

peritoneal dissemination, the most common disease

relapse, which is caused by the dispersal of free

gastric cancer cells into the peritoneal cavity (Baba

et al., 1989; Abe et al., 1995).

Disease

It has been proposed that increased DDC mRNA

expression could be an accurate tool for the

detection of gastric cancer micrometastases in the

peritoneal cavity. According to Sakakura et al.

(2004), DDC expression levels were equivalent to

the degree of dissemination potential of gastric

cancer cells.

Pheochromocytomas

Note

Pheochromocytomas are characterized by over-

production of catecholamines (Eisenhofer et al.,

2001).


Florou D, et al.


Disease

These non-innervated tumors originate, in most

cases, from adrenal medullary cells which are

capable for catecholamine biosynthesis (Yanase et

al., 1986). Catecholamine release by these cells is

not initiated by nerve impulses. Elevated DDC

mRNA levels have been detected in

pheochromocytoma tissues as compared to normal

adrenal medullary cells. Isobe et al. (1998)

suggested that high DDC expression could lead to

the development or growth of pheochromocytomas

(Isobe et al., 1998).

Neuroblastomas

Note

In the neuroblastoma cell line, the SH-SY5Y cells,

both neural full-length DDC mRNA and the neural

mRNA isoform lacking exon 3, were detected

(Chalatsa et al., 2011).

Disease

Neuroblastomas, the most common extracranial

solid neoplasms in children, originate from

sympathetic neural crest cells and their

characteristic is the production of catecholamines

and their metabolites (Boomsma et al., 1989).

Neuroblastomas are categorized as small round-cell

tumors of the childhood (Gilbert et al., 1999). In the

active untreated state, plasma L-Dopa values and/or

DDC enzymatic activity levels have been found to

be elevated. Interestingly, following chemotherapy

treatment, DDC enzymatic activity levels fall

within the physiological range. Elevated levels of

plasma L-Dopa and especially DDC enzyme

activity are observed during disease relapse

(Boomsma et al., 1989).

It is noted that conventional light microscopy

cannot clearly differentiate between neuroblastoma

and other small round-cell tumors of the childhood.

Co-expression of DDC and Tyrosine Hydroxylase

(TH) has been used for the differential diagnosis of

these types of tumors (Gilbert et al., 1999).

Prognosis

Elevated levels of plasma L-Dopa, in

neuroblastoma patients, could provide an indication

for residual tumor. These findings could be

associated with dismal prognosis for neuroblastoma

patients. Furthermore, a sharp increase in plasma

DDC enzymatic activity could be related to disease

reccurence (Boomsma et al., 1989). DDC mRNA

was detected in all bone marrow and peripheral

blood samples obtained from neuroblastoma

patients at relapse. Given these results, Bozzi et al.

(2004) have suggested that DDC mRNA expression

could represent a specific molecular marker for

monitoring bone marrow and peripheral blood

neuroblastoma metastases (Bozzi et al., 2004).

Furthermore, DDC mRNA levels could be used as a

sensitive indicator to predict minimal residual

disease as well as the outcome for patients (Träger

et al., 2008).

Lung carcinomas

Note

Elevated DDC enzymatic activity was observed in

small-cell lung carcinoma (SCLC) as compared to

normal lung epithelia (Nagatsu et al., 1985). The

majority of non-SCLC (NSCLC) exhibited low

levels or no DDC enzyme activity (Gazdar et al.,

1981; Bepler et al., 1988). It is noted that in some

NSCLC cases, high DDC activity values have been

reported (Baylin et al., 1980), although in these

lung lesions the detection of DDC activity was

restricted to large-cell carcinomas and

adenocarcinomas, while squamous cell carcinomas

did not exhibit any enzymatic activity (Gazdar et

al., 1988).

Disease

DDC activity appears to be a valuable

neuroendocrine marker for identifying SCLC tumor

cells in culture (Baylin et al., 1980). DDC

enzymatic activity is highest during the exponential

cellular growth phase and/or when the cells are

during the transition from G2 to the M phase of the

cell cycle (Francis et al., 1983). DDC activity has

been also used as a useful biomarker for the

distinction of SCLC from NSCLC. Furthermore,

DDC activity has been used for the differentiation

between the classical SCLC cell lines (SCLC-C),

which express high DDC activity levels, from the

variant subtype of the SCLC (SCLC-V), which

does not express the enzyme (Carney et al., 1985;

Gazdar et al., 1985).

Prognosis

The elevated DDC enzymatic activity, which is

observed in patients harboring SCLC tumors, seems

to be associated with disease differentiation grade.

High DDC activity has been associated with better

prognosis and patient's outcome (Bepler et al.,

1987).

Medullary thyroid carcinoma

Note

The expression of L-Dopa decarboxylase has been

detected in medullary carcinoma of the thyroid

gland (Pearse, 1969; Atkins et al., 1973).

Disease

Medullary thyroid carcinoma (MTC) originates

from the calcitonin (CT)-secreting thyroid C cells

and is a unique malignancy of endocrine origin

(Tashjian and Melvin, 1968). Malignancy

progression could be monitored, in patients with the

virulent phenotype of the disease, using the

simultaneous increased levels of DDC and

histaminase (Trump et al., 1979; Lippman et al.,

1982). It has been proposed that increased DDC

enzymatic activity might represent an early

differentiation marker in the virulent form of this

neoplasm (Berger et al., 1984).


Florou D, et al.


Neuroendocrine tumors (NETs): bronchial, liver and ileal carcinoids, gastric / pancreatic / pulmonary tumors

Note

DDC enzymatic activity constitutes an excellent

cellular marker for identifying tumors of the

neuroendocrine (NE) origin. The majority of NE

tumors tested were found to express relatively high

DDC enzymatic activity (Gazdar et al., 1988). DDC

expression and/or activity have been reported in

NETs, particularly in SCLC. For these reasons,

DDC has been considered as a general endocrine

marker (Gazdar et al., 1988; Jensen et al., 1990).

Disease

Strikingly higher DDC mRNA expression levels

were revealed in all bronchial carcinoids and

pulmonary NETs when compared to their normal

corresponding types of tissues.

Immunohistochemical data have confirmed DDC

protein expression in all of these tumors. In the

gastroenteropancreatic NETs examined, the

detected DDC mRNA levels were comparable to

those of normal gastric, ileal and pancreatic tissues.

Almost half of the pancreatic and stomach NETs

and all ileal carcinoids were found to be DDC

immunoreactive (Uccella et al., 2006).

Interestingly, hepatic carcinoid tumors

demonstrated a 20-fold increase in DDC activity as

compared with normal surrounding liver tissues

(Gilbert et al., 1995).

Hybrid/Mutated gene

Not yet discovered.

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Gene Section Review




DDR1 (discoidin domain receptor tyrosine kinase 1) Barbara Roig, Elisabet Vilella

Hospital Psiquiatic Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, C/Sant Llorenc

21, 43201 REUS, Spain (BR, EV)


Online updated version : http://AtlasGeneticsOncology.org/Genes/DDR1ID40280ch6p21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI DDR1ID40280ch6p21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: CAK; CD167; DDR; EDDR1;

HGK2; MCK10; NEP; NTRK4; PTK3; PTK3A;

RTK6; TRKE

HGNC (Hugo): DDR1

Location: 6p21.33

DNA/RNA

Description

The DDR1 gene comprises 17 exons and spans 12

kb of the genomic sequence on chromosome 6

(from position 30851861 bp to 30867933 bp in the

positive strand orientation).

Transcription

The 3840-bp mRNA is transcribed in a centromeric

to telomeric orientation. Alternative splicing can

occur, and 5 named isoforms (DDR1a-e) are

recognised.

Pseudogene

No pseudogene has been described.

Genomic organisation of the DDR1 gene on chromosome 6. Exons that are implicated in the alternative splicing process of

the DDR1 gene are represented by open boxes. The alternative splicing process of exon 10 to exon 14 generates 5 DDR1 isoforms, which are affixed a-e.

DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E


Protein

Schematic diagram of the DDR1 protein and

localization of the DDR1 Tyrosine phosphorylated sites at intracellular domain.

Description

DDR1 belongs to the DDRs subfamily of tyrosine

kinase receptors. This subfamily is composed of

only two members, DDR1 and DDR2, and it is

distinguished by an extracellular domain that is

homologous to the carbohydrate-binding lectin

discoidin-I in Dictyostelium discoideum. The

Discoidin domain is essential for the ability of

DDRs to bind ligands. To-date, collagen is the only

unique DDR1 ligand that has been identified. Five

isoforms of DDR1 that are generated by alternative

splicing have been described. The longest DDR1

transcript codes for the full-length receptor (DDR1c

isoform) and is composed of 919 amino acids.

DDR1a and DDR1b isoforms lack 37 amino acids

in the juxtamembrane domain or 6 amino acids in

the kinase domain. DDR1d and DDR1e isoforms

are C-terminally truncated receptors. DDR1d lacks

exons 11 and 12 causing a frame-shift mutation that

generates a stop codon and premature termination

of transcription. Finally, DDR1e lacks exons 11 and

12 as well as the first half of exon 10 (Alves et al.,

1995).

Expression

DDR1 is ubiquitously expressed in a variety of

epithelial tissues (Alves et al., 1995; Curat and

Vogel, 2002; Ferri et al., 2004; Hou et al., 2001;

Mohan et al., 2001; Sakamoto et al., 2001; Tanaka

et al., 1998). DDR1 is also expressed in endothelial

blood capillary cells and oligodendrocytes in the

human brain (Franco-Pons et al., 2009; Roig et al.,

2010). DDR1 is significantly overexpressed in

several human cancers (Barker et al., 1995; Colas et

al., 2011; Ford et al., 2007; Hajdu et al., 2010;

Heinzelmann-Schwarz et al., 2004; Laval et al.,

1994; Nemoto et al., 1997; Park et al., 2007; Tun et

al., 2011; Weiner et al., 1996; Weiner et al., 2000;

Yamanaka et al., 2006; Yoshida et al., 2007) and

carcinoma cell lines (Alves et al., 1995; Gu et al.,

2011; Park et al., 2007; Sakuma et al., 1996).

Localisation

Transmembrane.

Function

Receptor tyrosine kinases are key components of

several signal transduction pathways. These kinases

control multiple cellular processes, including

motility, proliferation, differentiation, metabolism

and survival.

DDR1 is actively involved in tumorigenesis and

promotes the proliferation of neoplasic cells. The

interaction of DDR1 and Notch1 displays a

prosurvival effect (Kim et al., 2011). DDR1

participates in the collective migration of cancer

cells by coordinating the cell polarity regulators

Par3 and Par6 (Hidalgo-Carcedo et al., 2011).

Homology

- P. troglodytes, discoidin domain receptor tyrosine

kinase 1, DDR1

- C. lupus, discoidin domain receptor tyrosine

kinase 1, DDR1

- M. musculus, discoidin domain receptor family

member 1, Ddr1

- R. norvegicus, discoidin domain receptor tyrosine

kinase 1

- D. rerio, discoidin domain receptor family

member 1

Mutations

Note

Few somatic mutations have been described. Four

mutations (G1486T, A496S, CC2469/2470TT,

R824W) have been identified in a cohort of 26

primary lung neoplasms (Davies et al., 2005). One

somatic mutation (A803V) was found in 4 acute

myeloid leukaemia patients (Tomasson et al.,

2008).



Implicated in

Breast cancer

Note

DDR1 overexpression was observed in human

primary breast tumours samples compared to that in

normal breast tissues (Barker et al., 1995). In

addition, invasive ductal and lobular carcinomas

showed differential expression of DDR1. DDR1

was downregulated in lobular carcinomas

(Turashvili et al., 2007a; Turashvili et al., 2007b).

Osteosarcoma

Note

The DDR1 promoter presents a potential p53

binding-site. A previous study has shown that p53

expression upregulated the mRNA expression

levels of DDR1 in human osteosarcoma cells

(Sakuma et al., 1996).

Oesophageal cancer

Note

The overexpression of DDR1 was reported in 12

carcinomatous oesophageal tissues compared to

that in normal tissues. Furthermore, a positive

correlation was identified between DDR1 mRNA

expression and the proliferative activity of the

tumoural cells (Nemoto et al., 1997).

Ovarian cancer

Note

DDR1 was highly expressed in 158 histological

subtypes of primary epithelial ovarian cancers

(EOC) compared to that in normal ovarian surface

epithelium samples (Heinzelmann-Schwarz et al.,

2004).

Endometrial cancer

Note

DDR1 has been implicated as a potential molecular

marker of endometrial cancer (Colas et al., 2011;

Domenyuk et al., 2007). A gene expression

screening of 52 carcinomas samples showed

differential expression of several genes, including

the DDR1 gene. These data were also demonstrated

in 50 tumoural and non-tumoural uterine aspirates

(Colas et al., 2011).

Brain tumours

Note

DDR1 was originally isolated in malignant

childhood brain tumours, which overexpressed

DDR1 (Weiner et al., 1996). Replicable findings

were found in metastatic brain neoplasms and

glioma cells (Yamanaka et al., 2006; Weiner et al.,

2000). In glioma cells, DDR1 was involved in cell

proliferation and invasion via cell interactions with

the extracellular matrix (Ram et al., 2005;

Yamanaka et al., 2006). Moreover, a study on

DDR1a and DDR1b isoforms overexpression in

glioma cells has identified distinct roles for each

DDR1 isoforms in the cell attachment process,

which is mediated by collagen I (Ram et al., 2005).

The analysis of the expression profile in mice that

had PDGF-induced glioma showed overexpression

of DDR1 (Johansson et al., 2005).

Primary central nervous system lymphoma (PCNSL)

Note

A PCNSL pathway analysis revealed upregulation

of DDR1 expression in the extracellular matrix and

the adhesion-related pathways (Tun et al., 2011).

Pituitary adenoma

Note

In different subtypes of pituitary adenoma, DDR1

expression was related to the hormonal background.

DDR1 was more highly expressed in

macroadenomas, compared to microadenomas, and

in PRL- and GH-producing adenomas (Yoshida et

al., 2007).

Lung cancer

Note

DDR1 was upregulated in tumour lung tissue

compared to that in normal tissue and was an

independent favourable predictor for prognosis

(Ford et al., 2007). Similarly, DDR1 was highly

phosphorylated in non-small cell lung cancer

(NSCLC) (Rikova et al., 2007).



One study described the presence of DDR1 somatic

mutations in lung cancer (Davies et al., 2005).

However, no mutations were detected in another

lung cancer study (Ford et al., 2007).

Liver cancer

Note

DDR1a and DDR1b isoforms were overexpressed

in hepatocellular carcinoma cell lines HLE and

Huh-7. DDR1 isoform overexpression enhanced the

migration and invasion of the hepatocellular

carcinoma cell lines in association with the matrix

metalloproteinases MMP2 and MMP9 (Park et al.,

2007).

The downregulation of miR-199a-5p, which is a

direct target of DDR1, deregulated DDR1

functionality and increased cell invasion in human

hepatocellular carcinoma (HCC) (Shen et al., 2010).

Finally, a profiling study on receptor tyrosine

kinase phosphorylation in cholangiocarcinoma

patients showed high levels of phosphorylation of

DDR1 and other tyrosine kinases in tumour tissues

in comparison to para-tumour tissues (Gu et al.,

2011).

Mesenchymal neoplasm

Note

Solitary fibrous tumour (SFT) expression profiling

of 23 samples showed an over-expression of several

receptor tyrosine kinase genes, including DDR1.

However, no mutations were identified using

cDNA sequencing (Hajdu et al., 2010).

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Ram R, Lorente G, Nikolich K, Urfer R, Foehr E, Nagavarapu U. Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2. J Neurooncol. 2006 Feb;76(3):239-48

Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Tanaka R, Sano M, Oide A, Sekijima M, Nishio K. Identification of expressed genes characterizing long-term survival in malignant glioma patients. Oncogene. 2006 Sep 28;25(44):5994-6002

Domenyuk VP, Litovkin KV, Verbitskaya TG, Dubinina VG, Bubnov VV. Identification of new DNA markers of endometrial cancer in patients from the Ukrainian population. Exp Oncol. 2007 Jun;29(2):152-5

Ford CE, Lau SK, Zhu CQ, Andersson T, Tsao MS, Vogel WF. Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma. Br J Cancer. 2007 Mar 12;96(5):808-14

Park HS, Kim KR, Lee HJ, Choi HN, Kim DK, Kim BT, Moon WS. Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. Oncol Rep. 2007 Dec;18(6):1435-41

Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb



MJ. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007 Dec 14;131(6):1190-203

Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, Hajduch M, Murray P, Kolar Z. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer. 2007a Mar 27;7:55

Turashvili G, Bouchal J, Ehrmann J, Fridman E, Skarda J, Kolar Z. Novel immunohistochemical markers for the differentiation of lobular and ductal invasive breast carcinomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007b Jun;151(1):59-64

Yoshida D, Teramoto A. Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1. J Neurooncol. 2007 Mar;82(1):29-40

Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood. 2008 May 1;111(9):4797-808

Tun HW, Personett D, Baskerville KA, Menke DM, Jaeckle KA, Kreinest P, Edenfield B, Zubair AC, O'Neill BP, Lai WR, Park PJ, McKinney M. Pathway analysis of primary central nervous system lymphoma. Blood. 2008 Mar 15;111(6):3200-10

Franco-Pons N, Tomàs J, Roig B, Auladell C, Martorell L, Vilella E. Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. J Mol Neurosci. 2009 May;38(1):2-11

Hajdu M, Singer S, Maki RG, Schwartz GK, Keohan ML, Antonescu CR. IGF2 over-expression in solitary fibrous tumours is independent of anatomical location and is related to loss of imprinting. J Pathol. 2010 Jul;221(3):300-7

Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G, Beckebaum S. Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer. 2010 Aug 27;9:227

Colas E, Perez C, Cabrera S, Pedrola N, Monge M, Castellvi J, Eyzaguirre F, Gregorio J, Ruiz A, Llaurado M, Rigau M, Garcia M, Ertekin T, Montes M, Lopez-Lopez R, Carreras R, Xercavins J, Ortega A, Maes T, Rosell E, Doll A, Abal M, Reventos J, Gil-Moreno A. Molecular markers of endometrial carcinoma detected in uterine aspirates. Int J Cancer. 2011 Jan 4;

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Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, Sahai E. Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat Cell Biol. 2011 Jan;13(1):49-58

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Gene Section Review




ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) Luca Braccioli, Marilena V Iorio, Patrizia Casalini

Molecular Targeting Unit, Experimenatal Oncology Department, Fondazione IRCCS Istituto

Nazionale dei Tumori, Via Amadeo, 42, 20133 Milano, Italy (LB, MVI, PC)


Online updated version : http://AtlasGeneticsOncology.org/Genes/ERBB2ID162ch17q11.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI ERBB2ID162ch17q11.txt This article is an update of : Casalini P, Iorio MV. ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) ). Atlas Genet Cytogenet Oncol Haematol 2005;9(1) This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: CD340; HER2; HER-2; HER-2/neu;

MLN 19; NEU; NGL; TKR1

Location: 17q12

Probe(s) - Courtesy Mariano Rocchi, Resources for

Molecular Cytogenetics.

Note

Tyrosine-kinase receptor (RTK). The HER family

of RTKs consists of four receptors: epidermal

growth factor receptor (EGFR, also called HER-1

or erbB-1), HER-2 (also called erbB-2 or Neu),

HER-3 and HER-4 (also called erbB-3 and erbB-4,

respectively).

DNA/RNA

Description

Sequence length: 40522; CDS: 3678. 30 exons, 26

coding exons; total exon length: 4816, max exon

length: 969, min exon length: 48. Number of SNPs:

17.

Polymorphisms: allelic variations at amino acid

positions 654 and 655 of isoform (a) (positions 624

and 625 of isoform (b)) have been reported, with

the most common allele B1 (Ile-654/Ile-655); allele

B2 (Ile-654/Val-655); allele B3 (Val-654/Val-655).

This nucleotide polymorphism could be associated

with development of gastric carcinoma and with

breast cancer risk, particularly among younger

women.

Transcription

Alternative splicing results in several additional

transcript variants, some encoding different

isoforms and others that have not been fully

characterized.

- mRNA transcript variant: this variant (1)

represents the shorter transcript but encodes the

longer isoform (a) (protein: erbB-2 isoform (a)).

- mRNA transcript variant: this variant (2)

(protein: erbB-2 isoform (b)) contains additional

exons at its 5' end and lacks an alternate 5'

noncoding exon, compared to variant (1). These

differences result in translation initiation at an in-

frame, downstream AUG and an isoform (b) with a

shorter N-terminus compared to isoform (a).

- mRNA transcript variant: herstatin HER2-ECD

1300 bp alternative erbB-2 transcript that retains

intron 8. This alternative transcript specifies 340

residues identical to subdomains I and II from the

extracellular domain of p185erbB-2 followed by a

unique C-terminal sequence of 79 aa encoded by

http://www.biologia.uniba.it/rmc

http://www.biologia.uniba.it/rmc

ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))

Braccioli L, et al.


intron 8. The herstatin mRNA is expressed in

normal human fetal kidney and liver, but is at

reduced levels relative to p185erbB-2 mRNA in

carcinoma cells that contain an amplified erbB-2

gene.

- mRNA transcript variant: an alternative

transcript form of the human homologous gene

erbB-2, containing an in-frame deletion

encompassing exon 19, has been detected in human

breast carcinomas.

- mRNA transcript variant: an alternative

transcript form of the human homologous gene

erbB-2, called HER2Δ16, has been detected in

human breast carcinomas. This splicing variant,

contains an in-frame deletion and encodes a

receptor lacking exon 16, which immediately

precedes the transmembrane domain containing two

cysteines. The loss of these cysteine residues might

induce a change in the conformation of HER2

receptor extracellular domain that promotes

intermolecular disulfide bonding and, in turn,

homodimers capable of transforming cells. Ectopic

expression of HER2Δ16 promotes receptor

dimerization, cell invasion, and trastuzumab

resistant tumor cell lines. The potential metastatic

and oncogenic properties of HER2Δ16 were

mediated through direct coupling of HER2Δ16 to

Src kinase.

Protein

Description

erbB2 encodes a 185-kDa, 1255 amino acids,

orphan receptor tyrosine kinase, and displays potent

oncogenic activity when overexpressed. The proto-

oncogene consists of three domains: a single

transmembrane domain that separates an

intracellular kinase domain from an extracellular

ligand-binding domain. An aberrant form of HER2,

missing the extracellular domain, so-called

HER2p95, has been found in some breast cancers.

HER2p95 is constitutively active because the

external domain of these receptors acts as an

inhibitor until they are bound by ligand. This

isoform can cause resistance to trastuzumab, an

antibody that works by binding to a domain in the

external domain of HER2. HER2p95 fragments

arise through at least 2 different mechanisms:

proteolytic shedding of the extracellular domain of

the full-length receptor and translation of the

mRNA encoding HER2 from internal initiation

codons. Shedding of the ectodomain of HER2

generates a 95- to 100-kDa HER2 p95 membrane-

anchored fragment. Translation of the mRNA

encoding HER2 can be initiated from the AUG

codon that gives rise to the full-length protein of

1255 amino acids or, alternatively, from 2 internal

initiation codons at positions 611 and 678, located

upstream and downstream of the transmembrane

domain, respectively.

Expression

HER2 protein is expressed in several human organs

and tissues: normal epithelium, endometrium and

ovarian epithelium and at neuromuscular level;

prostate, pancreas, lung, kidney, liver, heart,

hematopoietic cells. HER2 expression is low in

mononuclear cells from bone marrow, peripheral

blood (PB) and mobilized PB. The higher

expression has been found in cord blood-derived

cells. Quiescent CD34+ progenitor cells from all

blood sources and resting lymphocytes are HER2

negative, but the expression of this receptor is up-

regulated during cell-cycle recruitment of

progenitor cells. Similarly, it increases in mature,

hematopoietic proliferating cells, underlying the

correlation between HER2 and the proliferating

status of hematopoietic cells.

Localisation

Plasma membrane.

HER2 protein: schematic representation. Receptor tyrosin-kinases (RTKs) are cell surface allosteric enzymes consisting of:

an extracellular ligand-binding domain (blue); a single transmembrane (TM) domain has an extensive homology to the epidermal grow factor receptor (brown); a cytoplasmic domain with catalityc activity (green).


Braccioli L, et al.


Function

Activation and interactions

For the other member of the HER family, ligand

binding induces receptor homo- or

heterodimerization, which is essential for TKs

activation and subsequent recruitment of target

proteins, in turn initiating a complex signaling

cascade that leads into distinct transcriptional

programs. There are several HER-specific ligands.

HER2, which apparently has no direct or specific

ligand, plays a major coordinating role in the HER

network because of its ability to enhance and

stabilize the dimerization: each receptor with a

specific ligand appears in fact to prefer HER-2 as

its heterodimeric partner. HER-2-containing

heterodimers are characterized by extremely high

signaling potency because HER-2 dramatically

reduces the rate of ligand dissociation, allowing

strong and prolonged activation of downstream

signaling pathways.

Signaling and cellular

The most important intracellular pathways activated

by HER2 are those involving mitogen activated

protein kinase (MAPK) and phosphatidylinositol-3

kinase (PI3K). HER2 expression in cancer, besides

its role in proliferation, enhances and prolongs

survivals signals, associating up-regulation of this

receptor to the malignant phenotype. At the same

time, and depending on cellular status, the role of

this receptor in controlling cell fate can also lead to

differentiation and apoptosis.

Physiological

Role in development and differentiation:

- HER2 has several non-oncogenic roles in

regulating growth, differentiation, apoptosis and/or

remodeling in normal mammary glands. Dominant-

negative forms of HER2 have significant defects in

mammary development and lactation.

- HER2 has an important role in development and

function of heart. Cre-Lox technology to mutate

erbB-2 specifically in ventricular cardiomyocytes

leads to a severe cardiomyopathy. This is inferred

also by the adverse cardiac side effects observed in

breast cancer patients treated with the monoclonal

anti-HER2 Ab Trastuzumab.

- HER2 has a role in control of Schwann cell

myelination and it has been demonstrated that

HER2 signaling is also critical for oligodendrocyte

differentiation in vivo.

- HER2 has a dual role in both muscle spindle

maintenance and survival of myoblasts. Muscle-

specific HER2 KO results in fact in viable mice

with a progressive defect in proprioception due to

loss of muscles spindles.

Homology

Homolog to avian erythroblastic leukemia viral (v-

erb-b) oncogen 2.

Mutations

Somatic

The Cancer Genome Project and Collaborative

Group sequenced the erbB-2 gene from 120

primary lung tumors and identified 4% that had

mutations within the kinase domain; in the

adenocarcinoma subtype of lung cancer, 10% of

cases had mutations.

In non small cell lung cancer (adenocarcinoma) the

following erbB-2 mutations were found:

insertion/duplication of GCATACGTGATG at

nucleotide 2322 of the erbB-2 gene, resulting in a

4-amino acid insertion (AYVM) at codon 774.

Insertion of CTGTGGGCT at nucleotide 2335 of

the erbB-2 gene, resulting in a 3-amino acid

insertion (VGS) starting at codon 779; a 2-bp

substitution in the erbB-2 gene, TT-CC at

nucleotides 2263 and 2264, resulting in a leu755-to-

pro (L755P) substitution.

In lung cancer a C44645G transition in the erbB-2

gene that caused a pro1170-to-ala substitution

(P1170A).

In a glioblastoma a 2740G-A transition in the erbB-

2 gene that caused a glu914-to-lys substitution

(E914K).

In a gastric tumor a 2326G-A transition in the erbB-

2 gene that caused a gly776-to-ser (G776S)

substitution.

In an ovarian tumor, a 2570A-G transition in the

erbB-2 gene that caused an asn857-to-ser (N857S)

substitution.

Implicated in

Hematological malignancies

Disease

HER2 expression can be detected in blast cells from

patients with hematological malignancies including

acute lymphoblastic leukemia (ALL). It could be

used as a potential target for the application of

HER2-directed treatment strategies in ALL

including vaccination approaches.

Bladder cancer

Prognosis

HER2 is overexpressed in 25% to 40% of several

human tumors and associated with the malignancy

of the disease, high mitotic index and a shorter

survival time for the patient. Overexpression of

ErbB-2 is also associated with transitional cell

carcinoma of the bladder. HER2 overexpression

occurs in muscle-invasive urothelial carcinomas of

the bladder and is associated with worse survival;

amplifications of erbB-2 gene are also frequently

linked to alterations of the TOP2A gene in bladder

cancer. Furthermore, HER2 overexpression and

amplification in urothelial carcinoma of the bladder

is found associated with MYC co-amplification.


Braccioli L, et al.


Breast carcinoma

Prognosis

Normal tissues have a low content of HER2

membrane protein. Overexpression of HER2 is seen

in 20% of breast and it confers worse biological

behavior and clinical aggressiveness in breast

cancer. Breast cancers can have up to 25 to 50

copies of the HER2 gene and up to a 40- to 100-

fold increase in HER2 protein resulting in 2 million

receptors expressed at the tumor cell surface. The

differential HER2 expression between normal

tissues and tumors helps to define HER2 as an ideal

treatment target. Trastuzumab, the first treatment

targeting HER2, is well tolerated in patients and has

little toxicity because its effects are relatively

specific for cancer cells overexpressing HER2.

HER2 amplification is a relatively early event in

human breast tumorigenesis, occurring in almost

50% of in situ carcinomas. HER2 status is

maintained during progression to invasive disease

and to nodal and distant metastasis. The fact that

only 20% of invasive breast cancers are HER2

amplified suggests that many HER2-amplified in

situ cancers never progress to the invasive stage.

HER2 amplification defines a subtype of breast

cancer with a unique signature of genes and this is

maintained during progression. Some tumors lose

HER2 expression following treatment with

trastuzumab, presumably by selection of a HER2-

negative clone not killed by treatment. Conversely,

HER2 may become positive in some initially

negative tumors over time, especially after

endocrine therapy targeting ER. Indeed, estrogen

receptor has been shown to downregulate HER2

and, conversely, HER2 is able to downregulate ER

expression. Therefore, it is not surprising that

blocking ER might upregulate HER2 and that

blocking HER2 might upregulate ER. HER2-

amplified breast cancers have unique biological and

clinical characteristics. They have increased

sensitivity to certain cytotoxic agents such as

doxorubicin, relative resistance to hormonal agents,

and propensity to metastasize to the brain and

viscera. HER2-amplified tumors have an increased

sensitivity to doxorubicin possibly due to

coamplification of the topoisomerase-2 gene, which

is near the HER2 locus on chromosome 17 and is

the target of the drug. Half of HER2-positive breast

cancers are ER positive but they generally have

lower ER levels, and many have p53 alterations.

These tumors have higher proliferation rates and

more aneuploidy and are associated with poorer

patient prognosis. The poor outcome is dramatically

improved with appropriate chemotherapy combined

with the HER2-targeting drug trastuzumab.

Overexpression of the erbB-2 gene is associated

with tumor aggressiveness, and with patient

responsiveness to doxorubicin, cyclophosphamide,

methotrexate, fluorouracil (CMF), and to paclitaxel,

whereas tamoxifen was found to be ineffective and

even detrimental in patients with HER2-positive

tumors. In Paget's disease of breast, HER2 protein

overexpression is caused by amplification of the

erbB-2 gene. HER2 has a role in this disease of the

breast, where the epidermis of the nipple is

infiltrated by large neoplastic cells of glandular

origin. It seems that binding of heregulin-alpha to

the receptor complex on Paget cells results in

chemotaxis of these breast cancer cells. The

isoforms HER2p95 and HER2Δ16 are found in

some breast cancers and the expression of these

hyperactive forms of HER2 may contribute to the

malignant progression.

Cervical cancer

Prognosis

HER2 may be activated in the early stage of

pathogenesis of cervical carcinoma in geriatric

patients and is frequently amplified in squamous

cell carcinoma of the uterine cervix.

Childhood medulloblastoma

Prognosis

Overexpression of HER2 in medulloblastoma is

associated with poor prognosis and metastasis and

HER2-HER4 receptor heterodimerization is of

particular biological significance in this disease.

Colorectal cancer

Prognosis

Overexpression of HER2 occurs in a significant

number of colorectal cancers. It was significantly

associated with poor survival and related to tumor

progression in colorectal cancer.

Oral squamous cell carcinoma

Prognosis

E6/E7 proteins of HPV type 16 and HER2

cooperate to induce neoplastic transformation of

primary normal oral epithelial cells. Overexpression

of HER2 receptor is a frequent event in oral

squamous cell carcinoma and is correlated with

poor survival.

Gastric cancer

Prognosis

HER2 amplification/overexpression does not seem

to play a role in the molecular pathogenesis of most

gastrinomas. However, mild gene amplification

occurs in a subset of them, and overexpression of

this receptor is associated with aggressiveness of

the disease. HER2 overexpression in patients with

gastric cancer, and it has been solidly correlated to

poor outcomes and a more aggressive disease. The

overall HER2 positive rate is about 22%. HER2

overexpression rate in gastric cancer varies

according to the site of the tumor. A higher

overexpression rate (36%) was shown in

gastroesophageal junction (GEJ) tumors in

comparison to 21% in gastric tumors.


Braccioli L, et al.


Germ-cell testicular tumor

Prognosis

A significant correlation was observed between

HER2 overexpression and clinical outcome in

germ-cell testicular tumors.

Cholangiocarcinoma

Prognosis

Data are still controversial about HER2 role in this

carcinoma. Increased HER2 expression contributes

to the development of cholangiocarcinogenesis into

an advanced stage associated with tumor

metastasis. In addition, overexpression of HER2

and COX-2 correlated directly with tumor

differentiation. However, other studies report that

HER2 expression is associated with more favorable

clinical features, such as a polypoid macroscopic

type and absence of other organ involvement, and

has been reported that the proportion of HER2-

positive cases in papillary adenocarcinoma is higher

than in other histological types and is associated

with an early disease stage. HER2 is preferentially

expressed in well differentiated component, and it

is also expressed in dedifferentiated components in

progressive cases.

Lung cancer

Prognosis

HER2 is overexpressed in less than 20% of patients

with non-small cell lung cancer (NSCLC) and

studies have shown that overexpression of this

receptor is correlated with a poor prognosis in both

resected and advanced NSCLC. HER2

overexpression has an important function in the

biology of NSCLC and may have a prognostic

value for patients with metastatic NSCLC.

Osteosarcoma

Prognosis

Higher frequency of HER2 expression has been

observed in samples from patients with metastatic

disease at presentation and at the time of relapse,

and it correlates with worse histologic response and

decreased event-free survival. HER2 could be an

effective target for the immunotherapy of

osteosarcoma, especially the type with high

metastatic potential.

Ovarian cancer

Prognosis

HER2 overexpression varies from 9% to 32% of all

cases of ovarian cancer and its overexpression is

more frequent in advanced stage of ovarian cancer.

Overexpression of HER2 in ovarian cancer cells

leads to faster cell growth, higher abilities in DNA

repair and colony formation. A cross-talk between

HER2 and estrogen receptor (ER) was identified in

ovarian cancer cells. Estrogen has been proven to

induce the phosphorylation of HER2, and initiate

the HER2's signaling pathway.

Pancreatic adenocarcinoma

Prognosis

Overexpression of HER-2 in pancreatic

adenocarcinoma seems to be a result of increased

transcription rather than gene amplification. The

coexpression of HER2 oncogene protein, epidermal

growth factor receptor, and TGF-beta1 in pancreatic

ductal adenocarcinoma is related to the

histopathological grades and clinical stages of

tumors. The blockade of HER2 inhibits the growth

of pancreatic cancer cells in vitro. HER2

overexpression was reported to accumulate in well

differentiated pancreas adenocarcinomas whereas it

is only infrequently found in poorly differentiated

or undifferentiated tumors, in vivo and in vitro

analyses have suggested that targeting HER2 might

increase treatment effects of conventional

chemotherapies of pancreas adenocarcinoma.

However, unlike in breast cancer, the application of

antibodies directed against HER2 has not yet

become an established therapy for pancreas

adenocarcinoma.

Prostate cancer

Prognosis

HER2 plays pivotal roles in prostate cancer. Studies

have shown that 25% of untreated primary tumors,

59% of localized tumors after neoadjuvant hormone

therapy, and 78% of metastatic tumors

overexpressed HER2. Several lines of evidence

have implicated HER2 as a key mediator in the

recurrence of prostate cancer to a hormone-

refractory, androgen-independent tumor, which is

the hallmark of prostate cancer progress. The

driving force for prostate cancer recurrence is the

reactivation of androgen receptor (AR), which is a

type of nuclear receptors, activated by steroid

hormone but ablated in hormonal therapy.

Phosphorylation and reactivation of AR stimulate

cancer cell growth and trigger tumor progression. It

has been observed that overexpression of HER2

kinase enhanced AR function and hormone-

independent growth in prostate tumor cells. HER2

activated AR through the MAPK pathway.

Additionally, the HER2/HER3 dimmer increases

AR protein stability and promotes the binding of

AR to the promoter region of its target genes,

resulting in AR activation in an androgen-depleted

environment.

Salivary gland tumor

Prognosis

Several results demonstrated significant positive

staining of HER2 in the salivary tumorigenic tissue

but not in the surrounding non-tumorigenic tissue,

pointing to a biological role in the tumorigenic

process. HER2 amplification is present

predominantly in tumors with high HER2

expression and seems to be the dominant


Braccioli L, et al.


mechanism for HER2 overexpression in this tumor

type.

To be noted

Note

Possible therapeutic strategies: 1) growth inhibitory

antibodies (like Trastuzumab), used alone or in

combination with standard chemotherapeutics; 2)

tyrosin kinase inhibitors (TKI); 3) active

immunotherapy, because HER2 oncoprotein is

immunogenic in some breast carcinoma patients; 4)

dimerization inhibitor antibodies, like Pertuzumab:

its binding to HER2 inhibits the dimerization of

HER2 with other HER receptors.

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Hansel DE, Swain E, Dreicer R, Tubbs RR. HER2 overexpression and amplification in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of cases. Am J Clin Pathol. 2008 Aug;130(2):274-81

Jo UH, Han SG, Seo JH, Park KH, Lee JW, Lee HJ, Ryu JS, Kim YH. The genetic polymorphisms of HER-2 and the risk of lung cancer in a Korean population. BMC Cancer. 2008 Dec 4;8:359


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Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, Hirohashi S, Shibata T. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008 Jan 29;98(2):418-25

Hirsch FR, Varella-Garcia M, Cappuzzo F. Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene. 2009 Aug;28 Suppl 1:S32-7

Mitra D, Brumlik MJ, Okamgba SU, Zhu Y, Duplessis TT, Parvani JG, Lesko SM, Brogi E, Jones FE. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol Cancer Ther. 2009 Aug;8(8):2152-62

Higa GM, Singh V, Abraham J. Biological considerations and clinical applications of new HER2-targeted agents. Expert Rev Anticancer Ther. 2010 Sep;10(9):1497-509

Kimple RJ, Vaseva AV, Cox AD, Baerman KM, Calvo BF, Tepper JE, Shields JM, Sartor CI. Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status. Clin Cancer Res. 2010 Feb 1;16(3):912-23

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Braccioli L, Iorio MV, Casalini P. ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):963-971.





KIAA0101 (KIAA0101) Shannon Joseph, Lingbo Hu, Fiona Simpson

University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia (SJ,

LH, FS)


Online updated version : http://AtlasGeneticsOncology.org/Genes/KIAA0101ID41058ch15q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI KIAA0101ID41058ch15q22.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: FLJ58702; NS5ATP9; OEATC-1;

OEATC1; PAF; p15(PAF); p15PAF

HGNC (Hugo): KIAA0101

Location: 15q22.31

DNA/RNA

Note

Murine gene embryonic expression shows highly

restricted expression of KIAA0101 in facial

prominences, limbs, somites, brain, spinal cord and

hair follicles. It has a suggested role in embryonic

development (van Beuren et al., 2007).

Description

The gene is composed of 4 exons.

Transcription

One transcript. RNA was expressed as a 1.1 kb

message in liver, pancreas and placenta at high

levels (Yu et al., 2001). RNA profiling shows it is

highly expressed in a number of tumors,

specifically in esophageal tumors, anaplastic

thyroid carcinomas, pancreatic cancer and non-

small-cell lung cancer lines (Yu et al., 2001;

Hosokawa et al., 2007). KIAA0101 was also

reported to be down-regulated in colon cancer cells

(Simpson et al., 2006) and human hepatocellular

carcinoma (Guo et al., 2006). Nuclear protein NF-

kappaB (p50) (Li et al., 2008), the Hepatitis C virus

protein non-structural protein 5A (NS5A) (Shi et

al., 2008) and ATF3 (Turchi et al., 2009) bind to

the promoter region upstream of the KIAA0101

transcription initiation site promoting transcription

in response to DNA damage.

Pseudogene

None.

Protein

Note

NS5ATP9, Hepatitis C virus NS5A-transactivated

protein 9, HCV NS5A-transactivated protein 9,

Overexpressed in anaplastic thyroid carcinoma-1,

OEATC-1, OEATC1, p15(PAF), L5.

Description

The KIAA0101 gene encodes for a 111 amino acid

15 kDa protein. It contains a conserved

proliferating cell nuclear antigen (PCNA)-binding

motif (Yu et al., 2001).

DNA diagram. KIAA0101 9768 chr: 62444265-62460755. One transcript, 4 exons.

KIAA0101 (KIAA0101) Joseph S, et al.


Protein diagram. 111 aa in length, single transcript,

mutation I-A at position 65 and mutation F-A at position 68 results in loss of PCNA binding.

Expression

Predominant expression in liver, pancreas and

brain. Not detected in heart or liver (Yu et al.,

2001). The KIAA0101 protein was down-regulated

in human hepatocellular carcinoma (Guo et al.,

2006; Yuan et al., 2007). Increased protein levels

have been detected in pancreatic cancer cells

(Hosokawa et al., 2007).

Localisation

Nucleus, mitochondrion (Yu et al., 2001; Guo et al.,

2006; Simpson et al., 2006; Yuan et al., 2007).

Function

The KIAA0101 protein binds to PCNA through a

conserved PCNA binding domain. PCNA is

required for DNA replication or repair as a

supplementary factor for DNA polymerase

(Paunesku et al., 2001). Proteins bound to PCNA

can prevent its binding to DNA polymerase, in turn

leading to inhibition of DNA synthesis, cell cycle

progression and G1 cell cycle arrest (Yuan et al.,

2007). PCNA binding proteins also interact with

each other to modulate this regulation. For

example, KIAA0101 also interacts in a complex

with p33ING1 isoform 2, another PCNA binding

protein which is a potential tumor suppressor and

regulator of p53 (Simpson et al., 2006). UV

irradiation caused increased association of

KIAA0101 with PCNA suggesting that this

association occurs in response to DNA damage.

KIAA0101 also competes with p21WAF for

binding to PCNA (Yu et al., 2001). KIAA0101

most recently been shown to act in concert with

ATF3 to control genomic integrity after UV stress

(Turchi et al., 2009). KIAA0101 expression levels

are also regulated by NF-kappaB, this protein

family having significant roles in apoptosis, cell

cycle regulation and onocgenesis (Hosokawa et al.,

2007; Li et al., 2008). Together this data suggests a

likely role for KIAA0101 in DNA repair and in

protection from UV-induced cell death.

Mutations

Note

Experimentally mutation I-A at position 65 and F-A

at position 68 result in loss of PCNA binding (Yu et

al., 2001). No other mutations have been described.

Screening of colon tumour samples identified a

polymorphism in the intronic region just prior to the

start of exon 2 (982-15delT) (Simpson et al., 2006).

Implicated in

Hepatocellular carcinoma

Disease

KIAA0101 expression was proposed to promote

growth advantage and hypoxic insult resistance and

be associated with promoting cell proliferation

(Yuan et al., 2007). KIAA0101 overexpression was

associated with concomitant p53 mutation and

vascular invasion (Yuan et al., 2007). This study

suggested that high expression in hepatocellular

carcinoma was indicative of tumour recurrence,

metastatic potential and poor prognosis (Yuan et

al., 2007). KIAA0101 was also reported to be

downregulated in hepatocellular carcinoma (Guo et

al., 2006). This study suggested that KIAA0101 had

a growth inhibitory effect.

Astrocytomas

Disease

Grade IV (glioblastoma multiforme) astrocytomas

had 5 times higher expression levels when

compared to Grade I (pilocytic) astrocyomas

suggesting that KIAA0101 abundance correlates

with malignancy grade in human astrocytes (Marie

et al., 2008).

Pancreatic cancer

Disease

Pancreatic cells overexpress KIAA0101 both at

cDNA and protein level. Knock down of

KIAA0101 by siRNA attenuated proliferation and

DNA replication whereas overexpression enhanced

cell growth in pancreatic cancer cell lines

(Hosokawa et al., 2007).

Anaplastic thyroid carcinoma

Disease

Anaplastic thyroid carcinoma cell lines had

significant overexpression of KIAA0101. Cell

growth was inhibited by silencing KIAA0101

expression using siRNA. KIAA0101 may be

oncogenic or cell growth-promoting but the

mechanism for this is not understood (Mizutani et

al., 2005).

Follicular lymphoma

Disease

High expression of KIAA0101 (along with CCNB1

(cyclin B1), CDC2, CDKN3A, CKS1B, ANP32E)

was associated with better survival/response rate in

a univariate analysis following CHOP

(cyclophosphamide, vincristine, doxorubicin,

prednisone) chemotherapy for follicular lymphoma

treatment. Identification of these proteins aims to

develop a follicular lymphoma international

prognostic index to aid in informing a successful

treatment strategy (Bjorck et al., 2005).

KIAA0101 (KIAA0101) Joseph S, et al.


Oncogenesis

This gene is thought to be oncogenic through

modulation of DNA repair pathways via interaction

with PCNA.

References Nagase T, Miyajima N, Tanaka A, Sazuka T, Seki N, Sato S, Tabata S, Ishikawa K, Kawarabayasi Y, Kotani H. Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 1995;2(1):37-43

Paunesku T, Mittal S, Protić M, Oryhon J, Korolev SV, Joachimiak A, Woloschak GE. Proliferating cell nuclear antigen (PCNA): ringmaster of the genome. Int J Radiat Biol. 2001 Oct;77(10):1007-21

Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y. p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues. Oncogene. 2001 Jan 25;20(4):484-9

Björck E, Ek S, Landgren O, Jerkeman M, Ehinger M, Björkholm M, Borrebaeck CA, Porwit-MacDonald A, Nordenskjöld M. High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma. Blood. 2005 Apr 1;105(7):2908-15

Mizutani K, Onda M, Asaka S, Akaishi J, Miyamoto S, Yoshida A, Nagahama M, Ito K, Emi M. Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as a novel gene responsible for anaplastic thyroid carcinoma. Cancer. 2005 May 1;103(9):1785-90

Guo M, Li J, Wan D, Gu J. KIAA0101 (OEACT-1), an expressionally down-regulated and growth-inhibitory gene in human hepatocellular carcinoma. BMC Cancer. 2006 Apr 29;6:109

Simpson F, Lammerts van Bueren K, Butterfield N, Bennetts JS, Bowles J, Adolphe C, Simms LA, Young J, Walsh MD, Leggett B, Fowles LF, Wicking C. The PCNA-associated factor KIAA0101/p15(PAF) binds the potential tumor suppressor product p33ING1b. Exp Cell Res. 2006 Jan 1;312(1):73-85

Collado M, Garcia V, Garcia JM, Alonso I, Lombardia L, Diaz-Uriarte R, Fernández LA, Zaballos A, Bonilla F, Serrano M. Genomic profiling of circulating plasma RNA

for the analysis of cancer. Clin Chem. 2007 Oct;53(10):1860-3

Hosokawa M, Takehara A, Matsuda K, Eguchi H, Ohigashi H, Ishikawa O, Shinomura Y, Imai K, Nakamura Y, Nakagawa H. Oncogenic role of KIAA0101 interacting with proliferating cell nuclear antigen in pancreatic cancer. Cancer Res. 2007 Mar 15;67(6):2568-76

van Bueren KL, Bennetts JS, Fowles LF, Berkman JL, Simpson F, Wicking C. Murine embryonic expression of the gene for the UV-responsive protein p15(PAF). Gene Expr Patterns. 2007 Jan;7(1-2):47-50

Yuan RH, Jeng YM, Pan HW, Hu FC, Lai PL, Lee PH, Hsu HC. Overexpression of KIAA0101 predicts high stage, early tumor recurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5368-76

Li K, Ma Q, Shi L, Dang C, Hong Y, Wang Q, Li Y, Fan W, Zhang L, Cheng J. NS5ATP9 gene regulated by NF-kappaB signal pathway. Arch Biochem Biophys. 2008 Nov 1;479(1):15-9

Marie SK, Okamoto OK, Uno M, Hasegawa AP, Oba-Shinjo SM, Cohen T, Camargo AA, Kosoy A, Carlotti CG Jr, Toledo S, Moreira-Filho CA, Zago MA, Simpson AJ, Caballero OL. Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas. Int J Cancer. 2008 Feb 15;122(4):807-15

Shi L, Zhang SL, Li K, Hong Y, Wang Q, Li Y, Guo J, Fan WH, Zhang L, Cheng J. NS5ATP9, a gene up-regulated by HCV NS5A protein. Cancer Lett. 2008 Feb 8;259(2):192-7

Turchi L, Fareh M, Aberdam E, Kitajima S, Simpson F, Wicking C, Aberdam D, Virolle T. ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress. Cell Death Differ. 2009 May;16(5):728-37

Miller WR, Larionov A. Changes in expression of oestrogen regulated and proliferation genes with neoadjuvant treatment highlight heterogeneity of clinical resistance to the aromatase inhibitor, letrozole. Breast Cancer Res. 2010;12(4):R52


Joseph S, Hu L, Simpson F. KIAA0101 (KIAA0101). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):972-974.

Gene Section Review




PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) Nikki Minnebo, Nele Van Dessel, Monique Beullens, Aleyde van Eynde, Mathieu Bollen

Laboratory of Biosignaling & Therapeutics, Dept Molecular Cell Biology, University of Leuven,

Herestraat 49 box 901, 3000 Leuven, Belgium (NM, NV, MB, Av, MB)


Online updated version : http://AtlasGeneticsOncology.org/Genes/PPP1R8ID41811ch1p35.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI PPP1R8ID41811ch1p35.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: ARD-1; ARD1; NIPP-1; NIPP1;

PRO2047

HGNC (Hugo): PPP1R8

Location: 1p35.3

DNA/RNA

Note

ARD1 is a frequently used alias for NIPP1,

however, this name actually corresponds to an

alternative transcript (NIPP1gamma), which

encodes a truncated form of NIPP1 encompassing

residues 225-351 only. This transcript has been

shown to restore endoribonuclease activity to E.

coli rne gene mutants (Wang and Cohen, 1994;

Claverie-Martin et al., 1997; Chang et al., 1999; Jin

et al., 1999; Van Eynde et al., 1999). Moreover,

note that the name ARD1 is also used for a

completely unrelated protein, TRIM23 (Mishima et

al., 1993).

Description

The entire PPP1R8 gene spans 20.9 kb on the

forward strand of the long arm on chromosome 1.

The gene contains 7 exons of which exon 1 has 5'-

alternative splice sites.

Transcription

The PPP1R8 gene contains 7 exons which give rise

to 5 alternative splice products (see diagram above).

Genomic organization of the PPP1R8 gene and the alternative splice variants with their corresponding coding sequences (black

line). Exons and alternative splice sites are indicated by different colors.

PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8)

Minnebo N, et al.


When speaking about NIPP1, one usually refers to

the NIPP1alpha isoform (39 kDa, 351 residues)

which is by far the most abundant isoform in all

examined mammalian tissues. When visualized by

immunoblotting with C-terminal antibodies (which

recognize all isoforms except NIPP1epsilon), also

smaller polypeptides are visualized albeit at a much

lower intensity as compared to the alpha-isoform.

However, it is not clear yet whether these represent

some of the other NIPP1 isoforms or simply

degradation products of NIPP1alpha (Van Eynde et

al., 1999; Chang et al., 1999; Fardilha et al., 2004).

Pseudogene

A processed pseudogene, termed PPP1R8P, has

been mapped to chromosome 1p33-32 (48790762-

48791795 bp from pter according to hg19 - Feb

2009). Consistent with this notion, it is only 1034

bp in size, contains no introns and encodes an

incomplete NIPP1-transcript due to the presence of

various premature stop codons (Van Eynde et al.,

1999).

Protein

Note

Nuclear Inhibitor of PP1 (NIPP1) was first

identified in bovine thymus nuclei as a potent

inhibitor of the protein Ser/Thr phosphatase PP1

(Beullens et al., 1992; Beullens et al., 1993). Later

on, it became clear that NIPP1 exerts various

functions in the eukaryotic cell by serving as a kind

of scaffold protein onto which a variety of proteins

can bind. These interaction partners range from

protein kinase MELK, protein phosphatase PP1

(PPP1C-a/PPP1C-b/PPP1C-c), the pre-mRNA

splicing factors SAP155 (SF3B1) and CDC5L to

the chromatin modifiers EED and EZH2.

Description

NIPP1 consists of 351 amino acids and has a

molecular mass of 39 kDa. However, it migrates at

a size of about 45 kDa on SDS-PAGE. NIPP1

contains an N-terminal ForkHead Associated

(FHA) domain.

Via this established phosphothreonine-binding

domain, NIPP1 interacts with protein kinase

MELK, the splicing factors SAP155 and CDC5L

and the histone methyltransferase EZH2. Moreover,

it was shown that the NIPP1 FHA-domain binds to

its ligands via phosphorylated TP-dipeptide motifs,

present in the interacting proteins (Boudrez et al.,

2000; Boudrez et al., 2002; Vulsteke et al., 2004;

Nuytten et al., 2008).

Two additional interactors, PP1 and EED, have two

separate binding sites on NIPP1: one in the central

domain and the other at the C-terminus. In the

central domain, the binding of NIPP1 to PP1 is

mediated by a so called RVXF-motif, which is

present in about two thirds of all known PP1

interacting proteins (Beullens et al., 1999; Beullens

et al., 2000; Hendrickx et al., 2009). In addition, the

C-terminal 22 residues can interact with nucleic

acids (Jin et al., 1999).

Expression

NIPP1 is ubiquitously expressed (Van Eynde et al.,

1995).

Localisation

NIPP1 is a nuclear protein and is enriched in

splicing factor storage sites called speckles

(Trinkle-Mulcahy et al., 1999; Jagiello et al., 2000).

Although largely nuclear, some data suggest that

there also exists a cytoplasmic pool of NIPP1

(Boudrez et al., 1999; Jagiello et al., 1997).

Function

NIPP1 is a scaffold protein and exerts its functions

via its interacting proteins. NIPP1 was discovered

as a potent inhibitor and a major nuclear interactor

of the phosphatase PP1 (Beullens et al., 1999). PP1

functions as a holoenzyme in which the interacting

proteins confine substrate specificity, activity

and/or localization of PP1 (Bollen et al., 2010). For

NIPP1, it has been shown that it acts as a

physiological PP1 inhibitor for some substrates,

while functioning as an activator towards other

substrates (Parker et al., 2002; Lesage et al., 2004;

Comerford et al., 2006; Shi and Manley, 2007).

A schematic representation of the domain structure of NIPP1 and its interactor binding sites. The FHA-domain (red) binds the

indicated interactors via a phosphorylated TP dipeptide motif. NIPP1 binds PP1 via the indicated RVXF-motif and via a C-terminal binding site (green). EED and RNA binding sites are colored blue and orange, respectively. Known phosphorylation

sites are indicated in black (in vivo validated) or grey (in vitro data).


Minnebo N, et al.


Also, the interaction between NIPP1 and PP1 can

be regulated by phosphorylation (Beullens et al.,

1993; Van Eynde et al., 1994; Jagiello et al., 1995;

Vulsteke et al., 1997; Beullens et al., 1999). NIPP1

is also involved in 3 other major cellular processes:

splicing, transcription and development. Firstly,

NIPP1 is associated with spliceosomes and splicing

factor storage sites called "speckles", probably

mediated by its interaction with the splicing factors

CDC5L and SAP155 (Boudrez et al., 2000; Deckert

et al., 2006). Pre-mRNA splicing assays showed

that NIPP1 is required for late stage spliceosome

formation (Beullens and Bollen, 2002). Recently it

was published that NIPP1 directs associated PP1 to

dephosphorylate SAP155 (Tanuma et al., 2008).

Secondly, NIPP1 is a transcriptional repressor via

its interaction with EED and EZH2 (Jin et al., 2003;

Roy et al., 2007), two core components of the

Polycomb repressive complex 2 (PRC2). Through

its interaction with PRC2, NIPP1 directs it to a

subset of Polycomb target genes, where the

methyltransferase EZH2 will mark genes proned for

silencing by trimethylating histone 3 on lysine 27

(Nuytten et al, 2008). In 2010, Van Dessel et al.

showed that this targeting function of NIPP1 is

dependent on associated PP1. Finally, NIPP1 is

essential for embryonic development as a NIPP1

knock out mouse is embryonically lethal at the

onset of gastrulation (Van Eynde et al., 2004).

The splice variant NIPP1gamma or ARD1 displays

a site-specific Mg2+

-dependent endoribonuclease

activity, in contrast to the NIPP1alpha isoform,

which does not possess this function (Wang and

Cohen, 1994; Claverie-Martin et al., 1997; Chang et

al., 1999; Jin et al., 1999; Van Eynde et al., 1999).

Homology

NIPP1 is highly conserved in all multicellular

organisms.

Implicated in

Hepatoma

Disease

Cancer.

Prognosis

An increase in NIPP1 mRNA is correlated with a

malignant phenotype in rats (Kim et al., 2000).

References Beullens M, Van Eynde A, Stalmans W, Bollen M. The isolation of novel inhibitory polypeptides of protein phosphatase 1 from bovine thymus nuclei. J Biol Chem. 1992 Aug 15;267(23):16538-44

Mishima K, Tsuchiya M, Nightingale MS, Moss J, Vaughan M. ARD 1, a 64-kDa guanine nucleotide-binding protein with a carboxyl-terminal ADP-ribosylation factor domain. J Biol Chem. 1993 Apr 25;268(12):8801-7

Beullens M, Van Eynde A, Bollen M, Stalmans W. Inactivation of nuclear inhibitory polypeptides of protein

phosphatase-1 (NIPP-1) by protein kinase A. J Biol Chem. 1993 Jun 25;268(18):13172-7

Van Eynde A, Beullens M, Stalmans W, Bollen M. Full activation of a nuclear species of protein phosphatase-1 by phosphorylation with protein kinase A and casein kinase-2. Biochem J. 1994 Feb 1;297 ( Pt 3):447-9

Wang M, Cohen SN. ard-1: a human gene that reverses the effects of temperature-sensitive and deletion mutations in the Escherichia coli rne gene and encodes an activity producing RNase E-like cleavages. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10591-5

Jagiello I, Beullens M, Stalmans W, Bollen M. Subunit structure and regulation of protein phosphatase-1 in rat liver nuclei. J Biol Chem. 1995 Jul 21;270(29):17257-63

Van Eynde A, Wera S, Beullens M, Torrekens S, Van Leuven F, Stalmans W, Bollen M. Molecular cloning of NIPP-1, a nuclear inhibitor of protein phosphatase-1, reveals homology with polypeptides involved in RNA processing. J Biol Chem. 1995 Nov 24;270(47):28068-74

Claverie-Martin F, Wang M, Cohen SN. ARD-1 cDNA from human cells encodes a site-specific single-strand endoribonuclease that functionally resembles Escherichia coli RNase E. J Biol Chem. 1997 May 23;272(21):13823-8

Jagiello I, Beullens M, Vulsteke V, Wera S, Sohlberg B, Stalmans W, von Gabain A, Bollen M. NIPP-1, a nuclear inhibitory subunit of protein phosphatase-1, has RNA-binding properties. J Biol Chem. 1997 Aug 29;272(35):22067-71

Vulsteke V, Beullens M, Waelkens E, Stalmans W, Bollen M. Properties and phosphorylation sites of baculovirus-expressed nuclear inhibitor of protein phosphatase-1 (NIPP-1). J Biol Chem. 1997 Dec 26;272(52):32972-8

Beullens M, Van Eynde A, Vulsteke V, Connor J, Shenolikar S, Stalmans W, Bollen M. Molecular determinants of nuclear protein phosphatase-1 regulation by NIPP-1. J Biol Chem. 1999 May 14;274(20):14053-61

Boudrez A, Evens K, Beullens M, Waelkens E, Stalmans W, Bollen M. Identification of MYPT1 and NIPP1 as subunits of protein phosphatase 1 in rat liver cytosol. FEBS Lett. 1999 Jul 16;455(1-2):175-8

Chang AC, Sohlberg B, Trinkle-Mulcahy L, Claverie-Martin F, Cohen P, Cohen SN. Alternative splicing regulates the production of ARD-1 endoribonuclease and NIPP-1, an inhibitor of protein phosphatase-1, as isoforms encoded by the same gene. Gene. 1999 Nov 15;240(1):45-55

Jin Q, Beullens M, Jagiello I, Van Eynde A, Vulsteke V, Stalmans W, Bollen M. Mapping of the RNA-binding and endoribonuclease domains of NIPP1, a nuclear targeting subunit of protein phosphatase 1. Biochem J. 1999 Aug 15;342 ( Pt 1):13-9

Trinkle-Mulcahy L, Ajuh P, Prescott A, Claverie-Martin F, Cohen S, Lamond AI, Cohen P. Nuclear organisation of NIPP1, a regulatory subunit of protein phosphatase 1 that associates with pre-mRNA splicing factors. J Cell Sci. 1999 Jan;112 ( Pt 2):157-68

Van Eynde A, Pérez-Callejón E, Schoenmakers E, Jacquemin M, Stalmans W, Bollen M. Organization and alternate splice products of the gene encoding nuclear inhibitor of protein phosphatase-1 (NIPP-1). Eur J Biochem. 1999 Apr;261(1):291-300

Beullens M, Vulsteke V, Van Eynde A, Jagiello I, Stalmans W, Bollen M. The C-terminus of NIPP1 (nuclear inhibitor of protein phosphatase-1) contains a novel binding site for protein phosphatase-1 that is controlled by tyrosine phosphorylation and RNA binding. Biochem J. 2000 Dec 15;352 Pt 3:651-8


Minnebo N, et al.


Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M. NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry. J Biol Chem. 2000 Aug 18;275(33):25411-7

Kim SE, Ishita A, Shima H, Nakamura K, Yamada Y, Ogawa K, Kikuchi K. Increased expression of NIPP-1 mRNA correlates positively with malignant phenotype in rat hepatomas. Int J Oncol. 2000 Apr;16(4):751-5

Beullens M, Bollen M. The protein phosphatase-1 regulator NIPP1 is also a splicing factor involved in a late step of spliceosome assembly. J Biol Chem. 2002 May 31;277(22):19855-60

Boudrez A, Beullens M, Waelkens E, Stalmans W, Bollen M. Phosphorylation-dependent interaction between the splicing factors SAP155 and NIPP1. J Biol Chem. 2002 Aug 30;277(35):31834-41

Parker L, Gross S, Beullens M, Bollen M, Bennett D, Alphey L. Functional interaction between nuclear inhibitor of protein phosphatase type 1 (NIPP1) and protein phosphatase type 1 (PP1) in Drosophila: consequences of over-expression of NIPP1 in flies and suppression by co-expression of PP1. Biochem J. 2002 Dec 15;368(Pt 3):789-97

Jin Q, van Eynde A, Beullens M, Roy N, Thiel G, Stalmans W, Bollen M. The protein phosphatase-1 (PP1) regulator, nuclear inhibitor of PP1 (NIPP1), interacts with the polycomb group protein, embryonic ectoderm development (EED), and functions as a transcriptional repressor. J Biol Chem. 2003 Aug 15;278(33):30677-85

Fardilha M, Wu W, Sá R, Fidalgo S, Sousa C, Mota C, da Cruz e Silva OA, da Cruz e Silva EF. Alternatively spliced protein variants as potential therapeutic targets for male infertility and contraception. Ann N Y Acad Sci. 2004 Dec;1030:468-78

Lesage B, Beullens M, Nuytten M, Van Eynde A, Keppens S, Himpens B, Bollen M. Interactor-mediated nuclear translocation and retention of protein phosphatase-1. J Biol Chem. 2004 Dec 31;279(53):55978-84

Van Eynde A, Nuytten M, Dewerchin M, Schoonjans L, Keppens S, Beullens M, Moons L, Carmeliet P, Stalmans W, Bollen M. The nuclear scaffold protein NIPP1 is essential for early embryonic development and cell proliferation. Mol Cell Biol. 2004 Jul;24(13):5863-74

Vulsteke V, Beullens M, Boudrez A, Keppens S, Van Eynde A, Rider MH, Stalmans W, Bollen M. Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. J Biol Chem. 2004 Mar 5;279(10):8642-7

Comerford KM, Leonard MO, Cummins EP, Fitzgerald KT, Beullens M, Bollen M, Taylor CT. Regulation of protein phosphatase 1gamma activity in hypoxia through increased interaction with NIPP1: implications for cellular metabolism. J Cell Physiol. 2006 Oct;209(1):211-8

Deckert J, Hartmuth K, Boehringer D, Behzadnia N, Will CL, Kastner B, Stark H, Urlaub H, Lührmann R. Protein composition and electron microscopy structure of affinity-purified human spliceosomal B complexes isolated under physiological conditions. Mol Cell Biol. 2006 Jul;26(14):5528-43

Roy N, Van Eynde A, Beke L, Nuytten M, Bollen M. The transcriptional repression by NIPP1 is mediated by Polycomb group proteins. Biochim Biophys Acta. 2007 Sep-Oct;1769(9-10):541-5

Shi Y, Manley JL. A complex signaling pathway regulates SRp38 phosphorylation and pre-mRNA splicing in response to heat shock. Mol Cell. 2007 Oct 12;28(1):79-90

Nuytten M, Beke L, Van Eynde A, Ceulemans H, Beullens M, Van Hummelen P, Fuks F, Bollen M. The transcriptional repressor NIPP1 is an essential player in EZH2-mediated gene silencing. Oncogene. 2008 Feb 28;27(10):1449-60

Tanuma N, Kim SE, Beullens M, Tsubaki Y, Mitsuhashi S, Nomura M, Kawamura T, Isono K, Koseki H, Sato M, Bollen M, Kikuchi K, Shima H. Nuclear inhibitor of protein phosphatase-1 (NIPP1) directs protein phosphatase-1 (PP1) to dephosphorylate the U2 small nuclear ribonucleoprotein particle (snRNP) component, spliceosome-associated protein 155 (Sap155). J Biol Chem. 2008 Dec 19;283(51):35805-14

Hendrickx A, Beullens M, Ceulemans H, Den Abt T, Van Eynde A, Nicolaescu E, Lesage B, Bollen M. Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol. 2009 Apr 24;16(4):365-71

Bollen M, Peti W, Ragusa MJ, Beullens M. The extended PP1 toolkit: designed to create specificity. Trends Biochem Sci. 2010 Aug;35(8):450-8

Van Dessel N, Beke L, Görnemann J, Minnebo N, Beullens M, Tanuma N, Shima H, Van Eynde A, Bollen M. The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets. Nucleic Acids Res. 2010 Nov;38(21):7500-12


Minnebo N, Van Dessel N, Beullens M, van Eynde A, Bollen M. PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):975-978.





SMYD2 (SET and MYND domain containing 2) Hitoshi Tsuda, Shuhei Komatsu

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan

(HT), Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of

Medicine, Kyoto, Japan (SK)


Online updated version : http://AtlasGeneticsOncology.org/Genes/SMYD2ID47098ch1q32.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI SMYD2ID47098ch1q32.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: HSKM-B; KMT3C; MGC119305;

ZMYND14

HGNC (Hugo): SMYD2

Location: 1q32.3

DNA/RNA

Description

55913 bp, 12 exons.

Transcription

1689 bp mRNA.

Protein

Description

433 amino acids. The protein contains SET domain,

MYND domain/zinc-finger motif, and cysteine-rich

post-SET domain. The SET domain is split into two

segments by a MYND domain.

Expression

Wide, highly expressed in heart, brain, liver,

kidney, thymus, ovary, embryonic tissues (heart,

hypothalamus) (Brown et al., 2006).

Localisation

Cytoplasmic and nucleus (Brown et al., 2006).

Function

Regulation of transcription as a lysine

methyltransferase for histone 3, lysine 36 (H3K36)

and inhibition of p53's transactivation activity as a

lysine methyltransferase for lysine 370 (K370) of

p53 through the SET domain (Brown et al., 2006;

Huang et al., 2006). Possibly promotion of cell

proliferation and/or differentiation through its

overexpression/activation-induced inhibition of

p53's transactivation activity. Methylation of

retinoblastoma (RB) tumor suppressor at lysine

860, that is regulated during cell cycle progression,

cellular differentiation ,and in response to DNA

damage (Saddic et al., 2010). RB monomethylation

at lysine 860 provides a direct binding site for the

transcription repressor L3MBTL1. Through

interaction with HSP90alpha, SMYD2 histone

methyltransferase activity and specificity for

histone H3 at lysine 4 (H3K4) are enhanced in vitro

(Abu-Farha et al., 2008). SMYD2 gain of function

is correlated with the upregulation of 37 and down

regulation of 4 genes, the majority of which are

involved in the cell cycle, chromatin remodelling,

and transcriptional regulation (Abu-Farha et al.,

2008).

SMYD2 (SET and MYND domain containing 2) Tsuda H, Komatsu S


Homology

Xenopus laevis, Zebrafish, Chicken, Gray short-

tailed opossum, Mouse, Rat, Rabbit, Pig, Horse,

Cattle, Dog, White-tufted-ear marmoset, Rhesus

monkey, Sumatran orangutan, Chimpanzee.

Mutations

Note

Not found.

Implicated in

Esophageal squamous cell carcinoma (ESCC)

Note

Frequent overexpression of SMYD2 mRNA and

protein was observed in KYSE150 cells with

remarkable amplification at 1q32-q41.1 and other

ESCC cell lines (11/43 lines, 25.6%).

Overexpression of SMYD2 protein was frequently

detected in primary tumor samples of ESCC

(117/153 cases, 76.5%) as well and significantly

correlated with gender, venous invasion, the pT

category in the tumor-lymph node-metastasis

classification and status of recurrence. Patients with

SMYD2-overexpressing tumors had a worse overall

rate of survival than those with non-expressing

tumors. Knockdown of SMYD2 expression

inhibited and ectopic overexpression of SMYD2

promoted the proliferation of ESCC cells in a TP53

mutation-independent but SMYD2 expression

dependent manner (Komatsu et al., 2009).

Thyroid carcinoma and benign thyroid nodule

Note

Using differential display-polymerase chain

reaction method, the gene expression differences

between benign thyroid nodules (BTNs) and

follicular and classic variants of papillary thyroid

carcinoma (PTC) were evaluated in a group of 42

patients (15 BTNs, 14 follicular variant of PTC and

13 classic variant of PTC). SMYD2 had lower

expression in both carcinoma groups than in BTNs

(Igci et al., 2011).

Breast cancer

Note

Expression of a group of three genes (MTSS1,

RPL37, and SMYD2) evaluated by real-time PCR

was shown to be a potential candidate to predict

response to neoadjuvant chemotherapy (4 cycles of

doxorubicin and cyclophosphamide) in breast

cancer patients (Barros Filho et al., 2010).

References Brown MA, Sims RJ 3rd, Gottlieb PD, Tucker PW. Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer. 2006 Jun 28;5:26

Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL. Repression of p53 activity by Smyd2-mediated methylation. Nature. 2006 Nov 30;444(7119):629-32

Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics. 2008 Mar;7(3):560-72

Komatsu S, Imoto I, Tsuda H, Kozaki KI, Muramatsu T, Shimada Y, Aiko S, Yoshizumi Y, Ichikawa D, Otsuji E, Inazawa J. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis. 2009 Jul;30(7):1139-46

Barros Filho MC, Katayama ML, Brentani H, Abreu AP, Barbosa EM, Oliveira CT, Góes JC, Brentani MM, Folgueira MA. Gene trio signatures as molecular markers to predict response to doxorubicin cyclophosphamide neoadjuvant chemotherapy in breast cancer patients. Braz J Med Biol Res. 2010 Dec;43(12):1225-31

Saddic LA, West LE, Aslanian A, Yates JR 3rd, Rubin SM, Gozani O, Sage J. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem. 2010 Nov 26;285(48):37733-40

Igci YZ, Arslan A, Akarsu E, Erkilic S, Igci M, Oztuzcu S, Cengiz B, Gogebakan B, Cakmak EA, Demiryurek AT. Differential expression of a set of genes in follicular and classic variants of papillary thyroid carcinoma. Endocr Pathol. 2011 Jun;22(2):86-96


Tsuda H, Komatsu S. SMYD2 (SET and MYND domain containing 2). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):979-980.

Leukaemia Section Mini Review




t(1;9)(p34;q34) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,

France (JLH)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0109p34q34ID2143.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t0109p34q34ID2143.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology

Disease

B cell progenitor acute lymphoid leukemia (B-

ALL)

Epidemiology

Only one case to date, a 22-year-old male patient

(Hidalgo-Curtis et al., 2008).

Prognosis

Complete remission was obtained, a relapse

occured. The patient was in complete remission 6

years after diagnosis.

Cytogenetics

Cytogenetics morphological

The translocation was found solely in the main

clone, and a subclone also showed a +21.

Genes involved and proteins

SFPQ

Location

1p34.3

Protein

DNA- and RNA binding protein; pre-mRNA

splicing factor; binds specifically to intronic

polypyrimidine tracts.

Role in transcription and RNA splicing: SFPQ,

often called PSF, is a coactivator of Fox proteins,

which bind the RNA element UGCAUG and

regulate alternative pre-mRNA splicing. SFPQ and

NONO are part of a large complex with all the

snRNPs. SFPQ is phosphorylated by GSK3, which

prevents SFPQ from binding PTPRC (CD45

antigen) pre-mRNA. The association of HNRNPL

and SFPQ drives the change in PTPRC (CD45)

splicing (CD45 undergoes alternative splicing in

response to T-cell activation).

DNA damage: DNA double-strand breaks are

repaired via nonhomologous DNA end joining and

homologous recombination. The SFPQ/NONO

heterodimer enhances DNA strand break rejoining.

SFPQ has homologous recombination and non-

homologous end joining activities. SFPQ is

associated with the RAD51 protein complex.

Role in transcriptional regulation: SFPQ and PTK6

(protein tyrosine kinase 6, also called BRK) play a

role downstream of the EGF receptor (EGFR).

SFPQ and NONO form complexes with the

androgen receptor (AR) and modulate its

transcriptional activity (Huret, 2011).

ABL1

Location

9q34

Protein

ABL1, when localized in the nucleus, induces

apoptosis after DNA damage. Cytoplasmic ABL1

has a possible function in adhesion signalling

(Turhan, 2008).

Result of the chromosomal anomaly

Hybrid gene

Description

Break in the 3' of SFPQ exon 10 and reunion with

ABL1 intron 3; a further mRNA splicing gives rise

t(1;9)(p34;q34) Huret JL


to a chimeric SFPQ exons 1 to 9 (nucleotide 2072)

fused to ABL1 exon 4 to end.

Fusion protein

Description

1609 amino acids fusion protein of 174 kDa; retains

most of SFPQ, including the RNA recognition

motifs and the coiled-coil domain (dimerization

domain), fused to the SH2 domain of ABL1; the

fusion protein also includes the SH1 domain

(tyrosine kinase activity), the nuclear localization

domain, and the actin binding domain of ABL1.

Oncogenesis

Constitutive tyrosine kinase activation is likely,

through dimerization of the fusion protein.

References Huret JL.. SFPQ (splicing factor proline/glutamine-rich). Atlas Genet Cytogenet Oncol Haematol. January 1999. http://atlasgeneticsoncology.org/Genes/PSFID167.html

Hidalgo-Curtis C, Chase A, Drachenberg M, Roberts MW, Finkelstein JZ, Mould S, Oscier D, Cross NC, Grand FH.. The t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA processing proteins SFPQ (PSF) and CPSF6 to ABL and FGFR1. Genes Chromosomes Cancer. 2008 May;47(5):379-85.

Turhan AG.. ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1). Atlas Genet Cytogenet Oncol Haematol. August 2008. http://atlasgeneticsoncology.org/Genes/ABL.html


Huret JL. t(1;9)(p34;q34). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):981-982.

Deep Insight Section




Understanding the structure and function of ASH2L Paul F South, Scott D Briggs

Department of Biochemistry and Purdue University Center for Cancer Research, Purdue University,

West Lafayette, Indiana 47907, USA (PFS, SDB)

Published in Atlas Database: June 2011

Online updated version : http://AtlasGeneticsOncology.org/Deep/ASH2LFunctionID20097.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI ASH2LFunctionID20097.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Introduction ASH2L (Absent, Small, or Homeotic-Like) encodes

the protein ASH2L which was named after the

Drosophila protein Ash2 a known regulator of

HOX genes (Ikegawa et al., 1999). ASH2L is

known to be a component of histone H3 lysine 4

(H3K4) methyltransferase complexes and H3K4

methylation is commonly associated with active

gene transcription (Ikegawa et al., 1999; Hughes et

al., 2004; Dou et al., 2006; Steward et al., 2006;

Cho et al., 2007). Previous studies have shown that

disruption of ASH2L leads to a decrease in H3K4

trimethylation, which negatively affects gene

expression (Dou et al., 2006; Steward et al., 2006).

Furthermore, disruption of ASH2L or the

methyltransferases involved in H3K4 methylation

can lead to oncogenesis mostly through the

regulation of HOX gene expression (Hughes et al.,

2004; Lüscher-Firzlaff et al., 2008). Interestingly,

overexpression of ASH2L leads to tumor

proliferation and knock-down of ASH2L inhibits

tumorigenesis, which is the reason why ASH2L is

thought to be an oncoprotein (Lüscher-Firzlaff et

al., 2008). Understanding the role that ASH2L

plays in facilitating proper H3K4 methylation may

provide insight into how disruption of ASH2L can

lead to abnormal cell proliferation and oncogenesis.

ASH2L function Genetic information and sequence alignments

identified ASH2L to be homologous to the

transcriptional activator Drosophila Ash2 (Wang et

al., 2001; Ikegawa et al., 1999). Drosophila Ash2

(Absent, small, and homeotic discs) is a member of

the Trithorax family, known regulators of

developmental homeotic genes (LaJeunesse and

Shearn, 1995). Mammalian ASH2L is known to be

important for development because ASH2L-null

mice exhibit an embryonic lethal phenotype (Stoller

et al., 2010). Work has established ASH2L as a

core component of the H3K4 methyltransferase

complexes MLL1-4 and SET1A and SET1B.

Furthermore, ASH2L containing methyltransferase

complexes are shown to be important for the

maintenance of HOX gene expression by binding to

HOX gene promoters and by adding H3K4 di- and

trimethylation (Fig. 1) (Hughes et al., 2004; Tan et

al., 2008; Yates et al., 2010). HOX gene expression

is important for proper development and

differentiation, and disruption in H3K4 methylation

leads to defects in HOX gene expression and the

development of cancer (Tan et al., 2008; Hess,

2006; Rampalli et al., 2007; MacConaill et al.,

2006; Hughes et al., 2004).

Biochemical data has shown that ASH2L is found

in a methyltransferase core complex composed of

ASH2L, RBBP5, DPY30, WDR5, and the catalytic

SET domain containing protein (Fig. 1). This core

complex is highly conserved and similar to the

budding yeast Set1 complex that consists of Set1

(MLL/SET1), Bre2 (ASH2L), Swd1 (RBBP5),

Swd3 (WDR5), Swd2 (WDR82), Sdc1 (DPY-30),

Spp1 (CFP1/CGBP). ASH2L is also known to

associate with numerous additional factors listed in

Table 1. Many of these additional factors are

thought to associate with ASH2L and the H3K4

methyltransferase complexes to target the complex

to specific sites within the genome (Stoller et al.,

2010; Cho et al., 2007; Steward et al., 2006; Dou et

al., 2006; Hughes et al., 2004).

Understanding the structure and function of ASH2L South PF, Briggs SD


Figure 1. ASH2L functions in a histone methyltransferase complex. The role of ASH2L within the MLL histone H3K4 methyltransferase complex. ASH2L interacts with RBBP5 and DPY-30 increasing the activity of the MLL complex. Histone H3K4 methylation in mammals peaks at the start sight of open reading frames and is important in active transcription. Knock-down of ASH2L in mammalian cells results in a decrease in H3K4 trimethylation and changes in gene expression.

ASH2L interacting protein Function

MLL1-4/ SET1 A and B Catalytic core; Histone methyltransferase (HMT)

RBBP5 Component of HMT complex

DPY-30 Component of HMT complex

WDR5 Component of HMT complex

CXXC1 Component of HMT complex

C16orf53/PA1 Glutamate rich coactivator

C17orf49 Unknown

CHD8 Chromatin remodeling factor

E2F6 Transcription factor

HCFC1 Host cell factor

IN080C Unknown

KDM6A H3K27 demethylase

KIAA1267 Unknown

LAS1L Unknown

MAX Transcription factor

MCRS1 Transcriptional repressor

MEN1 Tumor suppressor

MYST1/MOF Histone acetyltransferase

NCOA6 Transcriptional co-activator

PAXIP1/PTIP Transcription factor

PELP1 Transcription factor

PHF20 Unknown

PRP31 Component of spliceosome

RING2 E3-ligase

SENP3 Sumo-specific protease

TAF1, 4, 6, 7, 9 TATA-box binding proteins

TEX10 Unknown

TBX1 Transcription factor

Table 1.

http://atlasgeneticsoncology.org/Genes/E2F6ID521.html

http://atlasgeneticsoncology.org/Genes/MEN1ID148.html



ASH2L and Bre2 subunits are important for proper

histone methylation. Studies done in yeast show

that deletion of the ASH2L homolog BRE2 leads to

a complete loss of H3K4 trimethylation and

reductions in mono- and dimethylation (Dehé et al.,

2006; South et al., 2010; Roguev et al., 2001). In

addition, knock-down of ASH2L using siRNA

globally decreases H3K4 trimethylation (Steward et

al., 2006; Dou et al., 2006). These data suggest that

ASH2L may act in a similar manner to yeast Bre2.

From these studies it is clear that ASH2L is playing

an important role in histone methyltransferase

complexes in order to maintain proper H3K4

methylation and gene expression (Patel et al., 2009;

Roguev et al., 2001).

Alternative to ASH2L's function in H3K4

methylation ASH2L may also be playing a role in

endosomal trafficking (Xu et al., 2009). ASH2L,

DPY-30 and WDR5 were originally implicated in

endosomal trafficking when siRNA knock-down of

these genes increased the amount of internalized

CD8-CIMPR and overexpression increased the

amount of cells displaying a altered CIMPR

distribution (Xu et al., 2009). This affect was

limited to components of H3K4 methyltransferases

and not to other methyl marks such as lysine 9 (Xu

et al., 2009). The mechanism in which ASH2L and

other components of H3K4 methyltransferase

complexes modulate endosomal trafficking remains

unclear. However, two possible mechanisms have

been suggested, one is that the H3K4

methyltransferase components are part of an

unknown complex that regulates trafficking, or that

changes in H3K4 methylation lead to changes in

expression of another regulating factor (Xu et al.,

2009).

ASH2L structure One way to better understand the function of

ASH2L is to determine the role of specific domains

within ASH2L in facilitating H3K4 methylation.

There are three known isoforms of ASH2L (Wang

et al., 2001). Isoform 1 is considered the canonical

sequence and consists of 628 amino acids (Wang et

al., 2001). Isoform 2 is missing amino acids 1-94

and 541-573 from isoform 1 (Wang et al., 2001).

Isoform 3 is missing the amino acids 1-94 from

isoform 1 (Fig. 2) (Wang et al., 2001). There are

four identified domains within ASH2L which

include a N-terminus containing a PHD finger and a

winged helix motif (WH) and the C-terminus

containing a SPRY domain and a newly identified

Sdc1 DPY-30 Interacting domain (SDI) (Fig. 2)

(Wang et al., 2001; Roguev et al., 2001; South et

al., 2010; Sarvan et al., 2011; Chen et al., 2011).

Interestingly, the domains with known biological

function are the C-terminal SDI domain, which is

responsible for the interaction with another histone

methyltransferase component DPY-30 and the

winged helix motif which binds to DNA (South et

al., 2010; Sarvan et al., 2011; Chen et al., 2011).

The function of the SDI domain was determined

using in vitro binding experiments. ASH2L was

shown to directly interact with DPY-30 without any

additional MLL or Set1 complex components

(South et al., 2010). The function of the SDI

domain is conserved from yeast to humans because

the yeast ASH2L homolog Bre2 was also shown to

interact with the DPY-30 homolog Sdc1 (South et

al., 2010). There are conserved hydrophobic

residues in both the SDI domain of ASH2L and the

Dpy-30 domain of DPY-30 that are important for

binding, which suggests that the interaction

between the SDI domain of ASH2L and the DPY-

30 domain of DPY-30 is through hydrophobic

interactions (South et al., 2010). In addition,

binding affinities between ASH2L and DPY-30, as

well as ASH2L and RBBP5 have been determined

by sedimentation velocity analytical

ultracentrifugation showing dissociation constants

of 0.1 μM and 0.75 μM respectively (Patel et al.,

2009). Interestingly, in yeast the ASH2L homolog

Bre2 must interact with Sdc1 through the SDI

domain to interact with the yeast Set1 histone

methyltransferase complex (South et al., 2010). In

contrast, in vitro experiments have shown ASH2L

does not require DPY-30 to interact with MLL

complex. To better understand how ASH2L

interacts with MLL, in vivo studies must be done to

determine if DPY-30 is required for ASH2L

interaction. However, it is quite possible that the

yeast and human complexes assemble differently.

Figure 2. ASH2L has three known isoforms. Schematic model of the three known isoforms of ASH2L and the amino acid

sequence changes compared to the canonical isoform 1 (aa 1-628). The positions of known domains within ASH2L are displayed. PHD finger (aa 95-161), WH motif (aa 162-273), SPRY domain (aa 360-583), and SDI domain (aa 602-628). Isoform

2 and 3 are numbered according to isoform 1.



The N-terminal winged helix (WH) motif was

recently discovered when the crystal structure of the

N-terminus of ASH2L was solved (Sarvan et al.,

2011; Chen et al., 2011). Using in vitro DNA

binding analyses as well as chromatin

immunoprecipitation, it was determined that

ASH2L can bind DNA at the HS2 promoter region

and the β-globin locus as well as non-specific DNA

sequence (Sarvan et al., 2011; Chen et al., 2011).

The DNA binding activity of ASH2L promotes

H3K4 methylation and gene expression at the β-

globin locus by 50% when overexpressed in a cell

line where ASH2L is knocked-down by siRNA

(Sarvan et al., 2011). In addition, chromatin

immunoprecipitation followed by a tiling array

(ChIP-chip) analysis shows that disruption of the

winged helix motif causes mis-localization of

ASH2L (Chen et al., 2011). It was also shown that

the DNA binding activity of the N-terminus of

ASH2L increases when the C-terminal SPRY and

SDI domains are present (Chen et al., 2011).

Altogether, these data suggests that multiple

domains in ASH2L may contribute to its ability to

bind chromatin. However, more work will be

needed to clearly establish the function of each

domain.

The largest of the three identified domains within

ASH2L is the SPRY domain, which is also

conserved from yeast to humans. SPRY domains

were originally named after the SPIa kinase and the

RYanodine receptor proteins in which it was first

identified (Rhodes et al., 2005). Multiple crystal

structures have been solved for proteins that contain

an SPRY domain. Crystal structures of SPRY

domain containing proteins show primarily a β-

sandwich structure with extending loops (Woo et

al., 2006b; Kuang et al., 2009; Filippakopoulos et

al., 2010; Simonet et al., 2007). The SPRY domain

is thought to be a specific protein-protein

interaction domain with specific partners, but

instead of recognizing a particular motif or

interaction domain the SPRY domain binds to

interaction partners using non-conserved binding

loops (Filippakopoulos et al., 2010; Woo et al.,

2006b; Woo et al., 2006a). SPRY domain-

containing proteins are involved in a wide array of

functions including RNA metabolism, calcium

release, and developmental processes (Woo et al.,

2006b; Kuang et al., 2009; Filippakopoulos et al.,

2010; Simonet et al., 2007; Woo et al., 2006a).

Recent work has shown that the C-terminus of

ASH2L that contains the SPRY domain and the

SDI domain are able to interact with the other MLL

complex member RBBP5 in vitro (Avdic et al.,

2011). This interaction is most likely through the

SPRY domain and not the SDI domain, though

further work would need to be done to better map

this interaction.

ASH2L also contains a putative Plant Homeo

Domain (PHD) finger in its N-terminus (Wang et

al., 2001). PHD fingers are a family of zinc finger

domains that are known to bind to both modified

and unmodified histone tails (Bienz, 2006; Mellor,

2006). The structure of PHD fingers shows that

conserved cysteine and histidine residues bind to

Zn2+

ions (Champagne et al., 2008; van Ingen et al.,

2008; Champagne and Kutateladze, 2009). PHD

fingers generally form a globular fold, consisting of

a two-stranded beta-sheet and an alpha-helix. Loop

regions of PHD fingers tend to vary giving rise to

specificity of the domain. Some PHD fingers are

considered to be readers of epigenetic marks by

binding to specific modifications or sites on

histones to stabilize or localize an interaction

(Mellor, 2006). Primarily, PHD fingers have been

shown to interact with trimethylated histone

residues such as trimethylated histone H3 lysine 4

and lysine 9 (Mellor, 2006). There is no known

function attributed to the PHD finger in ASH2L,

though in conjunction with the winged helix motif

it may be necessary for DNA binding. However, the

PHD finger may also be needed in binding to MLL,

other MLL/SET1 components, or recognizing a

specific histone modification or for binding to a

histone tail. Additional studies are needed to

determine how the PHD finger of ASH2L and the

SPRY domain may help the MLL and Set1

methyltransferase complexes interact and catalyze

H3K4 methylation.

Conclusion Currently, relatively little is known about the

contribution of ASH2L to facilitate and or regulate

the degree of methylation along the eukaryotic

genome, but disruption of ASH2L and H3K4

methylation both appear to play a key role in

oncogenesis (Lüscher-Firzlaff et al., 2008; Hess,

2006). Interestingly, recent work has suggested that

ASH2L in combination with WDR5 and RBBP5

exhibits H3K4 methyltransferase activity (Cao et

al., 2010; Patel et al., 2009; Patel et al., 2011). In

addition, this catalytic activity is not dependent on

the SET domain containing proteins such as MLL1

(Patel et al., 2009; Cao et al., 2010; Patel et al.,

2011). One report shows the catalytic activity of the

ASH2L, WDR5, RBBP5, DPY-30 complex in an in

vitro histone methyltransferase assay is observed

but only after eight hours of incubation (Patel et al.,

2009; Patel et al., 2011). In contrast, more

methyltransferase activity and much shorter

incubation times are required when these

components are incubated with the MLL1 SET

domain containing methyltransferase (Patel et al.,

2009; Patel et al., 2011). This indicates the sub-

complex has poor catalytic activity when the main

catalytic SET domain-containing subunit is not

present in the reaction. However, Cao et al. shows

that only ASH2L/RBBP5 heterodimer is needed for

weak H3K4 methyltransferase activity (Cao et al.,

2010). Because ASH2L, WDR5, RBBP5, and



DPY-30 complex does not contain a known

methyltransferase domain, more work needs to be

done to determine if a new class of

methyltransferase has been identified and whether

or not this methyltransferase activity is biologically

relevant.

ASH2L is found to be over abundant in many

cancer cell lines and knock-down of ASH2L by

siRNA can prevent tumorigenesis (Lüscher-Firzlaff

et al., 2008). ASH2L is important for proper H3K4

methylation but how ASH2L contributes to the

distribution and degree of methylation and its role

in gene expression remains unclear. To better

understand the role of ASH2L in methylation and

gene expression several questions need to be

addressed. What is the mechanism of interaction

that contributes to ASH2L's interaction with histone

methyltransferase complexes? What is ASH2L's

role in regulating the degree of methylation along

genes and what genes are affected by changes in

ASH2L? Additional structural studies will help

address the mechanism of how ASH2L interacts

with other methyltransferase complex members and

microarray experiments will be needed to determine

the genes that are affected by changes in ASH2L

expression levels. Addressing these questions could

provide valuable information for the development

specific inhibitors for the treatment of various

cancers.

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Rhodes DA, de Bono B, Trowsdale J.. Relationship between SPRY and B30.2 protein domains. Evolution of a component of immune defence? Immunology. 2005 Dec;116(4):411-7. (REVIEW)

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Dehe PM, Dichtl B, Schaft D, Roguev A, Pamblanco M, Lebrun R, Rodriguez-Gil A, Mkandawire M, Landsberg K, Shevchenko A, Shevchenko A, Rosaleny LE, Tordera V, Chavez S, Stewart AF, Geli V.. Protein interactions within the Set1 complex and their roles in the regulation of histone 3 lysine 4 methylation. J Biol Chem. 2006 Nov 17;281(46):35404-12. Epub 2006 Aug 18.

Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG.. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol. 2006 Aug;13(8):713-9. Epub 2006 Jul 30.

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Steward MM, Lee JS, O'Donovan A, Wyatt M, Bernstein BE, Shilatifard A.. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol. 2006 Sep;13(9):852-4. Epub 2006 Aug 6.

Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH.. Structural and functional insights into the B30.2/SPRY domain. EMBO J. 2006a Mar 22;25(6):1353-63. Epub 2006 Feb 23.

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Tan CC, Sindhu KV, Li S, Nishio H, Stoller JZ, Oishi K, Puttreddy S, Lee TJ, Epstein JA, Walsh MJ, Gelb BD.. Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription. Proc Natl Acad Sci U S A. 2008 May 27;105(21):7472-7. Epub 2008 May 21.

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Case Report Section Paper co-edited with the European LeukemiaNet




A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature Sarah M Heaton, Frederick Koppitch, Anwar N Mohamed

Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit

Medical Center, Detroit MI, USA (SMH, FK, ANM)

Published in Atlas Database: March 2011

Online updated version : http://AtlasGeneticsOncology.org/Reports/t0412HeatonID100051.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t0412HeatonID100051.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics

Age and sex

57 years old male patient.

Previous history

No preleukemia. Previous malignancy Hodgkin's

Lymphoma, stage IVA at age 25 year, treated with

ABVD for 12 months. Tumor mass in the upper

cervical spine diagnosed at age 27 year, treated with

laminectomy and five doses of radiation. No inborn

condition of note.

Organomegaly

No hepatomegaly, no splenomegaly, no enlarged

lymph nodes, no central nervous system

involvement.

Blood WBC : 0.8X 10

9/l

HB : 9.7g/dl

Platelets : 21.0X 109/l

Blasts : 18%

Bone marrow : Variably cellular with 20%

myeloblasts and dysplastic changes in the erythroid

and myeloid cell lines.

Cyto-Pathology Classification

Cytology

His bone marrow showed 60% blasts, and

dysplastic changes were noted in the erythroid and

myeloid cell lines.

Immunophenotype

Flow cytometry (FCM) revealed that the blasts

were of myeloid lineage expressing CD13, CD33,

CD34, CD117, HLA-DR, and CD56.

Diagnosis

Acute myeloid leukemia (AML) with dysplastic

changes.

Survival

Date of diagnosis: 08-2007

Treatment

He was treated with Idarubicin+Ara-c (3+7)

regimen. Because of 15% residual blasts in bone

marrow, patient received additional 2+5 therapy,

and then he underwent consolidation with Ara-C.

Result of karyotype: 46,XY[20]. On April 2008, the

patient received a matched unrelated female donor

stem cell transplant (SCT). 30 days post transplant;

bone marrow revealed no morphological evidence

of leukemia and the karyotype was 46,XX[20]. On

June 2008; patient developed pancytopenia; WBC:

2.2 x 109/l; Hb: 11.6 g/dl; platelets: 18.0 x 10

3/l. His

bone marrow showed an increased dysplastic

changes and <5% blasts, suggestive of possible

early relapse. The karyotype became abnormal (see

below). On June 2010; bone marrow was

hypocellular with 20% blasts and dysplastic

changes in the erythroid and myeloid lineages.

FCM revealed myeloblasts expressing CD4, CD7,

CD33, CD34, CD56, CD117 and HLA-DR.

myeloperoxidase was negative. Non-specific

esterase was positive in occasional blasts.

Cytology: AML possibly of monocytic origin

(AML-M5).

Treatment related death : no

A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature

Heaton SM, et al.


Figure 1. G-banded karyotype showing the balanced t(4;12)(q12;p13) translocation.

Figure 2. FISH on abnormal metaphases; (A) Metaphase hybridized with LSI 4q12 tricolor DNA probe showed a translocation of

PDGFRA (SA) to derivative chromosome 12 (arrow), with the dual fusion of spectrunOrange (SO) and spectrunGreen (SG) remained on derivative 4. (B) Metaphase hybridized with LSI ETV6/RUNX1 ES dual color probe revealed a split of ETV6 (SG)

with the smaller signal being translcated to derivative 4 (arrows). (C) Metaphase hybridized with both LSI 4q12 and ETV6/RUNX1 probes showed PDGFRA (SA) translocted to derivative 12 adjacent to ETV6 locus (arrows).

Phenotype at relapse: M5-AML

Status: Alive. Last follow up: 06-2010.

Survival: 24 months

Karyotype

Sample: Bone marrow

Culture time: 24 and 48h with 10% conditioned

medium

Banding: GTG

Results

46,XY,t(4;12)(q12;p13)[6]/46,XX[14] in June 2008

(post transplant)

Karyotype at Relapse

46,XY,t(4;12)(q12;p13)[12]/

46,idem,del(7)(q22q36)[4]/ 47,idem,+19[2]/

46,XX[2], consistent with the recurrence and clonal

evolution of the leukemic clone.

Other molecular cytogenetics technics

Fluorescence in situ hybridization (FISH) using LSI

4q12 tricolor and LSI ETV6/RUNX1 ES dual color

DNA probes were performed (Abbott Molecular.

Downers Grove, IL) on the abnormal metaphase

cells.

Other molecular cytogenetics results

Translocation of the PDGFRA gene in Toto,

spectrunAqua (SA), to derivative 12 and

colocalized with centromeric region of ETV6;

Break within ETV6 gene locus, sepctrunGreen

(SG) and the telomeric region of ETV6 translocated

to derivative 4 (Figure 2 A-C).

Comments Acute leukemia with t(4;12)(q11-q12;p13) is a rare,

nonrandom event with an estimated incidence of

0.6% among adults according to Harada et al.

(Harada et al., 1997). This translocation is seen

mostly in adult AML but less frequent in pediatric

ALL (Hamaguchi et al., 1999). A review of the

literature revealed at least twenty-two additional

cases with a t(4;12)(q11-q12;p13); eighteen adults

and four children. The male to female ratio is 1.5:1

(1.7:1 in adults and 1:1 in children). The majority

of patients are adults, aged 18 to 82 with the mean

being 58.9 years old (Harada et al., 1995; Harada et

al., 1997; Ma et al., 1997; Cools et al., 1999;

Hamaguchi et al., 1999; Chaufaille et al., 2003;

Manabe et al., 2010). Four children have been

reported, aged 3-14 years old, of which three had

ALL and the oldest had AML (Harada et al., 1997).

Among the 23 cases including our case with t(4;12)

leukemia; 19 had AML; 3 ALL, and one

unclassified leukemia. Common features to t(4;12)

AML include dysplasia of three hematopoietic

lineages (erythroid, myeloid and megakaryocytic),

low or absent myeloperoxidase activity, basophilia

and a pseudo-lymphoid morphology. The surface

markers of the blasts show positivity for CD7,

CD13, CD33, CD34 and HLA DR, suggesting that

the leukemic cells have an immature myeloid stem

A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature

Heaton SM, et al.


cell origin (Harada et al., 1995; Ma et al., 1997;

Hamaguchi et al., 1999). Of the reported t(4;12)

AML cases; seven were characterized as AML-M0

and four AML-M1. Previous reports suggest that

less than 50% of cases achieve remission with

intensive induction chemotherapy. Of the patients

who do not achieve morphologic remission, none

survived beyond six months (Hamaguchi et al.,

1999; Chaufaille et al., 2003; Manabe et al., 2010).

The breakpoint at 12p13 in t(4;12) AML is located

within or near the ETV6 gene locus. The ETV6

gene has been implicated in both myeloid and

lymphoid malignancies (Wlodarska et al., 1998).

ETV6 belongs to the ETS family of transcription

factors and has two important domains: HLH and

an ETS DNA binding domain. Cools et al, found

the t(4;12) caused the ETV6 gene recombined to

CHIC2 (formerly BLT) (Cools et al., 1999). A

number of genes have been mapped to the band

4q12 including mac25, PDGFRA, AFP, and a beta-

sarcoglycan gene (Hamaguchi et al., 1999).

The case reported here shared some features to

those reported in the literature including positivity

for CD7, CD33, CD34, CD117 and HLA-DR, lack

of myeloperoxidase activity and dysplastic bone

marrow. Unlike other reported cases, bone marrow

basophilia and high platelets were not found.

Clearly in our case, FISH showed a break within

ETV6/12p13 gene, and colocalization of PDGFR1

gene to derivative 12 next to 5’ ETV6 region.

References Harada H, Asou H, Kyo T, Asaoku H, Iwato K, Dohy H, Oda K, Harada Y, Kita K, Kamada N. A specific chromosome abnormality of t(4;12)(q11-12;p13) in CD7+ acute leukaemia. Br J Haematol. 1995 Aug;90(4):850-4

Harada H, Harada Y, Eguchi M, Dohy H, Kamada N. Characterization of acute leukemia with t(4;12). Leuk Lymphoma. 1997 Mar;25(1-2):47-53

Ma SK, Lie AK, Au WY, Wan TS, Chan LC. CD7+ acute myeloid leukaemia with 'mature lymphoid' blast morphology, marrow basophilia and t(4;12)(q12;p13) Br J Haematol. 1997 Dec;99(4):978-80

Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den Berghe H, Marynen P. Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. Blood. 1998 Feb 15;91(4):1399-406

Cools J, Bilhou-Nabera C, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P. Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). Blood. 1999 Sep 1;94(5):1820-4

Hamaguchi H, Nagata K, Yamamoto K, Kobayashi M, Takashima T, Taniwaki M. A new translocation, t(2;4;12)(p21;q12;p13), in CD7-positive acute myeloid leukemia: a variant form of t(4;12). Cancer Genet Cytogenet. 1999 Oct 15;114(2):96-9

Chauffaille Mde L, Fermino FA, Pelloso LA, Silva MR, Bordin JO, Yamamoto M. t(4;12)(q11;p13): a rare chromosomal translocation in acute myeloid leukemia. Leuk Res. 2003 Apr;27(4):363-6

Manabe M, Nakamura K, Inaba A, Fujitani Y, Kosaka S, Yamamura R, Inoue A, Hino M, Senzaki H, Ohta K. A rare t(4;12)(q12;p13) in an adolescent patient with acute myeloid leukemia. Cancer Genet Cytogenet. 2010 Jul 1;200(1):70-2


Heaton SM, Koppitch F, Mohamed AN. A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):989-991.





Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome: Case 0002M Kavita S Reddy

Kaiser Permanente Southern California, 4580 ElectronicPlace, Los Angeles, CA 90039, USA (KSR)


Online updated version : http://AtlasGeneticsOncology.org/Reports/der918Case2ReddyID100053.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI der918Case2ReddyID100053.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics

Age and sex


Previous history

Preleukemia. Previous malignancy Bladder cancer,

status post removal and BCG treatment. No inborn

condition of note.

Organomegaly

No hepatomegaly, no splenomegaly, no enlarged


involvement.

Blood WBC : 1.9X 10

9/l

HB : 10.9g/dl

Platelets : 57X 109/l


Cytology

MDS (normocellular marrow with

dysmegakaryopoiesis and dysgranulopoiesis;

consistent with myelodysplastic syndrome)

Immunophenotype: NA

Rearranged Ig Tcr: NA

Diagnosis: MDS

Survival


Treatment: not on any treatment

Complete remission : None

Treatment related death : NA

Relapse : no

Phenotype at relapse: NA

Status: Alive. Last follow up: 12-2010

Survival: 66 months.

Karyotype

Sample: 3/2005 BM, 6/2007 BM and 12/2010 BM

Culture time : 24 and 72 hours with overnight

Colcemid

Banding: GTW at 400 bands

Results

3/2005 BM 45,X,-Y[5]/46,XY,+9,

der(9;18)(p10;q10)[11]/46,XY[4];

6/2007 BM 45,X,-Y[5][4]/46,XY[16];

12/2010 BM 46,XY,+9,

der(9;18)(p10;q10)[15]/46,XY[5]

Karyotype at Relapse: NA

Other molecular cytogenetics technics: None

Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M.

Reddy KS


Case 0002M : two partial karyotypes with a normal

chromosome 9 pair, a der(9;18)and a normal chromosome 18 and arrow)

Comments Both the cases described in this study were

followed for >5 years. Case 0001M, had

thrombocytosis and could not tolerate Interferon or

Hydrea treatment and hence was treated with

Busulfan. The patient was positive for JAK2

mutation (on chromosome 9). A recent study was to

rule out transformation of MPN as there was

myelofibrosis, splenomegaly and apparent

progression of the disease. The der(9;18) was first

identified in the stem line and a sideline had partial

deletion of chromosome 13q. Case 0002M was a

MDS case with a der(9;18) detected in the initial

study and again when the patient was suspected to

be transforming >5 years later. This patient had

very little symptoms and was not treated.

In this report for the first time a long standing MDS

case was found to have the der(9;18) at initial

diagnosis and after over 5 years . Others reported

with der(9;18)(n 7) had PV (n 3) or post PV

myelofibrosis (n 4) and one had sAML after ET.

The JAK2V617F is a gain in function mutation on

chromosome 9. Hence, the extra copy of 9p may

exacerbate the MPN as observed in 0001M case.

The patient had splenomegaly and also

myelofibrosis when the patient was found with the

der(9;18). Der(9;18) is the sole abnormality in most

reported cases, balanced translocations or complex

aberrant karyotypes were reported as additional

abnormalities. Our patient had del(13) in a sideline

and this abnormality is observed in MPN. Among

the 9 patients with der(9;18) two arose post

treatment (present case 0001M and Andrieux et al

2003). and the other were at diagnosis.

The der(9;18) supports progression of the disease in

case 0001M but in case 0002M with MDS it

reappears when there is suspicion of transformation

and its role is less uncertain.

References Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer. 1998 Aug;22(4):321-4

Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Jan 15;140(2):118-23

Bacher U, Haferlach T, Schoch C. Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Cancer Genet Cytogenet. 2005 Jul 15;160(2):179-83

Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90

Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas Genet Cytogenet Oncol Haematol. April 2010. URL : http://AtlasGeneticsOncology.org/Reports/der0918XuID100044.html


Reddy KS. Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M.. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):992-993.





Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm: Case 0001M Kavita S Reddy

Kaiser Permanente Southern California, 4580 ElectronicPlace, Los Angeles, CA 90039, USA (KSR)


Online updated version : http://AtlasGeneticsOncology.org/Reports/der918Case1ReddyID100052.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI der918Case1ReddyID100052.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics

Age and sex


Previous history

Preleukemia. No previous malignancy. No inborn

condition of note.

Organomegaly

No hepatomegaly, splenomegaly (Spleen appears

enlarged measures 15.8 cm in length), no enlarged


involvement.

Blood WBC : 112.7X 10

9/l

HB : 13.3g/dl

Platelets : 42X 109/l


Cytology

MPN (near 100% cellular marrow with

granulocytic and megakaryocytic hyperplasia

consistent with chronic myeloproliferative

neoplasm).

Immunophenotype: NA

Rearranged Ig Tcr: NA

Diagnosis: CMPN

Survival


Treatment: Could tolerate Interferon or Hydrea

and is on regulated dose of Busulfan.

Complete remission : None

Treatment related death : NA

Relapse : no

Phenotype at relapse: NA

Status: Alive. Last follow up: 12-2010.

Survival: 74 months

Karyotype

Sample: 10/2004 BM, 6/2007 PB and 12/2010 BM

Culture time: 24 and 72 hours with overnight

Colcemid

Banding: GTW at 400 bands

Results

10/2004 BM 46,XY[20];

6/2007 PB 46,XY[10];

12/2010 BM 46,XY,+9,der(9;18)(p10;q10)

[8]/46,sl,del(13)(q12q14)[cp6]/46,XY[6]

Karyotype at Relapse: NA

Other molecular cytogenetics technics: None

Other Molecular Studies

Technics: PCR

Results: JAK2V617F mutation

Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M.

Reddy KS


Case 0001M : two partial karyotypes of the stemline (row1-

2) with 2 normal chromosomes 9 a der(9;18), 13 pairs, a one normal chromosome 18 and arrow). Two partial

karyotpes of the sideline (row 3-4) with a normal chromosome 9 pair, a der(9;18), a normal chromosome 13

and a deleted 13 (arrow) and a normal 18 (arrow).

Comments

Both the cases described in this study were

followed for > 5 years. Case 0001M, had

thrombocytosis and could not tolerate Interferon or

Hydrea treatment and hence was treated with

Busulfan. The patient was positive for JAK2

mutation (on chromosome 9). A recent study was to

rule out transformation of MPN as there was

myelofibrosis, splenomegaly and apparent

progression of the disease. The der(9;18) was first

identified in the stem line and a sideline had partial

deletion of chromosome 13q. Case 0002M was a

MDS case with a der(9;18) detected in the initial

study and again when the patient was suspected to

be transforming > 5 years later. This patient had

very little symptoms and was not treated.

In this report for the first time a long standing MDS

case was found to have the der(9;18) at initial

diagnosis and after over 5 years . Others reported

with der(9;18)(n 7) had PV (n 3) or post PV

myelofibrosis (n 4) and one had sAML after ET.

The JAK2V617F is a gain in function mutation on

chromosome 9. Hence, the extra copy of 9p may

exacerbate the MPN as observed in 0001M case.

The patient had splenomegaly and also

myelofibrosis when the patient was found with the

der(9;18). Der(9;18) is the sole abnormality in most

reported cases, balanced translocations or complex

aberrant karyotypes were reported as additional

abnormalities. Our patient had del(13) in a sideline

and this abnormality is observed in MPN. Among

the 9 patients with der(9;18) two arose post

treatment (present case 0001M and Andrieux et al

2003). and the other were at diagnosis.

The der(9;18) supports progression of the disease in

case 0001M but in case 0002M with MDS it

reappears when there is suspicion of transformation

and its role is less uncertain.

References Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer. 1998 Aug;22(4):321-4

Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Jan 15;140(2):118-23

Bacher U, Haferlach T, Schoch C. Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Cancer Genet Cytogenet. 2005 Jul 15;160(2):179-83

Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90

Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas Genet Cytogenet Oncol Haematol. April 2010. URL : http://AtlasGeneticsOncology.org/Reports/der0918XuID100044.html


Reddy KS. Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M.. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):994-995.



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