Download - Retinoic Acid Receptor Alpha (RARα)
Retinoic Acid Receptor AlphaRetinoic Acid Receptor Alpha(RARα)(RARα)
Acute Promyelocytic Acute Promyelocytic LeukemiaLeukemia
(APL)(APL)
APL OverviewAPL Overview
Subtype of AML (5-8% of AML adults)Subtype of AML (5-8% of AML adults) Abnormal accumulation of Abnormal accumulation of
promyelocytes resulting in decreased promyelocytes resulting in decreased production of RBCsproduction of RBCs
Median age is 40 yearsMedian age is 40 years Increased incidence in patients from Increased incidence in patients from
Latin AmericaLatin America Anemia and thrombocytopeniaAnemia and thrombocytopenia
RARα is a transcription factorRARα is a transcription factor
Nuclear receptorNuclear receptor Ligand-inducible Ligand-inducible
transcriptional transcriptional regulatorregulator
Ligand is retinoic Ligand is retinoic acid (RA)acid (RA)
Cyberlipid Center; www.cyberlipid.org
RARα
Active transcription factor is a Active transcription factor is a heterodimerheterodimer
RARα forms RARα forms heterodimer with heterodimer with RXRs RXRs
Heterodimer binds Heterodimer binds DNA sequence DNA sequence called RA-response called RA-response element (RARE)element (RARE)
Marlétaz F, et al. Int J Biol Sci 2006; 2:38-47.
Retinoic Acid AbsentRetinoic Acid Absent
RAR-RXR heterodimer is a repressorRAR-RXR heterodimer is a repressor Co-repressors modify histonesCo-repressors modify histones
SMRT, N-CoRSMRT, N-CoR mSin3mSin3 HDACsHDACs
Marlétaz F, et al. Int J Biol Sci 2006; 2:38-47.
Retinoic Acid PresentRetinoic Acid Present
Repression complex dissociates and Repression complex dissociates and a co-activator complex assemblesa co-activator complex assembles
Co-activator complex modifies Co-activator complex modifies histones to induce transcriptional histones to induce transcriptional activationactivation
Marlétaz F, et al. Int J Biol Sci 2006; 2:38-47.
Scientists knocked outScientists knocked out RARα RARα Gene in MiceGene in Mice
Homologous Homologous recombinationrecombination
Disrupt exon 8, Disrupt exon 8, which prevents which prevents synthesis of all synthesis of all RARRARα α isoformsisoforms
Lufkin, Thomas, et al. Proc. Natl. Acad. Sci. USA. Vol. 90, pp. 7225-7229
RARαRARα-null mutants viable but -null mutants viable but generally die before 2 generally die before 2
monthsmonths Intercross Intercross RARα RARα
heterozygotes to heterozygotes to give give RARαRARα-null -null homozygoteshomozygotes
RARα RARα gene gene disruption is not disruption is not embryonic lethalembryonic lethal
RARα, RARβ and RARα, RARβ and RARγ are highly RARγ are highly redundantredundant
Lufkin, Thomas, et al. Proc. Natl. Acad. Sci. USA. Vol. 90, pp. 7225-7229
Testis Degeneration in Testis Degeneration in RARαRARα Mutant MiceMutant Mice
MaleMale RARα RARα-null homozygotes that survived -null homozygotes that survived for > 2 months were sterilefor > 2 months were sterile
Severe degeneration of germinal epithelium Severe degeneration of germinal epithelium in testesin testes
Lufkin, Thomas, et al. Proc. Natl. Acad. Sci. USA. Vol. 90, pp. 7225-7229
Chromosomal Translocation Chromosomal Translocation causes mutationcauses mutation
Chromosome 17Chromosome 17 Fusion proteins Fusion proteins
created with 5 created with 5 common partnerscommon partners PMLPML PLZFPLZF NPMNPM NuMANuMA Stat5bStat5b
Medicine OnLine. www.meds.com
Fusion proteins can form Fusion proteins can form homodimershomodimers
Homodimer Homodimer associates with associates with multiple units of multiple units of the co-repressor the co-repressor complexcomplex
Enhanced Enhanced transcriptional transcriptional repressionrepression
Lin, Richard, et. al. “Transcriptional regulation in APL”
Fusion proteins react Fusion proteins react strongly with co-repressors strongly with co-repressors
to recruit HDACsto recruit HDACs Physiological [RA] will not dissociate Physiological [RA] will not dissociate
repression complexrepression complex
Lin, Richard, et. al. “Transcriptional regulation in APL”
High [RA] dissociates High [RA] dissociates repression complex formed by repression complex formed by
some fusion proteinssome fusion proteins PML-RARα but not PLZF-RARαPML-RARα but not PLZF-RARα
Lin, Richard, et. al. “Transcriptional regulation in APL”
Target genes involved in Target genes involved in myeloid proliferation and myeloid proliferation and
differentiationdifferentiation p21WAF, C/EBP, HoxA1, etc.p21WAF, C/EBP, HoxA1, etc. Inhibition blocks differentiationInhibition blocks differentiation
Lin, Richard, et. al. “Transcriptional regulation in APL”
TreatmentTreatment
Pharmacological [RA] with Pharmacological [RA] with chemotherapychemotherapy
Possibly HDAC inhibitorsPossibly HDAC inhibitors
Lin, Richard, et. al. “Transcriptional regulation in APL”