The Story of jun: c-jun and v-jun

Katie Vogeler

The Plan...

• Discovery of jun

• Function of c-jun

• c-jun vs. v-jun

• Relationship to cancer

The Beginning... • A search for a new retrovirus that would

harbor and transduce cellular oncogenes

• Led Peter Vogt to a chicken slaughter house

• 1 in 100,000 birds had a tumor

• Transforming virus in most of these tumors

Avian Sarcoma Virus 17

• 2 indicators for presence of oncogene in its genome1) Transforming activity in

cell cultures

2) Defectiveness in replication

Is it a new oncogene?• Dot-blot hybridization of DNA from several

oncogenes and jun

New oncogene = jun

• Short for the Japanese word for 17: jun-nana

• Homology with Japanese quail, mouse, rat, and human genes

New oncogene = jun

• Short for the Japanese word for 17: jun-nana

• Homology with Japanese quail, mouse, rat, and human genes

“Retroviral oncogenes are not viral genes but cellular genes hitching a ride in the viral genome” Vogt

What does it do?

Jun protein related to GCN4 (yeast transcriptional regulator)

What does it do?

Jun protein related to GCN4 (yeast transcriptional regulator)

Jun protein related to AP-1 of mammalian cells

What does it do?

Jun protein related to GCN4 (yeast transcriptional regulator)

Jun protein related to AP-1 of mammalian cells

Jun binds to Fos

What does it do?• Jun is the product of an immediate-early gene

– highly responsive to external growth signals

• Regulation is integrated into the cell cycle– Undergoes activating phosphorylation at the M-

G1 transition– Jun can transactivate the promoter of cyclin D1

• Elevated Jun activity may advance the cell through G1

Fos and jun form a heterodimer• ‘bZIP protein’

• Leucine zipper in

C-terminal region– dimerization

• Basic region is

located N-terminal

to zipper– DNA contact surface

c-jun vs. v-jun

• c-jun requires an upstream signal from Jun N-terminal kinase (JNK)

• v-jun does not interact with JNK– It is autonomous and constitutively active– 27 a.a. deletion near N-terminus (delta deletion)

and 2 or 3 a.a. substitutions in C-terminal

• Address overlapping but not identical sets of genes

c-jun

• Jun N-terminal kinase (JNK) uses delta domain as docking surface with c-jun

• JNK is activated by phosphorylation triggered by a signal that originates in Ras pathway

• 2 participants in signal to JNK are Ras-like GTPase Ral and its GEF Raf

Ras Pathway

Relation to Cancer?

• Promotes Growth

• Retards differentiation

Summary of info on genes that are differentially expressed in Jun-transforming cells: upregulated

Summary of info on genes that are differentially expressed in Jun-transforming cells: downregulated

Relation to Cancer?• Mechanism of Jun-induced oncogenic

transformation is known only in general terms

• Not overtly involved in human tumors

• Has not been identified as a partner in a cancer-specific chromosomal translocation

• Is not amplified in tumors and is usually not overexpressed

Relation to Cancer?• Jun is located at the end of signal cascades that

include important oncogenes active in human tumors

• Dominant negative mutants of Jun attenuate the growth behavior of various human tumor cell lines (interfere with transformation by oncogenes linked to the Ras pathway)

• Jun activity=determinant factor in many tumors?

Summary

• Discovered in chicken tumors

• Transcription factor

• Forms heterodimers with Fos

• Upregulates/downregulates certain genes in jun-transforming cells

• No specific relation to human cancer