the story of jun: c-jun and v-jun
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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 - PowerPoint PPT PresentationTRANSCRIPT
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The Story of jun: c-jun and v-jun
Katie Vogeler
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The Plan...
• Discovery of jun
• Function of c-jun
• c-jun vs. v-jun
• Relationship to cancer
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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
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Avian Sarcoma Virus 17
• 2 indicators for presence of oncogene in its genome1) Transforming activity in
cell cultures
2) Defectiveness in replication
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Is it a new oncogene?• Dot-blot hybridization of DNA from several
oncogenes and jun
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New oncogene = jun
• Short for the Japanese word for 17: jun-nana
• Homology with Japanese quail, mouse, rat, and human genes
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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
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What does it do?
Jun protein related to GCN4 (yeast transcriptional regulator)
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What does it do?
Jun protein related to GCN4 (yeast transcriptional regulator)
Jun protein related to AP-1 of mammalian cells
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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
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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
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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
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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
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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
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Ras Pathway
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Relation to Cancer?
• Promotes Growth
• Retards differentiation
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Summary of info on genes that are differentially expressed in Jun-transforming cells: upregulated
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Summary of info on genes that are differentially expressed in Jun-transforming cells: downregulated
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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
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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?
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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