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

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
genome
1) 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 MG1 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
•
•
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Discovered in chicken tumors
Transcription factor
Forms heterodimers with Fos
Upregulates/downregulates certain genes in
jun-transforming cells
• No specific relation to human cancer