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 Presentation

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<ul><li><p>The Story of jun: c-jun and v-junKatie Vogeler</p></li><li><p>The Plan...Discovery of jun</p><p>Function of c-jun</p><p>c-jun vs. v-jun</p><p>Relationship to cancer</p></li><li><p>The Beginning... A search for a new retrovirus that would harbor and transduce cellular oncogenesLed Peter Vogt to a chicken slaughter house1 in 100,000 birds had a tumorTransforming virus in most of these tumors </p></li><li><p>Avian Sarcoma Virus 172 indicators for presence of oncogene in its genome1) Transforming activity in cell cultures2)Defectiveness in replication </p></li><li><p>Is it a new oncogene?Dot-blot hybridization of DNA from several oncogenes and jun </p></li><li><p>New oncogene = junShort for the Japanese word for 17: jun-nana</p><p>Homology with Japanese quail, mouse, rat, and human genes</p></li><li><p>New oncogene = junShort for the Japanese word for 17: jun-nana</p><p>Homology with Japanese quail, mouse, rat, and human genesRetroviral oncogenes are not viral genes but cellular genes hitching a ride in the viral genome Vogt</p></li><li><p>What does it do?Jun protein related to GCN4 (yeast transcriptional regulator) </p></li><li><p>What does it do?Jun protein related to GCN4 (yeast transcriptional regulator) Jun protein related to AP-1 of mammalian cells</p></li><li><p>What does it do?Jun protein related to GCN4 (yeast transcriptional regulator) Jun protein related to AP-1 of mammalian cellsJun binds to Fos</p></li><li><p>What does it do?Jun is the product of an immediate-early genehighly responsive to external growth signalsRegulation is integrated into the cell cycleUndergoes activating phosphorylation at the M-G1 transitionJun can transactivate the promoter of cyclin D1Elevated Jun activity may advance the cell through G1</p></li><li><p>Fos and jun form a heterodimerbZIP proteinLeucine zipper in C-terminal regiondimerizationBasic region is located N-terminal to zipperDNA contact surface</p></li><li><p>c-jun vs. v-junc-jun requires an upstream signal from Jun N-terminal kinase (JNK)v-jun does not interact with JNKIt is autonomous and constitutively active27 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</p></li><li><p>c-junJun 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 pathway2 participants in signal to JNK are Ras-like GTPase Ral and its GEF Raf</p></li><li><p>Ras Pathway</p></li><li><p>Relation to Cancer?Promotes Growth</p><p>Retards differentiation</p></li><li><p>Summary of info on genes that are differentially expressed in Jun-transforming cells: upregulated</p></li><li><p>Summary of info on genes that are differentially expressed in Jun-transforming cells: downregulated</p></li><li><p>Relation to Cancer?Mechanism of Jun-induced oncogenic transformation is known only in general termsNot overtly involved in human tumorsHas not been identified as a partner in a cancer-specific chromosomal translocationIs not amplified in tumors and is usually not overexpressed</p></li><li><p>Relation to Cancer?Jun is located at the end of signal cascades that include important oncogenes active in human tumorsDominant 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?</p></li><li><p>SummaryDiscovered in chicken tumorsTranscription factorForms heterodimers with FosUpregulates/downregulates certain genes in jun-transforming cellsNo specific relation to human cancer</p><p>Old hens were important because no solid retrovirus-induced tumors in your broiler varietyChicken emryo fibroblastsTransforming cell foci-refractile cells growing in parallel orientation and in multiple layersDont release infectious virus-DNA from each oncogene was spotted and hybridized to a jun specific probe-32P labeled probeNFAT: nuclear factor of activated T-cells-Dimerization is a prerequisite for DNA binding-Dimerization of jun and fos also enhances nuclear translocation</p></li></ul>