Abstract
Pro-inflammatory cytokines, environmental stresses, as well as receptor tyrosine kinases regulate the activity of JNK. In turn, JNK phosphorylates Jun members of the AP-1 family of transcription factors, thereby controlling processes as different as cell growth, differentiation, and apoptosis. Still, very few targets of the JNK-Jun pathway have been identified. Here we show that JNK is required for the induction of c-myc expression by PDGF. Furthermore, we identify a phylogenetically conserved AP-1-responsive element in the promoter of the c-myc proto-oncogene that recruits in vivo the c-Jun and JunD AP-1 family members and controls the PDGF-dependent transactivation of the c-myc promoter. These findings suggest the existence of a novel biochemical route linking tyrosine kinase receptors, such as those for PDGF, and c-myc expression through JNK activation of AP-1 transcription factors. They also provide a novel potential mechanism by which both JNK and Jun proteins may exert either their proliferative or apoptotic potential by stimulating the expression of the c-myc proto-oncogene.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Base Sequence
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Blotting, Northern
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Blotting, Western
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Cell Division
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Chromatin / metabolism
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Drosophila
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Enzyme Activation
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Genes, Reporter
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Humans
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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MAP Kinase Signaling System
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Mice
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Models, Biological
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Molecular Sequence Data
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Mutation
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NIH 3T3 Cells
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Phylogeny
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Platelet-Derived Growth Factor / metabolism*
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Structure, Tertiary
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-myc / metabolism*
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RNA, Messenger / metabolism
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Recombinant Proteins / chemistry
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Signal Transduction*
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Transcription Factor AP-1 / metabolism*
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Transcriptional Activation
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Transfection
Substances
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Chromatin
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MAS1 protein, human
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Platelet-Derived Growth Factor
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Recombinant Proteins
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Transcription Factor AP-1
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Protein-Tyrosine Kinases
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases