Signaling pathways in the induction of c-fos and c-jun proto-oncogenes by 3-methylcholanthrene.
3-methylcholanthrene (MC), a potent promutagen and procarcinogen, is also an inducer of mammalian CYPIAI (cytochrome P1-450) gene. The CYPIAI enzyme is responsible for the detoxification of MC and its oxidation into reactive epoxide intermediates. Through its epoxide metabolites, MC functions also as an inducer of drug-metabolizing enzyme glutathione S-transferase (GST) gene expression. Induction of murine GST Ya gene by MC and a variety of other chemical agents is mediated by a regulatory element composed of two adjacent AP-1-like sites, and activated by the Fos/Jun heterodimeric complex (AP-1). In cultured cells, MC causes the induction of AP-1 activity, which is the result of an increased expression of c-Fos and c-Jun proteins. The mechanisms involved in MC activation of c-fos and c-jun gene expression were examined in the present study. Evidence is presented that stimulation of c-fos transcription by MC involves a signal transduction pathway, which includes activation of the small G protein Ras, Raf-1 kinase, and the mitogen-activated protein (MAP) kinases, ERK1 and ERK2. Furthermore, we find that phorbol 12-myristate 13-acetate, which uses both protein kinase C and protein-tyrosine kinase activities to induce c-fos promoter, may share a common pathway with MC downstream of Ras. The signal transduction pathway induced by MC to stimulate c-jun promoter involves Ras activation and the JNK group of MAP-kinases.
Ainbinder
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Department of Biochemistry, The Weizmann Institute of Science, Rehovot, Israel.
Bergelson
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Daniel
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V
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms; D008748:Methylcholanthrene / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D008748:Methylcholanthrene; D015500:Chloramphenicol O-Acetyltransferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate