title: Bile acid-induced activation of activator protein-1 requires both extracellular signal-regulated kinase and protein kinase C signaling.
abstract: Elevated concentrations of fecal bile aids are known to promote colon cancer and increasing evidence suggests that alterations in cellular signaling and gene expression may play an important role in this process. In this study, we examined the molecular mechanisms underlying bile acid-mediated gene regulation using GADD153 as our model gene. Promoter deletion analyses revealed that the activator protein-1 (AP-1) transcription factor was crucial for deoxycholic acid (DCA)-mediated GADD153 gene transcription. Electrophoretic mobility shift assays and transient transfection analyses demonstrated that both DNA binding and transactivation activities of AP-1 were induced by DCA in a dose-dependent manner. The AP-1 complex induced by DCA consisted of JunD, Fra-1, and c-Fos. Examination of the signaling pathways stimulated by DCA showed that extracellular signal-regulated kinases (ERKs) were required for AP-1 activation. Inhibition of ERK by the mitogen-activated protein kinase/ERK kinase inhibitor PD 98059 or by expression of a dominant negative mutant ERK suppressed AP-1 activation. Notably, the PKC inhibitor, calphostin C, also abolished DCA-induced AP-1 activation but did not affect DCA-mediated ERK activation, suggesting that ERK and PKC function in separate signaling pathways that cooperatively mediate DCA-induced AP-1 activation. Hence, bile acid-stimulated signaling appears to converge on the AP-1 protooncogene.
authors.affiliation: Arizona Cancer Center, Department of Radiation Oncology, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: D
authors.initials: D
authors.lastname: Qiao
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: E D
authors.initials: ED
authors.lastname: Stratagoules
authors.forename: J D
authors.initials: JD
authors.lastname: Martinez
mesh_terms: D000230:Adenocarcinoma; D022762:CCAAT-Enhancer-Binding Proteins; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D003840:Deoxycholic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009281:Naphthalenes; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D003840:Deoxycholic Acid; D051742:Transcription Factor CHOP; D015500:Chloramphenicol O-Acetyltransferase; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C058819:calphostin C; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one