Bile acid-induced activation of activator protein-1 requires both extracellular signal-regulated kinase and protein kinase C signaling

Dianhua Qiao, Weixing Chen, Elias D. Stratagoules, Jesse D Martinez

Research output: Contribution to journalArticle

92 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)15090-15098
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number20
DOIs
StatePublished - May 19 2000

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Extracellular Signal-Regulated MAP Kinases
Transcription Factor AP-1
Deoxycholic Acid
Bile Acids and Salts
Protein Kinase C
Chemical activation
Gene expression
Genes
Cell signaling
Electrophoretic mobility
Electrophoretic Mobility Shift Assay
Transcription
Mitogen-Activated Protein Kinases
Bile
Colonic Neoplasms
Transcriptional Activation
Transfection
Assays
Transcription Factors
Phosphotransferases

ASJC Scopus subject areas

  • Biochemistry

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Bile acid-induced activation of activator protein-1 requires both extracellular signal-regulated kinase and protein kinase C signaling. / Qiao, Dianhua; Chen, Weixing; Stratagoules, Elias D.; Martinez, Jesse D.

In: Journal of Biological Chemistry, Vol. 275, No. 20, 19.05.2000, p. 15090-15098.

Research output: Contribution to journalArticle

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