Journal Article

Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis

Dianhua Qiao, Elias D. Stratagouleas and Jesse D. Martinez

in Carcinogenesis

Volume 22, issue 1, pages 35-41
Published in print January 2001 | ISSN: 0143-3334
Published online January 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.1.35
Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis

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The bile acid deoxycholic acid (DCA) is a known tumor promoter and it has been suggested that DCA-induced apoptosis plays an important role in colon tumor development. In this study we have characterized the capacity of DCA to stimulate mitogen-activated protein kinase (MAPK) activity and examined the effect that MAPK activity had on DCA-induced apoptosis. Analysis of MAPK activity in DCA-treated HCT116 cells using phosphorylation-specific antibodies and in vitro kinase assays indicated that both the extracellular signal-regulated kinase (ERK) and p38 MAPK (p38), but not the c-Jun N-terminal kinase (JNK), were activated. Using pharmacological inhibitors we determined that only ERK could influence DCA cytotoxicity and that elevated ERK activity could suppress DCA-induced apoptosis. This observation was confirmed genetically. Suppressing ERK activity by overexpressing a dominant negative form of the ERK MAP kinase resulted in increased sensitivity to DCA-induced apoptosis whereas elevated ERK activity artificially produced by overexpression of the wild-type ERK kinase blunted DCA-induced apoptosis. Taken together, our results suggest that DCA can stimulate pro-apoptotic and anti-apoptotic signaling pathways and that sensitivity to DCA-induced apoptosis can be modulated by the ERK MAP kinase.

Keywords: AOM, azoxymethane; DCA, deoxycholic acid; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; NGF, neuron growth factor; p38, p38 MAP kinase; PKC, protein kinase C.

Journal Article.  5030 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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