Carcinogenesis Advance Access originally published online on November 6, 2003
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Carcinogenesis, Vol. 25, No. 2, 249-261,
February 2004
© Oxford University Press; all rights reserved
CARCINOGENESIS |
Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway
1 Molecular and Cellular Biology Program, 2 Center for Bioenvironmental Research, 3 Department of Pharmacology, 4 Department of Microbiology and Immunology, 5 Department of Environmental Health Sciences, 6 Department of Medicine, Section of Hematology and Medical Oncology, 7 Department of Surgery, Tulane University Health Science Center, New Orleans, LA 70112, USA and 8 Department of Molecular Genetics, Alton Ochsner Medical Foundation, New Orleans, LA 70121, USA
Organochlorine compounds have been demonstrated to have detrimental health effects in both wildlife and humans, an effect largely attributed to their ability to mimic the hormone estrogen. Our laboratory has studied cell signaling by environmental chemicals associated with the estrogen receptor (ER) and more recently via ER-independent mechanisms. Here, we show that the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolites induce a stress mitogen-activated protein kinase (MAPK) that leads to AP-1 activation. Through the use of a dominant negative c-Fos mutant, we show that DDT exposure induces the collagenase promoter in an AP-1-dependent manner. DDT stimulates an AP-1 complex shift at the DNA to one favoring c-Jun/c-Fos dimers through both increasing c-Jun levels and by post-translational activation of c-Jun and c-Fos in HEK 293 and human endometrial Ishikawa cells. DDT treatment induces phosphorylation of ERK and p38, while JNK phosphorylation levels are slightly decreased. Using pharmacological and molecular inhibitors of the various MAPKs, we implicate the p38 signaling cascade, and to a lesser extent ERK, as necessary pathways for AP-1-mediated gene expression induction by organochlorines. Taken together, these results demonstrate that organochlorines induce the collagenase promoter via sequential activation of the p38 kinase cascade and AP-1.
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