Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway.
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.
Frigo
Daniel E
DE
Molecular and Cellular Biology Program, Tulane University Health Science Center, New Orleans, LA 70112, USA.
Tang
Yan
Y
Beckman
Barbara S
BS
Scandurro
Aline B
AB
Alam
Jawed
J
Burow
Matthew E
ME
McLachlan
John A
JA
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003634:DDT / Q000633:toxicity*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; D003634:DDT; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases