Journal Article

Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway

Daniel E. Frigo, Yan Tang, Barbara S. Beckman, Aline B. Scandurro, Jawed Alam, Matthew E. Burow and John A. McLachlan

in Carcinogenesis

Volume 25, issue 2, pages 249-261
Published in print February 2004 | ISSN: 0143-3334
Published online February 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh009
Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway

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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.

Keywords: AP-1, activator protein-1; ATF2, activating transcription factor 2; BMK1, big MAPK 1; DCC-FBS, 5% dextran-coated charcoal-treated fetal bovine serum; p,p′-DDA, 2,2-bis(p-chlorophenyl)acetic acid; o,p′-DDD, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane; p,p′-DDD, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane; o,p′-DDE, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-phenyl) ethylene; p,p′-DDE, 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene; DDOH, 2,2-bis(p-chlorophenyl)ethanol; DDT, dichlorodiphenyltrichloroethane; o,p′-DDT, 2,2-bis(o,p-dichlorophenyl)-1,1,1-trichloroethane; p,p′-DDT, 2,2-bis(p,p-chlorophenyl)-1,1,1-trichloroethane; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethylsulfoxide; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPKs, mitogen-activated protein kinases; MEF2, myocyte enhancer factor 2; PBS, phosphate-buffered saline; PMA, 12-O-tetradecanylphorbol 13-acetate; SRE, serum response element

Journal Article.  8513 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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