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Carcinogenesis Advance Access published online on November 6, 2003
Carcinogenesis, doi:10.1093/carcin/bgh009
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CARCINOGENESIS

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

Daniel E. Frigo 1, Yan Tang 2, Barbara S. Beckman 3, Aline B. Scandurro 4, Jawed Alam 5, Matthew E. Burow 6*, and John A. McLachlan 3*

1 Molecular and Cellular Biology Program and Center for Bioenvironmental Research, Tulane University Health Science Center, New Orleans, LA 70112
2 Department of Pharmacology, Tulane University Health Science Center, New Orleans, LA 70112
3 Center for Bioenvironmental Research and Department of Pharmacology, Tulane University Health Science Center, New Orleans, LA 70112
4 Department of Microbiology and Immunology, Tulane University Health Science Center, New Orleans, LA 70112
5 Department of Environmental Health Sciences, Tulane University Health Science Center, New Orleans, LA 70112; Department of Molecular Genetics, Alton Ochsner Medical Foundation, New Orleans, LA 70121
6 Center for Bioenvironmental Research, Department of Medicine-Section of Hematology and Medical Oncology and Department of Surgery, Tulane University Health Science Center, New Orleans, LA 70112

* Corresponding author. E-mail: john.mclachlan{at}tulane.edu.

Received 19 June 2003 ; revised 4 August 2003 ; accepted 21 October 2003

Abstract

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 the organochlorine pesticide, dichlorodiphenyltrichloroethane (DDT), and its metabolites signal a stress MAPK that leads to AP-1 activation. Through use of a dominant negative c-Fos mutant, we show 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 posttranslational 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 by organochlorines. Taken together, these results demonstrate organochlorines induce the collagenase promoter via sequential activation of the p38 kinase cascade and AP-1.

AP-1, DDT, HEK 293, Ishikawa, MAPK, p38, collagenase
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