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J. Biol. Chem., Vol. 279, Issue 28, 29013-29022, July 9, 2004

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The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression^*

Jennifer L. Marlowe, Erik S. Knudsen¶, Sandy Schwemberger||, and Alvaro Puga**

From the Center for Environmental Genetics and the Department of Environmental Health, and the ^¶Department of Cell Biology, Neurobiology, and Anatomy, the University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, and the ^||Shriners Hospital for Children, Cincinnati, Ohio 45229

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic, teratogenic, and carcinogenic effects. TCDD is a ligand for the aromatic hydrocarbon receptor (AHR), a ligand-activated transcription factor believed to be the primary mediator of these effects. Activation of the AHR by TCDD also elicits a variety of effects on cell cycle progression, ranging from proliferation to arrest. In this report, we have characterized further the role of the activated AHR in cell cycle regulation. In human mammary carcinoma MCF-7 and mouse hepatoma Hepa-1 cells, TCDD treatment decreased the number of cells in S phase and caused the accumulation of cells in G₁. In Hepa-1 cells, this effect correlated with the transcriptional repression of several E2F-regulated genes required for S phase progression. AHR-mediated gene repression was dependent on its interaction with retinoblastoma protein but was independent of its transactivation function because AHR mutants lacking DNA binding or transactivation domains repressed E2F-dependent expression as effectively as wild type AHR. Overexpression of p300 suppressed retinoblastoma protein-dependent gene repression, and this effect was reversed by TCDD. Chromatin immunoprecipitation assays showed that TCDD treatment caused the recruitment of AHR to E2F-dependent promoters and the concurrent displacement of p300. These results delineate a novel mechanism whereby the AHR, a known transcriptional activator, also mediates gene repression by pathways involving combinatorial interactions at E2F-responsive promoters, leading to the repression of E2F-dependent, S phase-specific genes. The AHR seems to act as an environmental checkpoint that senses exposure to environmental toxicants and responds by signaling cell cycle inhibition.

Received for publication, April 19, 2004

^* This work was supported in part by Grants ES06273 and P30 ES06096 from the NIEHS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by predoctoral functional genomics and Ryan fellowships from the University of Cincinnati.

^** To whom correspondence should be addressed: Dept. of Environmental Health, University of Cincinnati Medical Center, P. O. Box 670056, Cincinnati, OH 45267-0056. Tel.: 513-558-0916; Fax: 513-558-0925; E-mail: Alvaro.Puga{at}UC.edu.

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