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Molecular and Cellular Biology, November 2003, p. 7920-7925, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7920-7925.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Agonist and Chemopreventative Ligands Induce Differential Transcriptional Cofactor Recruitment by Aryl Hydrocarbon Receptor

Eli V. Hestermann{dagger} and Myles Brown*

Department of Molecular Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Received 23 April 2003/ Returned for modification 7 July 2003/ Accepted 5 August 2003

Aryl hydrocarbon receptor (AHR) is a transcription factor whose activity is regulated by environmental agents, including several carcinogenic agonists. We measured recruitment of AHR and associated proteins to the human cytochrome P4501A1 gene promoter in vivo. Upon treatment with the agonist ß-naphthoflavone, AHR is rapidly associated with the promoter and recruits the three members of the p160 family of coactivators as well as the p300 histone acetyltransferase, leading to recruitment of RNA polymerase II (Pol II) and induction of gene transcription. AHR, coactivators, and Pol II cycle on and off the promoter, with a period of ~60 min. In contrast, the chemopreventative AHR ligand 3,3'-diindolylmethane promotes AHR nuclear translocation and p160 coactivator recruitment but, remarkably, fails to recruit Pol II or cause histone acetylation. This novel mechanism of receptor antagonism may account for the antitumor properties of chemopreventative compounds targeting the AHR.

* Corresponding author. Mailing address: 44 Binney St., D730, Boston, MA 02115. Phone: (617) 632-3948. Fax: (617) 632-5417. E-mail: Myles_Brown{at}dfci.harvard.edu.

{dagger} Present address: Biology Department, Furman University, Greenville, SC 29613.

Molecular and Cellular Biology, November 2003, p. 7920-7925, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7920-7925.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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