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Molecular and Cellular Biology, May 2002, p. 3373-3388, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3373-3388.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Androgen Receptor Acetylation Governs trans Activation and MEKK1-Induced Apoptosis without Affecting In Vitro Sumoylation and trans-Repression Function

Maofu Fu,1 Chenguang Wang,1 Jian Wang,1 Xueping Zhang,1 Toshiyuki Sakamaki,1 Y. G. Yeung,1 Chawnshang Chang,2 Torsten Hopp,3 Suzanne A. W. Fuqua,3 Ellis Jaffray,4 Ron T. Hay,4 Jorma J. Palvimo,5 Olli A. Jänne,5 and Richard G. Pestell1*

Department of Developmental and Molecular Biology and Medicine, The Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461,1 George Whipple Laboratory for Cancer Research, Departments of Urology, Pathology, Radiation Oncology, Biochemistry, and Toxicology, and The Cancer Center, University of Rochester, Rochester, New York 14642,2 Baylor College of Medicine, Houston, Texas 77030,3 School of Biology, University of St. Andrews, The North Haugh, St. Andrews KY16 9ST, Scotland,4 Biomedicum Helsinki, Institute of Biomedicine and Department of Clinical Chemistry, FIN-00014 University of Helsinki, Finland5

Received 16 July 2001/ Returned for modification 10 September 2001/ Accepted 14 February 2002

The androgen receptor (AR) is a nuclear hormone receptor superfamily member that conveys both trans repression and ligand-dependent trans-activation function. Activation of the AR by dihydrotestosterone (DHT) regulates diverse physiological functions including secondary sexual differentiation in the male and the induction of apoptosis by the JNK kinase, MEKK1. The AR is posttranslationally modified on lysine residues by acetylation and sumoylation. The histone acetylases p300 and P/CAF directly acetylate the AR in vitro at a conserved KLKK motif. To determine the functional properties governed by AR acetylation, point mutations of the KLKK motif that abrogated acetylation were engineered and examined in vitro and in vivo. The AR acetylation site point mutants showed wild-type trans repression of NF-{kappa}B, AP-1, and Sp1 activity; wild-type sumoylation in vitro; wild-type ligand binding; and ligand-induced conformational changes. However, acetylation-deficient AR mutants were selectively defective in DHT-induced trans activation of androgen-responsive reporter genes and coactivation by SRC1, Ubc9, TIP60, and p300. The AR acetylation site mutant showed 10-fold increased binding of the N-CoR corepressor compared with the AR wild type in the presence of ligand. Furthermore, histone deacetylase 1 (HDAC1) bound the AR both in vivo and in cultured cells and HDAC1 binding to the AR was disengaged in a DHT-dependent manner. MEKK1 induced AR-dependent apoptosis in prostate cancer cells. The AR acetylation mutant was defective in MEKK1-induced apoptosis, suggesting that the conserved AR acetylation site contributes to a pathway governing prostate cancer cellular survival. As AR lysine residue mutations that abrogate acetylation correlate with enhanced binding of the N-CoR repressor in cultured cells, the conserved AR motif may directly or indirectly regulate ligand-dependent corepressor disengagement and, thereby, ligand-dependent trans activation.

* Corresponding author. Mailing address: The Albert Einstein Cancer Center, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Chanin 302, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-8662. Fax: (718) 430-8674. E-mail: pestell{at}aecom.yu.edu.

Molecular and Cellular Biology, May 2002, p. 3373-3388, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3373-3388.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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