title: Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function.
abstract: 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.
authors.affiliation: Department of Developmental and Molecular Biology, The Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Maofu
authors.initials: M
authors.lastname: Fu
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhang
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakamaki
authors.forename: Y G
authors.initials: YG
authors.lastname: Yeung
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.forename: Torsten
authors.initials: T
authors.lastname: Hopp
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
authors.forename: Ellis
authors.initials: E
authors.lastname: Jaffray
authors.forename: Ron T
authors.initials: RT
authors.lastname: Hay
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
authors.forename: Olli A
authors.initials: OA
authors.lastname: Jänne
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism; D017930:Genes, Reporter; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D048728:MAP Kinase Kinase Kinase 1; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D011944:Receptors, Androgen; C497790:SMAD3 protein, human; D025842:SUMO-1 Protein; D051900:Smad3 Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D013196:Dihydrotestosterone; C012589:trichostatin A; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases