title: Androgen receptor (AR) NH2- and COOH-terminal interactions result in the differential influences on the AR-mediated transactivation and cell growth.
abstract: Early reports showed that androgen receptor (AR) NH2- and COOH-terminal (N-C) interaction was important for full AR function. However, the influence of these interactions on the AR in vivo effects remains unclear. Here we tested some AR-associated peptides and coregulators to determine their influences on AR N-C interaction, AR transactivation, and AR coregulator function. The results showed that AR coactivators such as ARA70N, gelsolin, ARA54, and SRC-1 can enhance AR transactivation but showed differential influences on the N-C interaction. In contrast, AR corepressors ARA67 and Rad9 can suppress AR transactivation, with ARA67 enhancing and Rad9 suppressing AR N-C interaction. Furthermore, liganded AR C terminus-associated peptides can block AR N-C interaction, but only selective peptides can block AR transactivation and coregulator function. We found all the tested peptides can suppress prostate cancer LNCaP cell growth at different levels in the presence of 5alpha-dihydrotestosterone, but only the tested FXXLF-containing peptides, not FXXMF-containing peptides, can suppress prostate cancer CWR22R cell growth. Together, these results suggest that the effects of AR N-C interactions may not always correlate with similar effects on AR-mediated transactivation and/or AR-mediated cell growth. Therefore, drugs designed by targeting AR N-C interaction as a therapeutic intervention for prostate cancer treatment may face unpredictable in vivo effects.
authors.affiliation: The George H. Whipple Laboratory for Cancer Research, Department of Pathology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Hsu
authors.forename: Yuh-Ling
authors.initials: YL
authors.lastname: Chen
authors.forename: Huei-Ju
authors.initials: HJ
authors.lastname: Ting
authors.forename: Wen-Jye
authors.initials: WJ
authors.lastname: Lin
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Yang
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Wu
authors.forename: Hong-Chiang
authors.initials: HC
authors.lastname: Chang
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Sanjay W
authors.initials: SW
authors.lastname: Pimplikar
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000737:chemistry; D018260:Gelsolin / Q000378:metabolism; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D008297:Male; D008856:Microscopy, Fluorescence; D056920:Nuclear Receptor Coactivator 1; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D018260:Gelsolin; D008024:Ligands; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D010455:Peptides; D011944:Receptors, Androgen; D014157:Transcription Factors; D013196:Dihydrotestosterone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1