Modulation of androgen receptor transactivation by FoxH1 - A newly identified androgen receptor corepressor

被引:37
作者
Chen, GC
Nomura, M
Morinaga, H
Matsubara, E
Okabe, T
Goto, K
Yanase, T
Zheng, H
Lu, J
Nawata, H
机构
[1] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, Fukuoka 8128582, Japan
[2] Second Mil Med Univ, Dept Pathophysiol, Shanghai 200433, Peoples R China
[3] Second Mil Med Univ, Lab Ctr Pharmacol, Shanghai 200433, Peoples R China
关键词
D O I
10.1074/jbc.M506147200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Androgen signaling plays key roles in the development and progression of prostate cancer, and numerous ongoing studies focus on the regulation of androgen receptor (AR) transactivity to develop novel therapies for the treatment of androgen-independent prostate cancer. FoxH1, amember of the Forkhead-box ( FOX) gene family of transcription factors, takes part in mediating transforming growth factor-beta/activin signaling through its interaction with the Smad2 center dot Smad4 complex. Using a series of experiments, we found that FoxH1 repressed both ligand-dependent and - independent transactivation of the AR on androgen-induced promoters. This action of FoxH1 was independent of its transactivation capacity and activin A but relieved by Smad2 center dot Smad4. In addition, the repression of the AR by FoxH1 did not require deacetylase activity. A protein-protein interaction was identified between the AR and FoxH1 independently of dihydrotestosterone. Furthermore, a confocal microscopic analysis of LNCaP cells revealed that the interaction between the AR and FoxH1 occurred in the nucleus and that FoxH1 specifically blocked the foci formation of dihydrotestosterone-activated AR, which has been shown to be correlated with the AR transactivation potential. Taken together, our results indicate that FoxH1 functions as a new corepressor of the AR. Our observations not only strengthen the role of FoxH1 in AR-mediated transactivation but also suggest that therapeutic interventions based on AR-coregulator interactions could be designed to block both androgen-dependent and - independent growth of prostate cancer.
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收藏
页码:36355 / 36363
页数:9
相关论文
共 81 条
[71]   Androgen receptor corepressors: An overview [J].
Wang, L ;
Hsu, CL ;
Chang, CS .
PROSTATE, 2005, 63 (02) :117-130
[72]   Activin inhibits basal and androgen-stimulated proliferation and induces apoptosis in the human prostatic cancer cell line, LNCaP [J].
Wang, QF ;
Tilly, KI ;
Tilly, JL ;
Preffer, F ;
Schneyer, AL ;
Crowley, WF ;
Sluss, PM .
ENDOCRINOLOGY, 1996, 137 (12) :5476-5483
[73]   Activation functions 1 and 2 of nuclear receptors:: Molecular strategies for transcriptional activation [J].
Wärnmark, A ;
Treuter, E ;
Wright, APH ;
Gustafsson, JÅ .
MOLECULAR ENDOCRINOLOGY, 2003, 17 (10) :1901-1909
[74]   A Smad transcriptional corepressor [J].
Wotton, D ;
Lo, RS ;
Lee, S ;
Massagué, J .
CELL, 1999, 97 (01) :29-39
[75]  
YING SY, 1989, J STEROID BIOCHEM, V33, P705
[76]  
Ying SY, 1997, P SOC EXP BIOL MED, V214, P114
[77]   Inhibition of androgen receptor-mediated transcription by amino-terminal enhancer of split [J].
Yu, X ;
Li, P ;
Roeder, RG ;
Wang, ZX .
MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (14) :4614-4625
[78]   Regulation of growth and prostatic marker expression by activin A in an androgen-sensitive prostate cancer cell line LNCAP [J].
Zhang, Z ;
Zhao, YL ;
Batres, Y ;
Lin, MF ;
Ying, SY .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 234 (02) :362-365
[79]   Activation function-1 domain of androgen receptor contributes to the interaction between subnuclear splicing factor compartment and nuclear receptor compartment - Identification of the p102 U5 small nuclear ribonucleoprotein particle-binding protein as a coactivator for the receptor [J].
Zhao, Y ;
Goto, K ;
Saitoh, M ;
Yanase, T ;
Nomura, M ;
Okabe, T ;
Takayanagi, R ;
Nawata, H .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (33) :30031-30039
[80]   Signal transduction targets in androgen-independent prostate cancer [J].
Zhou, J ;
Scholes, J ;
Hsieh, JT .
CANCER AND METASTASIS REVIEWS, 2001, 20 (3-4) :351-362