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学科主题: 临床医学
题名:
Nuclear Export Signal of Androgen Receptor (NESAR) Regulation of Androgen Receptor Level in Human Prostate Cell Lines via Ubiquitination and Proteasome-Dependent Degradation
作者: Gong, Yanqing1,2,4; Wang, Dan4; Dar, Javid A.4; Singh, Prabhpreet4; Graham, Lara4; Liu, Weijun4; Ai, Junkui4; Xin, Zhongcheng1,2; Guo, Yinglu1,2; Wang, Zhou4,5
刊名: ENDOCRINOLOGY
发表日期: 2012-12-01
DOI: 10.1210/en.2012-1841
卷: 153, 期:12, 页:5716-5725
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Endocrinology & Metabolism
研究领域[WOS]: Endocrinology & Metabolism
关键词[WOS]: AGGRESOME FORMATION ; LIVING CELLS ; CANCER CELLS ; BINDING ; SYNPHILIN-1 ; DYNAMICS ; PHOSPHORYLATION ; OVEREXPRESSION ; STABILIZATION ; TRANSCRIPTION
英文摘要:

Androgen receptor (AR) plays a key role in prostate development and carcinogenesis. Increased expression and/or stability of AR is associated with sensitization of prostate cancer cells to low levels of androgens, leading to castration resistance. Hence, understanding the mechanisms regulating AR protein stability is clinically relevant and may lead to new approaches to prevent and/or treat prostate cancer. Using fluorescence microscopy, Western blot, and pulse chase assay, we showed that nuclear export signal (NES)(AR), a nuclear export signal in the ligand binding domain (LBD) of AR, can significantly enhance the degradation of fusion protein constructs in PC3 prostate cancer cells. The half-life of GFP-NESAR was less than 3 h, which was 10 times shorter than that of green fluorescent protein (GFP) control. Further analysis showed tha tNES(AR) can signal for polyubiquitination and that degradation of NESAR-containing fusion proteins can be blocked by proteasome inhibitor MG132. Ubiquitination of GFP-AR or GFP-LBD was suppressed in the presence of dihydrotestosterone, which is known to suppress NESAR while inducing nuclear localization signal 2 in AR or LBD, suggesting that the export activity of NESAR is required for NESAR-mediated polyubiquitination. Treatment with MG132 also induced aggresome formation of NESAR-containing fusion proteins in perinuclear regions of the transfected PC3 cells, indicating a role for NESAR in inducing unfolded protein responses. The above observations suggest that NESAR plays a key role in AR ubiquitination and proteasome-dependent degradation in prostate cancer cells. (Endocrinology 153: 5716-5725, 2012)

语种: 英语
所属项目编号: R01 CA108675 ; R37 DK51193 ; P50 CA090386
项目资助者: National Institutes of Health ; China Scholarship Council
WOS记录号: WOS:000311752300005
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/60475
Appears in Collections:北京大学第一临床医学院_泌尿外科_期刊论文

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作者单位: 1.Peking Univ, Inst Urol, Beijing 100034, Peoples R China
2.Natl Urol Canc Ctr, Beijing 100034, Peoples R China
3.Peking Univ, Dept Urol, Peking Univ Hosp 1, Beijing 100034, Peoples R China
4.Univ Pittsburgh, Sch Med, Dept Urol, Inst Canc, Pittsburgh, PA 15232 USA
5.Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Inst Canc, Pittsburgh, PA 15232 USA

Recommended Citation:
Gong, Yanqing,Wang, Dan,Dar, Javid A.,et al. Nuclear Export Signal of Androgen Receptor (NESAR) Regulation of Androgen Receptor Level in Human Prostate Cell Lines via Ubiquitination and Proteasome-Dependent Degradation[J]. ENDOCRINOLOGY,2012,153(12):5716-5725.
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