Destruction of Full-Length Androgen Receptor by Wild-Type SPOP, but Not Prostate-Cancer-Associated Mutants

被引：253

作者：

An, Jian ^{[1
,2
]}

Wang, Chenji ^{[1
]}

Deng, Yibin ^{[3
]}

Yu, Long ^{[1
,4
]}

Huang, Haojie ^{[2
,5
,6
]}

机构：

[1] Fudan Univ, Inst Genet, State Key Lab Genet Engn, Shanghai 200433, Peoples R China

[2] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA

[3] Univ Minnesota, Hormel Inst, Canc Genet Lab, Austin, MN 55912 USA

[4] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China

[5] Mayo Clin, Coll Med, Dept Urol, Rochester, MN 55905 USA

[6] Mayo Clin, Coll Med, Ctr Canc, Rochester, MN 55905 USA

来源：

CELL REPORTS | 2014年 / 6卷 / 04期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

SPLICE VARIANTS; UBIQUITIN LIGASE; TRANSCRIPTIONAL ACTIVITY; INCREASED SURVIVAL; E3; LIGASE; PROTEIN; RESISTANCE; CELLS; FOXO1; GENE;

D O I：

10.1016/j.celrep.2014.01.013

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

The SPOP E3 ubiquitin ligase gene is frequently mutated in human prostate cancers. Here, we demonstrate that SPOP recognizes a Ser/Thr-rich degron in the hinge domain of androgen receptor (AR) and induces degradation of full-length AR and inhibition of AR-mediated gene transcription and prostate cancer cell growth. AR splicing variants, most of which lack the hinge domain, escape SPOP-mediated degradation. Prostate-cancer-associated mutants of SPOP cannot bind to and promote AR destruction. Furthermore, androgens antagonize SPOP-mediated degradation of AR, whereas antiandrogens promote this process. This study identifies AR as a bona fide substrate of SPOP and elucidates a role of SPOP mutations in prostate cancer, thus implying the importance of this pathway in resistance to antiandrogen therapy of prostate cancer.

引用

页码：657 / 669

页数：13

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