Abstract
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 ofwhich lack the hinge domain, escape SPOP-mediated degradation. Prostate-cancer-associated mutants of SPOP cannot bind to and promote ARdestruction. 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.
Original language | English (US) |
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Pages (from-to) | 657-669 |
Number of pages | 13 |
Journal | Cell reports |
Volume | 6 |
Issue number | 4 |
DOIs | |
State | Published - 2014 |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology