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 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.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Androgen Receptor Antagonists / pharmacology
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Androgens / pharmacology
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Binding Sites
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Cell Growth Processes
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Cell Line, Tumor
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HEK293 Cells
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Humans
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Male
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Molecular Sequence Data
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Mutation*
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Prostatic Neoplasms / enzymology*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proteolysis
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Receptors, Androgen / metabolism*
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription, Genetic
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Ubiquitination
Substances
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Androgen Receptor Antagonists
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Androgens
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Nuclear Proteins
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Protein Isoforms
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Receptors, Androgen
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Repressor Proteins
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SPOP protein, human