Journal
NUCLEIC ACIDS RESEARCH
Volume 45, Issue 7, Pages 3738-3751Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw1291
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Funding
- NIH [K99/R00 CA135592, P01 CA163227]
- DOD [W81XWH-14-1-0016]
- SPORE in Prostate Cancer P50 [CA090381]
- Tongji Hospital, Tongji Medical School, HuaZhong University of Science and Technology (Wuhan, China) Scholarship
- U.S. Department of Defense [W81XWH-14-1-0016]
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P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1 alpha (PP1 alpha), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription. AR S81 is also phosphorylated by CDK1, and blocking basal CDK1-mediated S81 phosphorylation markedly suppresses AR activity and initiation of this positive feedback loop. Finally, androgen-independent AR activity in castration-resistant prostate cancer (CRPC) cells is driven by increased CDK1-mediated S81 phosphorylation. Collectively these findings reveal a mechanism involving PP1 alpha, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC.
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