Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer

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Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer

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Title: Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer
Author: Liu, Xiaming; Gao, Yanfei; Ye, HuiHui; Gerrin, Sean; Ma, Fen; Wu, Yiming; Zhang, Tengfei; Russo, Joshua; Cai, Changmeng; Yuan, Xin; Liu, Jihong; Chen, Shaoyong; Balk, Steven P.

Note: Order does not necessarily reflect citation order of authors.

Citation: Liu, X., Y. Gao, H. Ye, S. Gerrin, F. Ma, Y. Wu, T. Zhang, et al. 2017. “Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer.” Nucleic Acids Research 45 (7): 3738-3751. doi:10.1093/nar/gkw1291. http://dx.doi.org/10.1093/nar/gkw1291.
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Abstract: Abstract 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 1α (PP1α), 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 PP1α, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC.
Published Version: doi:10.1093/nar/gkw1291
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397168/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630536
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