title: Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer.
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.
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xiaming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: HuiHui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Gerrin
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Ma
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Russo
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Chen
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D059002:Androgen Receptor Antagonists; D002843:Chromatin; D011944:Receptors, Androgen; D042925:Positive Transcriptional Elongation Factor B; D016203:CDC2 Protein Kinase; D042863:Cyclin-Dependent Kinase 9; D054645:Protein Phosphatase 1