Positive transcription elongation factor b (P-TEFb) functions as a central regulator of transcription elongation. Activation of P-TEFb occurs through its dissociation from the transcriptionally inactive P-TEFb/HEXIM1/7SK snRNP complex. However, the mechanisms of signal-regulated P-TEFb activation and its roles in human diseases remain largely unknown. Here, we demonstrate that cAMP-PKA signaling disrupts the inactive P-TEFb/HEXIM1/7SK snRNP complex by PKA-mediated phosphorylation of HEXIM1 at serine-158. The cAMP pathway plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD), and we show that P-TEFb is hyperactivated in mouse and human ADPKD kidneys. Genetic activation of P-TEFb promotes cyst formation in a zebrafish ADPKD model, while pharmacological inhibition of P-TEFb attenuates cyst development by suppressing the pathological gene expression program in ADPKD mice. Our study therefore elucidates a mechanism by which P-TEFb activation by cAMP-PKA signaling promotes cystogenesis in ADPKD.
[1]Tianjin Med Univ, 2011 Collaborat Innovat Ctr Tianjin Med Epigenet, Tianjin Key Lab Med Epigenet,Sch Basic Med Sci, Key Lab Immune Microenvironm & Dis,Minist Educ,De, Tianjin 300070, Peoples R China.
[2]Tianjin Med Univ, 2011 Collaborat Innovat Ctr Tianjin Med Epigenet, Tianjin Key Lab Med Epigenet, Dept Pharmacol,Sch Basic Med Sci, Tianjin 300070, Peoples R China.
[3]Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China.
[4]Peking Union Med Coll, Beijing 100050, Peoples R China.
[5]Second Mil Med Univ, Kidney Inst, Dept Nephrol, Shanghai Changzheng Hosp, Shanghai 200003, Peoples R China.
[6]Shanghai Univ Tradit Chinese Med, Shanghai Key Lab Tradit Chinese Clin Med, Dept Nephrol, Shuguang Hosp,TCM Inst Kidney Dis, Shanghai 201203, Peoples R China.
[7]Tongji Univ, Clin & Translat Res Ctr, Shanghai First Matern & Infant Hosp, Sch Life Sci & Technol, Shanghai 200092, Peoples R China.
[8]Nankai Univ, Dept Pathol, Sch Med, 94 Weijin Rd, Tianjin 300071, Peoples R China.
[9]Peking Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing 100038, Peoples R China.
[10]Tianjin Med Univ Canc Inst & Hosp, Dept Thyroid & Neck Tumor, Oncol Key Lab Canc Prevent & Therapy, Natl Clin Res Ctr Canc, Tianjin 300060, Peoples R China.
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