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Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease

Sun Y, Liu Z, Cao X, Lu Y, Mi Z, He C, Liu J, Zheng Z, Li MJ, Li T, Xu D, Wu M, Cao Y, Li Y, Yang B, Mei C, Zhang L, Chen Y
Sci Adv. 2019:5(6):eaaw3593 doi:10.1126/sciadv.aaw3593
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.
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