期刊
SCIENCE ADVANCES
卷 5, 期 6, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aaw3593
关键词
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资金
- National Natural Science Foundation of China [81670612, 81873595, 31571336, 81770658, 31571337]
- Tianjin Municipal Science and Technology Commission [15JCYBJC54100, 15JCYBJC54000]
- National Key Research and Development Program of China [2016YFC0901502, 2017YFA0504102]
- Shanghai Top Priority Clinical Disciplines Construction Project [2017ZZ02009]
- Excellent Talent Project of Tianjin Medical University
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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