| Title | Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease |
| Authors | Sun, Yongzhan Liu, Zhiheng Cao, Xinyi Lu, Yi Mi, Zeyun He, Chaoran Liu, Jing Zheng, Zhanye Li, Mulin Jun Li, Tiegang Xu, Dechao Wu, Ming Cao, Ying Li, Yuhao Yang, Baoxue Mei, Changlin Zhang, Lirong Chen, Yupeng |
| Affiliation | 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 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 Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China Peking Union Med Coll, Beijing 100050, Peoples R China Second Mil Med Univ, Kidney Inst, Dept Nephrol, Shanghai Changzheng Hosp, Shanghai 200003, Peoples R China 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 Tongji Univ, Clin & Translat Res Ctr, Shanghai First Matern & Infant Hosp, Sch Life Sci & Technol, Shanghai 200092, Peoples R China Nankai Univ, Dept Pathol, Sch Med, 94 Weijin Rd, Tianjin 300071, Peoples R China Peking Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing 100038, Peoples R China 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 |
| Issue Date | 2019 |
| Publisher | SCIENCE ADVANCES |
| Abstract | 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. |
| URI | http://hdl.handle.net/20.500.11897/547710 |
| ISSN | 2375-2548 |
| DOI | 10.1126/sciadv.aaw3593 |
| Indexed | SCI(E) EI |
| Appears in Collections: | 基础医学院 |
