| First Author | Sun Y | Year | 2019 |
| Journal | Sci Adv | Volume | 5 |
| Issue | 6 | Pages | eaaw3593 |
| PubMed ID | 31183407 | Mgi Jnum | J:338737 |
| Mgi Id | MGI:7514474 | Doi | 10.1126/sciadv.aaw3593 |
| Citation | Sun Y, et al. (2019) Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease. Sci Adv 5(6):eaaw3593 |
| abstractText | 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. |
