PUBLICATION
Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease
- Authors
- Sun, Y., Liu, Z., Cao, X., Lu, Y., Mi, Z., He, C., Liu, J., Zheng, Z., Li, M.J., Li, T., Xu, D., Wu, M., Cao, Y., Li, Y., Yang, B., Mei, C., Zhang, L., Chen, Y.
- ID
- ZDB-PUB-190612-6
- Date
- 2019
- Source
- Science advances 5: eaaw3593 (Journal)
- Registered Authors
- Cao, Ying, Li, Yuhao
- Keywords
- none
- MeSH Terms
-
- TRPP Cation Channels/deficiency
- TRPP Cation Channels/genetics
- TRPP Cation Channels/metabolism
- Kidney/drug effects
- Kidney/metabolism
- PubMed
- 31183407 Full text @ Sci Adv
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping