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
  • Kidney/pathology
  • Protein Binding
  • Positive Transcriptional Elongation Factor B/antagonists & inhibitors
  • Positive Transcriptional Elongation Factor B/genetics
  • Positive Transcriptional Elongation Factor B/metabolism*
  • Cysts/metabolism
  • Cysts/pathology
  • Cyclic AMP-Dependent Protein Kinases/chemistry
  • Cyclic AMP-Dependent Protein Kinases/metabolism*
  • Transcription Factors/metabolism
  • Signal Transduction
  • Phosphorylation
  • Disease Models, Animal
  • Mice, Knockout
  • Cyclic AMP/metabolism*
  • Mice
  • Humans
  • Piperidines/pharmacology
  • Piperidines/therapeutic use
  • Flavonoids/pharmacology
  • Flavonoids/therapeutic use
  • Polycystic Kidney, Autosomal Dominant/drug therapy
  • Polycystic Kidney, Autosomal Dominant/metabolism
  • Polycystic Kidney, Autosomal Dominant/pathology*
  • Zebrafish/metabolism
  • Ribonucleoproteins, Small Nuclear/chemistry
  • Ribonucleoproteins, Small Nuclear/metabolism
  • Animals
  • RNA-Binding Proteins/metabolism
(all 34)
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
Figures
No images available
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
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. (2019) Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease. Science advances. 5:eaaw3593.