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CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus
- Source :
- Genes Dev
- Publication Year :
- 2019
-
Abstract
- Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12 binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphorylates Yki/Yap/Taz at S169/S128/S90 to inhibit CRL4DCAF12 recruitment, leading to Yki/Yap/Taz stabilization. As a consequence, inactivation of CDK7 reduced organ size and inhibited tumor growth, which could be reversed by restoring Yki/Yap activity. Our study identifies an unanticipated layer of Hippo pathway regulation, defines a novel mechanism by which CDK7 regulates tissue growth, and implies CDK7 as a drug target for Yap/Taz-driven cancer.
- Subjects :
- Carcinogenesis
Antineoplastic Agents
Biology
Phenylenediamines
Cell Line
03 medical and health sciences
Mice
0302 clinical medicine
Ubiquitin
Cell Line, Tumor
Genetics
Animals
Drosophila Proteins
Humans
030304 developmental biology
Cell Nucleus
0303 health sciences
Hippo signaling pathway
Effector
fungi
Liver Neoplasms
Nuclear Proteins
YAP-Signaling Proteins
Organ Size
Cyclin-Dependent Kinases
Ubiquitin ligase
Cell biology
body regions
Enzyme Activation
Gene Expression Regulation, Neoplastic
Drosophila melanogaster
Pyrimidines
Tumor progression
Hippo signaling
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Proteolysis
biology.protein
Trans-Activators
Phosphorylation
Cyclin-dependent kinase 7
Cyclin-Dependent Kinase-Activating Kinase
Outlook
Developmental Biology
Subjects
Details
- ISSN :
- 15495477
- Volume :
- 34
- Issue :
- 1-2
- Database :
- OpenAIRE
- Journal :
- Genesdevelopment
- Accession number :
- edsair.doi.dedup.....946118e9b506d1cbb6cc4424a511622a