MassIVE MSV000080728

Imported Reanalysis Dataset Public PXD001237

Cyclin C-CDK3/8/19 kinases play a tumor-suppressive role in vivo

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Description

Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Cyclin C ; Notch1 ; Proteomics ; LC-MS/MS

Contact

Principal Investigators:
(in alphabetical order) 		Steven P Gygi, Department of Cell Biology, Harvard Medical School, Boston, USA, N/A
Submitting User: ccms

Publications

Li N, Fassl A, Chick J, Inuzuka H, Li X, Mansour MR, Liu L, Wang H, King B, Shaik S, Gutierrez A, Ordureau A, Otto T, Kreslavsky T, Baitsch L, Bury L, Meyer CA, Ke N, Mulry KA, Kluk MJ, Roy M, Kim S, Zhang X, Geng Y, Zagozdzon A, Jenkinson S, Gale RE, Linch DC, Zhao JJ, Mullighan CG, Harper JW, Aster JC, Aifantis I, von Boehmer H, Gygi SP, Wei W, Look AT, Sicinski P.
Cyclin C is a haploinsufficient tumour suppressor.
Nat. Cell Biol. 2014 Nov;16(11):1080-91. Epub 2014 Oct 26.

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