Author: ["Na Li","Anne Fassl","Joel Chick","Hiroyuki Inuzuka","Xiaoyu Li","Marc R. Mansour","Lijun Liu","Haizhen Wang","Bryan King","Shavali Shaik","Alejandro Gutierrez","Alban Ordureau","Tobias Otto","Taras Kreslavsky","Lukas Baitsch","Leah Bury","Clifford A. Meyer","Nan Ke","Kristin A. Mulry","Michael J. Kluk","Moni Roy","Sunkyu Kim","Xiaowu Zhang","Yan Geng","Agnieszka Zagozdzon","Sarah Jenkinson","Rosemary E. Gale","David C. Linch","Jean J. Zhao","Charles G. Mullighan","J. Wade Harper","Jon C. Aster","Iannis Aifantis","Harald von Boehmer","Steven P. Gygi","Wenyi Wei","A. Thomas Look","Piotr Sicinski"]
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Abstract
Cyclin C was cloned as a growth-promoting G1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an ‘orphan’ CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C–CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C–CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C. Through gene knockout experiments, Sicinski and colleagues reveal a role for cyclin C as a haploinsufficient tumour suppressor in T-cell acute lymphoblastic leukaemia, acting through phosphorylation of intracellular Notch1, mediating its degradation.Cite this article
Li, N., Fassl, A., Chick, J. et al. Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol 16, 1080–1091 (2014). https://doi.org/10.1038/ncb3046 