Cyclin C is a haploinsufficient tumour suppressor

• DOI: 10.1038/ncb3046
• Publication Date: 2014-10-26T19:30:57Z
• Authors: 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
• Keywords: Cyclin D; Cyclin A2; Cyclin A; Cyclin E; Cyclin-dependent kinase complex; Cyclin B

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.