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Cyclin C is a haploinsufficient tumour suppressor.

Nature cell biology (2014-10-27)
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
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.

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