| Literature DB >> 25344755 |
Na Li1, Anne Fassl1, Joel Chick2, Hiroyuki Inuzuka3, Xiaoyu Li4, Marc R Mansour5, Lijun Liu1, Haizhen Wang1, Bryan King6, Shavali Shaik3, Alejandro Gutierrez7, Alban Ordureau2, Tobias Otto1, Taras Kreslavsky4, Lukas Baitsch8, Leah Bury1, Clifford A Meyer9, Nan Ke1, Kristin A Mulry1, Michael J Kluk10, Moni Roy10, Sunkyu Kim11, Xiaowu Zhang12, Yan Geng1, Agnieszka Zagozdzon1, Sarah Jenkinson13, Rosemary E Gale13, David C Linch13, Jean J Zhao8, Charles G Mullighan14, J Wade Harper2, Jon C Aster10, Iannis Aifantis6, Harald von Boehmer4, Steven P Gygi2, Wenyi Wei3, A Thomas Look7, Piotr Sicinski1.
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.Entities:
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Year: 2014 PMID： 25344755 PMCID： PMC4235773 DOI： 10.1038/ncb3046
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824