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|Title:||Cyclin C is a haploinsufficient tumour suppressor|
|Citation:||Nature Cell Biology, 2014; 16(11):1080-+|
|Publisher:||Nature Publishing Group|
|Na Li, Anne Fassl, Joel Chick, Hiroyuki Inuzuka, Xiaoyu Li, …, Charles G. Mullighan … et al.|
|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.|
|Keywords:||Cancer; cell division; tumour-suppressor proteins|
|Rights:||© 2014 Macmillan Publishers Limited. All rights reserved.|
|Appears in Collections:||Medicine publications|
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