Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/104564
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Type: Journal article
Title: Cyclin C is a haploinsufficient tumour suppressor
Author: Li, N.
Fassl, A.
Chick, J.
Inuzuka, H.
Li, X.
Mansour, M.
Liu, L.
Wang, H.
King, B.
Shaik, S.
Gutierrez, A.
Ordureau, A.
Otto, T.
Kreslavsky, T.
Baitsch, L.
Bury, L.
Meyer, C.
Ke, N.
Mulry, K.
Kluk, M.
et al.
Citation: Nature Cell Biology, 2014; 16(11):1080-+
Publisher: Nature Publishing Group
Issue Date: 2014
ISSN: 1465-7392
1476-4679
Statement of
Responsibility: 
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.
RMID: 0030061206
DOI: 10.1038/ncb3046
Appears in Collections:Medicine publications

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