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https://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. |
DOI: | 10.1038/ncb3046 |
Published version: | http://dx.doi.org/10.1038/ncb3046 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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