Cyclin C is a haploinsufficient tumour suppressor

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. KlukMoni 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

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66 Citations (Scopus)

Abstract

Cyclin C was cloned as a growth-promoting G 1 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.

Original languageEnglish
Pages (from-to)1080-1091
Number of pages12
JournalNature cell biology
Volume16
Issue number11
DOIs
Publication statusPublished - 2014 Oct 31

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Li, N., Fassl, A., Chick, J., Inuzuka, H., Li, X., Mansour, M. R., Liu, L., Wang, H., King, B., Shaik, S., Gutierrez, A., Ordureau, A., Otto, T., Kreslavsky, T., Baitsch, L., Bury, L., Meyer, C. A., Ke, N., Mulry, K. A., ... Sicinski, P. (2014). Cyclin C is a haploinsufficient tumour suppressor. Nature cell biology, 16(11), 1080-1091. https://doi.org/10.1038/ncb3046