Journal
NATURE CELL BIOLOGY
Volume 16, Issue 11, Pages 1080-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3046
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Funding
- American Syrian Lebanese Associated Charities of St. Jude Children's Research Hospital [P01 CA109901, R01 CA083688, GM094777, R01 AG011085]
- MRC [G0500389] Funding Source: UKRI
- Cancer Research UK [15556] Funding Source: researchfish
- Medical Research Council [G0500389] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10370, NF-SI-0513-10144] Funding Source: researchfish
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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.
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