biostudies-literatureLi NCancer Research UKNIA NIH HHSMedical Research CouncilNational Institute for Health Research (NIHR)NCI NIH HHSNIGMS NIH HHS1080-91https://www.ebi.ac.uk/biostudies/studies/S-EPMC4235773biostudies-literatureUnknown16(11)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.Nature cell biologyCyclin C is a haploinsufficient tumour suppressor.PMC4235773G0500389R01 CA108950R01 CA133379GM094777K01 AG041218R01 AG011085P01 CA119070R01 CA105129NF-SI-0513-10144P30 CA021765R01 CA149655NF-SI-0507-1037015556Gale RELiu LShaik Svon Boehmer HWang HOrdureau AKe NWei WHarper JWOtto TLinch DCZhao JJMulry KAInuzuka HGeng YMeyer CARoy MBaitsch LBury LAster JCLook ATKluk MJGutierrez AAifantis IZagozdzon AJenkinson SLi NKing BKim SSicinski PLi XKreslavsky TMansour MRFassl AZhang XMullighan CGChick JGygi SPfalseCyclin C is a haploinsufficient tumour suppressor.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.2014-01-01T00:00:00Z2014 Nov2024-11-20T04:11:18.707Z2019-03-27T01:39:50ZS-EPMC42357732534475510.1038/ncb3046