| First Author | Li N | Year | 2014 |
| Journal | Nat Cell Biol | Volume | 16 |
| Issue | 11 | Pages | 1080-91 |
| PubMed ID | 25344755 | Mgi Jnum | J:217695 |
| Mgi Id | MGI:5615331 | Doi | 10.1038/ncb3046 |
| Citation | Li N, et al. (2014) Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol 16(11):1080-91 |
| abstractText | 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. |
