Cyclin C Suppresses T-ALL via Regulation of NOTCH1 Protein Stability

Cyclin C was first described as a proproliferative G₁ cyclin that functions in cell-cycle reentry from quiescence and as a negative regulator of gene transcription. The gene encoding cyclin C, CCNC, is located in a region that is frequently lost in various human tumors, including acute lymphoblastic leukemia (ALL); however, the role of cyclin C in tumorigenesis remains unclear. Li and colleagues sought to determine the molecular roles of cyclin C in development and tumorigenesis in vivo using a conditional cyclin C knockout mouse model. Germline loss of cyclin C resulted in embryonic lethality, and acute cyclin C deletion in murine cells in vitro demonstrated that loss of cyclin C did not alter global transcription or affect cell proliferation, but did impair cell-cycle reentry from quiescence. Surprisingly, acute hematopoietic-specific ablation of cyclin C in mice enhanced the differentiation of bone marrow cells along the T-cell lineage and resulted in elevated levels of the NOTCH1 intracellular domain (ICN1) without altering expression of NOTCH1 mRNA or levels of full-length NOTCH1, suggesting that cyclin C modulates ICN1 protein stability. Consistent with this idea, cyclin C promoted ICN1 protein degradation by activating the cyclin-dependent kinases CDK3, CDK8, and CDK19; these cyclin C–CDK complexes directly phosphorylated ICN1, resulting in its polyubiquitination and proteolytic degradation. Although cyclin C loss was not sufficient to induce tumorigenesis, deletion or heterozygous loss of cyclin C accelerated NOTCH1-driven T-ALL development in combination with other genetic lesions. Furthermore, heterozygous deletion of CCNC and point mutations in ICN1 that prevented cyclin C–CDK-mediated phosphorylation were detected in human T-ALL and augmented T-ALL development in mice. These results define an important role for cyclin C in the regulation of oncogenic NOTCH1 levels in hematopoietic cells and identify cyclin C as a haploinsufficient tumor suppressor in T-ALL.

Li N, Fassl A, Chick J, Inuzuka H, Li X, Mansour MR, et al. Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol 2014;16:1080–91.