Editors' ChoiceCancer

Cyclin, Notch, and ALL

Science Signaling  11 Nov 2014:
Vol. 7, Issue 351, pp. ec316
DOI: 10.1126/scisignal.aaa2547

Cyclin C interacts with cyclin-dependent kinases (CDKs) to promote cell proliferation and to regulate transcription. The gene encoding cyclin C (CCNC) is deleted in several tumor types and heterozygous in T-cell acute lymphoblastic leukemia (T-ALL). T-ALL cells frequently have activating mutations in the transmembrane receptor Notch1, which promotes T-cell differentiation and proliferation. Li et al. generated conditional cyclin C-deficient mice to investigate its role in T-ALL in vivo (see also Trakala and Malumbres). Mice with cyclin C-deficient hematopoietic cells had larger thymuses, more thymocytes (T-cell progenitors), and increased differentiation of T-cells in the bone marrow than did wild-type mice. When crossed with a long-latency T-ALL mouse model, cyclin C-deficiency accelerated development of T-ALL. Consistent with the role of Notch signaling in T-cell regulation, cyclin C-deficient thymocytes and bone marrow cells had increased abundance of the intracellular domain of Notch1 (NICD), which is cleaved from the plasma membrane-localized receptor to mediate transcriptional regulation. In the presence of cyclohexamide (to block de novo protein synthesis) and γ-secretase inhibitor (to block production of NICD), NICD in cyclin C-deficient thymocytes had a longer half-life than that in wild-type thymocytes. Treating wild-type thymocytes with proteasomal inhibitors increased the abundance of NICD and revealed a fraction of NICD that migrated more slowly by gel electrophoresis. In MOLT-16 human leukemic T-cells, cyclin C bound CDK19, a CDK family member that has not been associated with a regulatory cyclin and thus is considered an “orphan,” as well as to its known partners, CDK3 and CDK8. Incubation of cyclin C with any of the three CDKs induced the phosphorylation of GST-tagged NICD in an in vitro kinase assay, and knockdown of any of the three CDKs increased the abundance of NICD in T-cells. Mass spectrometry of thymocytes revealed cyclin C-dependent phosphorylatoin sites on NICD. Mutations in one of these phosphorylation sites in the NICD were identified in some T-ALL patient samples. Wild-type mice injected with hematopoietic progenitor cells expressing this patient mutation in NICD showed accelerated development of T-ALL, and cyclin C knockdown had no further effect on their tumorigenic capacity. The findings suggest that cyclin C teams up with CDKs to mark NICD for degradation and suppress the development of T-ALL.

N. Li, A. Fassl, J. Chick, H. Inuzuka, X. Li, M. R. Mansour, L. Liu, H. Wang, B. King, S. Shaik, A. Gutierrez, A. Ordureau, T. Otto, T. Kreslavsky, L. Baitsch, L. Bury, C. A. Meyer, N. Ke, K. A. Mulry, M. J. Kluk, M. Roy, S. Kim, X. Zhang, Y. Geng, A. Zagozdzon, S. Jenkinson, R. E. Gale, D. C. Linch, J. J. Zhao, C. G. Mullighan, J. W. Harper, J. C. Aster, I. Aifantis, H. von Boehmer, S. P. Gygi, W. Wei, A. T. Look, P. Sicinski, Cyclin C is a haploinsufficient tumour suppressor. Nat. Cell Biol. 16, 1080–1091 (2014). [PubMed]

M. Trakala, M. Malumbres, Cyclin C surprises in tumour suppression. Nat. Cell Biol. 16, 1031–1033 (2014). [PubMed]