Format

Send to

Choose Destination
Nat Cell Biol. 2014 Nov;16(11):1080-91. doi: 10.1038/ncb3046. Epub 2014 Oct 26.

Cyclin C is a haploinsufficient tumour suppressor.

Author information

1
1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
2
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
3
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
6
Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA.
7
1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
8
1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
9
1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Harvard School of Public Health, Boston, Massachusetts 02115, USA.
10
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
11
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
12
Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, USA.
13
Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
14
Department of Pathology, St. Jude Research Hospital, Memphis, Tennessee 38105, USA.

Abstract

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.

Comment in

PMID:
25344755
PMCID:
PMC4235773
DOI:
10.1038/ncb3046
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center