title: Cyclin C is a haploinsufficient tumour suppressor.
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.
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Fassl
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Chick
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: 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.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: King
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shavali
authors.initials: S
authors.lastname: Shaik
authors.affiliation: 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.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alban
authors.initials: A
authors.lastname: Ordureau
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Otto
authors.affiliation: 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.
authors.forename: Taras
authors.initials: T
authors.lastname: Kreslavsky
authors.affiliation: 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.
authors.forename: Lukas
authors.initials: L
authors.lastname: Baitsch
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Bury
authors.affiliation: 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.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Meyer
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Ke
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Mulry
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Moni
authors.initials: M
authors.lastname: Roy
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, USA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Geng
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagozdzon
authors.affiliation: Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jenkinson
authors.affiliation: Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.affiliation: Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.affiliation: 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.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Department of Pathology, St. Jude Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: 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.
authors.forename: Harald
authors.initials: H
authors.lastname: von Boehmer
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056745:Cyclin C / Q000378:metabolism*; D056849:Cyclin-Dependent Kinase 3 / Q000378:metabolism; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*
chemical_list: D056745:Cyclin C; D051881:Receptor, Notch1; D056849:Cyclin-Dependent Kinase 3; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases