ArticleNature cell biology2014
Cyclin C is a haploinsufficient tumour suppressor.
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Article in Nature cell biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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84citing papers in PubMed
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Who cites it
84 citing papers in PubMed, 163 citations in OpenAlex.
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- Cyclin C promotes pancreatic developmentand suppresses cancer initiation by maintenance of the autophagy-lysosome pathway.iScience · 2026Article
- UTERINE FIBROIDS.Physiological reviews · 2025Review
- Targeting Transcriptional Cyclin-Dependent Kinases in Cancer.Molecular cancer therapeutics · 2025Review
- Mediator Kinase Inhibitor Selectivity and Activity in Colorectal Cancer.ACS chemical biology · 2025Article
- Modes of Notch signalling in development and disease.Nature reviews. Molecular cell biology · 2025Review
- A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling.iScience · 2025Article
- Review
- Putting the brakes on cyclin C: a promising strategy to cure B-cell acute lymphoblastic leukemia?Haematologica · 2025Article
- Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses.Haematologica · 2025Article
- Novel determinants of NOTCH1 trafficking and signaling in breast epithelial cells.Life science alliance · 2025Article
- Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control.Frontiers of medicine · 2025Review
- Molecular insights and clinical implications for the tumor suppressor role of SCFBiochimica et biophysica acta. Reviews on cancer · 2024Review
- FBP1 inhibits NSCLC stemness by promoting ubiquitination of Notch1 intracellular domain and accelerating degradation.Cellular and molecular life sciences : CMLS · 2024Article
- Article
- Regulation of Notch1 Signalling by Long Non-Coding RNAs in Cancers and Other Health Disorders.International journal of molecular sciences · 2023Review
- In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer.Nature communications · 2023Article
- Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex.International journal of molecular sciences · 2023Review
- Multi-Omic Analysis of CIC's Functional Networks Reveals Novel Interaction Partners and a Potential Role in Mitotic Fidelity.Cancers · 2023Article
- Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia.Leukemia · 2023Article
24 more citing papers are in PubMed but not listed here.
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Authors and funding
38 authors at 10 institutions in 2 countries.
Na Li1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Anne Fassl1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Joel ChickDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hiroyuki InuzukaDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Xiaoyu Li1] 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.
Marc R Mansour1] 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.
Lijun Liu1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Haizhen Wang1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bryan KingHoward Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA.
Shavali ShaikDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Alejandro Gutierrez1] 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.
Alban OrdureauDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Tobias Otto1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Taras Kreslavsky1] 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.
Lukas Baitsch1] 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.
Leah Bury1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Clifford A Meyer1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Nan Ke1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kristin A Mulry1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Michael J KlukDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Moni RoyDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sunkyu KimNovartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Xiaowu ZhangCell Signaling Technology, Inc., Danvers, Massachusetts 01923, USA.
Yan Geng1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Agnieszka Zagozdzon1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sarah JenkinsonDepartment of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
Rosemary E GaleDepartment of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
David C LinchDepartment of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
Jean J Zhao1] 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.
Charles G MullighanDepartment of Pathology, St. Jude Research Hospital, Memphis, Tennessee 38105, USA.
J Wade HarperDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Jon C AsterDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Iannis AifantisHoward Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA.
Harald von Boehmer1] 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.
Steven P GygiDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wenyi WeiDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
A Thomas Look1] 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.
Piotr Sicinski1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Dana-Farber Cancer Institute · USHarvard University · USBeth Israel Deaconess Medical Center · USHoward Hughes Medical Institute · USUniversity College London · GBBrigham and Women's Hospital · USCell Signaling Technology (United States) · USLondon Cancer · GBNovartis (United States) · USSt. Jude Children's Research Hospital · US
Funding
Viral Vector Technology (VVTSR)P30CA021765 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI CHARLES ROBERTS · 1985 to 2026
$166.9MThe Molecular Function of D-cyclins in T-ALLP01CA109901 · NCI · DANA-FARBER CANCER INSTITUTE · PI LOOK, A. THOMAS · 2004 to 2014
$19.6MUbiquitin Mediated Proteolysis and Cell Cycle ControlR01AG011085 · NIA · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JEFFREY W HARPER · 1993 to 2026
$10.9MProtein CoreP01CA119070 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI ASTER, JON C. · 2006 to 2016
$10.3MSPECIFIC ROLES FOR D-CYCLINS IN ONCOGENESISR01CA083688 · NCI · DANA-FARBER CANCER INSTITUTE · PI SICINSKI, PETER · 2000 to 2016
$4.6ME-Cyclins in normal and oncogenic proliferationR01CA108950 · NCI · DANA-FARBER CANCER INSTITUTE · PI SICINSKI, PETER · 2004 to 2013
$3.7MThe role of the SCF/FBW7 ubiquitin ligase complex in hematopiesis and leukemia.R01CA133379 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI AIFANTIS, IANNIS · 2009 to 2018
$3.6MRegulation of hematopoietic stem cell differentiationR01CA105129 · NCI · UNIVERSITY OF CHICAGO · PI AIFANTIS, IANNIS · 2005 to 2014
$2.8MMechanisms of T cell leukemia induction and maintenanceR01CA149655 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI AIFANTIS, IANNIS · 2010 to 2015
$2.0MFunctional analysis of beta-TRCP in cell cycle control and DNA damage responseR01GM094777 · NIGMS · BETH ISRAEL DEACONESS MEDICAL CENTER · PI WEI, WENYI · 2012 to 2015
$1.3MNew insights into the role of the Fbw7 tumor suppressor in senescence and agingK01AG041218 · NIA · BETH ISRAEL DEACONESS MEDICAL CENTER · PI INUZUKA, HIROYUKI · 2011 to 2015
$621kCancer Research UK 15556Medical Research Council G0500389NCI NIH HHS P01 CA109901NCI NIH HHS P01 CA119070NCI NIH HHS P30 CA021765NCI NIH HHS R01 CA083688NCI NIH HHS R01 CA105129NCI NIH HHS R01 CA108950NCI NIH HHS R01 CA133379NCI NIH HHS R01 CA149655NIA NIH HHS K01 AG041218NIA NIH HHS R01 AG011085NIGMS NIH HHS GM094777
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.
Indexed as
AnimalsCells, CulturedCyclin CCyclin-Dependent Kinase 3Cyclin-Dependent Kinase 8Cyclin-Dependent KinasesHumansMiceMice, KnockoutMice, TransgenicPrecursor T-Cell Lymphoblastic Leukemia-LymphomaReceptor, Notch1Cyclin CCyclin-Dependent Kinase 3Cyclin-Dependent Kinase 8Cyclin-Dependent KinasesReceptor, Notch1
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