title: Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins.
abstract: Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4-implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING-containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Gong
authors.affiliation: 1] Broad Institute, Cambridge, Massachusetts, USA. [2] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [4] Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [5] Biophysics Program, Harvard University, Boston, Massachusetts, USA.
authors.forename: Travis Ian
authors.initials: TI
authors.lastname: Zack
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Luc G T
authors.initials: LG
authors.lastname: Morris
authors.affiliation: Weill Cornell College of Medicine, New York, New York, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Lin
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hukkelhoven
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Raheja
authors.affiliation: Weill Cornell College of Medicine, New York, New York, USA.
authors.forename: I-Li
authors.initials: IL
authors.lastname: Tan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Sevin
authors.initials: S
authors.lastname: Turcan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Selvaraju
authors.initials: S
authors.lastname: Veeriah
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Shasha
authors.initials: S
authors.lastname: Meng
authors.affiliation: Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: 1] Broad Institute, Cambridge, Massachusetts, USA. [2] Center for Biomedical Informatics, Harvard University, Boston, Massachusetts, USA.
authors.forename: Perry
authors.identifier: 0000000210585773
authors.initials: P
authors.lastname: Palmedo
authors.affiliation: 1] Broad Institute, Cambridge, Massachusetts, USA. [2] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [4] Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: 1] Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. [2] Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. [3] Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D016193:G1 Phase; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D007313:Insecta; D015513:Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C530104:CCND1 protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D019938:Cyclin D1; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4