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Nat Genet DOI:10.1038/ng.2981

Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins.

Publication TypeJournal Article
Year of Publication2014
AuthorsGong, Y, Zack, TIan, Morris, LGT, Lin, K, Hukkelhoven, E, Raheja, R, Tan, I-L, Turcan, S, Veeriah, S, Meng, S, Viale, A, Schumacher, SE, Palmedo, P, Beroukhim, R, Chan, TA
JournalNat Genet
Volume46
Issue6
Pages588-94
Date Published2014 Jun
ISSN1546-1718
KeywordsAnimals, Cell Cycle, Cell Line, Tumor, Cyclin D1, Cyclin E, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p16, G1 Phase, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Genome, Human, Genomics, Humans, Insects, Oncogene Proteins, RNA, Small Interfering, S Phase, Ubiquitin-Protein Ligases
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.

URLhttp://dx.doi.org/10.1038/ng.2981
DOI10.1038/ng.2981
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24793136?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID24793136
PubMed Central IDPMC4251771
Grant ListT32 CA160001 / CA / NCI NIH HHS / United States
R01 NS086875-01 / NS / NINDS NIH HHS / United States
K08 DE024774 / DE / NIDCR NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
5T32CA160001 / CA / NCI NIH HHS / United States
R01 NS086875 / NS / NINDS NIH HHS / United States