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Nat Genet. 2014 Jun;46(6):588-94. doi: 10.1038/ng.2981. Epub 2014 May 4.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
2
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.
3
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
4
Weill Cornell College of Medicine, New York, New York, USA.
5
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
6
Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
7
Broad Institute, Cambridge, Massachusetts, USA.
8
1] Broad Institute, Cambridge, Massachusetts, USA. [2] Center for Biomedical Informatics, Harvard University, Boston, Massachusetts, USA.
9
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.
10
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.

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.

PMID:
24793136
PMCID:
PMC4251771
DOI:
10.1038/ng.2981
[Indexed for MEDLINE]
Free PMC Article

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