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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle*
  • Cell Line, Tumor
  • Cyclin D1 / metabolism*
  • Cyclin E / metabolism*
  • Cyclin-Dependent Kinase 4 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • G1 Phase
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor
  • Genome, Human
  • Genomics
  • Humans
  • Insecta
  • Oncogene Proteins / metabolism*
  • RNA, Small Interfering / metabolism
  • S Phase
  • Ubiquitin-Protein Ligases / genetics*


  • CCND1 protein, human
  • CCNE1 protein, human
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p16
  • Oncogene Proteins
  • RNA, Small Interfering
  • Cyclin D1
  • Ubiquitin-Protein Ligases
  • parkin protein
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4