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

Yongxing Gong1, Travis Ian Zack2, Luc G T Morris3

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Nature Genetics
|May 6, 2014
PubMed

Insights

The PARK2 tumor suppressor coordinates cell cycle progression by controlling cyclin D and cyclin E stability. PARK2 inactivation leads to accelerated cell cycles, and its deletion in cancer suggests a critical role in tumor suppression.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Coordinate control of cyclins is crucial for cell cycle regulation and tumor suppression.
  • Mechanisms underlying cyclin coordination remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the PARK2 tumor suppressor in coordinating cyclin stability.
  • To elucidate the mechanisms by which PARK2 regulates cell cycle progression.

Main Methods:

  • Analysis of approximately 5,000 tumor genomes.
  • Investigation of PARK2's function as an E3 ubiquitin ligase.
  • Characterization of PARK2's role in targeting cyclin D and cyclin E for degradation.

Main Results:

  • PARK2 E3 ubiquitin ligase coordinately controls the stability of cyclin D and cyclin E.
  • PARK2 is frequently deleted in human cancer, with mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1, or CDK4.
  • PARK2 inactivation leads to cyclin D accumulation and accelerated cell cycle progression.
  • PARK2 is part of a novel class of cullin-RING-containing ubiquitin ligases.

Conclusions:

  • PARK2 acts as a master regulator of G1/S cyclin stability, coordinating cell cycle progression.
  • PARK2 plays a significant role in tumor suppression by regulating cyclin stability.
  • PARK2 functions in a common pathway with CCND1, CCNE1, and CDK4 in cancer.

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