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.

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Acknowledgements

We thank E. Holland, A.C. Koff and J. Huse for helpful advice. S.T. was a recipient of a US National Institutes of Health T32 grant (5T32CA160001).This work was supported by the US National Institutes of Health (RO1 NS086875-01) (T.A.C.), the Memorial Sloan-Kettering Cancer Center Brain Tumor Center (T.A.C.), the Sontag Foundation (T.A.C.) and the Frederick Adler Fund (T.A.C.).

Author information

Affiliations

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

    • Yongxing Gong
    • , Sevin Turcan
    • , Selvaraju Veeriah
    • , Shasha Meng
    •  & Timothy A Chan
  2. Broad Institute, Cambridge, Massachusetts, USA.

    • Travis Ian Zack
    • , Steven E Schumacher
    • , Perry Palmedo
    •  & Rameen Beroukhim
  3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Travis Ian Zack
    •  & Rameen Beroukhim
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Travis Ian Zack
    •  & Rameen Beroukhim
  5. Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Travis Ian Zack
    •  & Rameen Beroukhim
  6. Biophysics Program, Harvard University, Boston, Massachusetts, USA.

    • Travis Ian Zack
  7. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Luc G T Morris
  8. Weill Cornell College of Medicine, New York, New York, USA.

    • Kan Lin
    •  & I-Li Tan
  9. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Ellen Hukkelhoven
    •  & Radhika Raheja
  10. Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Agnes Viale
  11. Center for Biomedical Informatics, Harvard University, Boston, Massachusetts, USA.

    • Perry Palmedo
  12. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Timothy A Chan
  13. Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Timothy A Chan

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Contributions

T.A.C., Y.G., T.I.Z. and R.B. designed the experiments. Y.G., T.I.Z., K.L., I.-L.T., S.T., S.V., S.M., A.V., S.E.S. and P.P. performed the experiments. Y.G., T.A.C., R.B., T.I.Z. and L.G.T.M. analyzed the data. E.H. and R.R. contributed new reagents. T.A.C., Y.G., T.I.Z. and R.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Timothy A Chan.

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    Supplementary Figures 1–8 and Supplementary Tables 1, 2 and 5

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    Supplementary Table 3

    Gene expression changes after PARK2 knockdown.

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    Supplementary Table 4

    Pathway analyses, based on genes differentially expressed after PARK2 knockdown.

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DOI

https://doi.org/10.1038/ng.2981

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