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TSPYL5 suppresses p53 levels and function by physical interaction with USP7

Nature Cell Biology volume 13, pages 102108 (2011) | Download Citation

Abstract

We have previously reported a gene expression signature that is a powerful predictor of poor clinical outcome in breast cancer1. Among the seventy genes in this expression profile is a gene of unknown function: TSPYL5 (TSPY-like 5, also known as KIAA1750). TSPYL5 is located within a small region at chromosome 8q22 that is frequently amplified in breast cancer, which suggests that TSPYL5 has a causal role in breast oncogenesis2,3. Here, we report that high TSPYL5 expression is an independent marker of poor outcome in breast cancer. Mass spectrometric analysis revealed that TSPYL5 interacts with ubiquitin-specific protease 7 (USP7; also known as herpesvirus-associated ubiquitin-specific protease; HAUSP). USP7 is the deubiquitylase for the p53 tumour suppressor4 and TSPYL5 reduces the activity of USP7 towards p53, resulting in increased p53 ubiquitylation. We demonstrate that TSPYL5 reduces p53 protein levels and inhibits activation of p53-target genes. Furthermore, expression of TSPYL5 overrides p53-dependent proliferation arrest and oncogene-induced senescence, and contributes to oncogenic transformation in multiple cell-based assays. Our data identify TSPYL5 as a suppressor of p53 function through its interaction with USP7.

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Acknowledgements

We thank C. Bishop and D. Beach for the gift of HMEC cells with inducible RASV12 and members of the Bernards and Pandolfi laboratories for discussions and critical reading of the manuscript. This work was supported by grants from the Dutch Cancer Society and the Netherlands Genomics Initiative to R.B., by grants from the Netherlands Proteomics Centre and the Netherlands Genomics Initiative to J.L.B. and by NIH grants to P.P.P.

Author information

Affiliations

  1. Division of Molecular Carcinogenesis, Centre for Biomedical Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.

    • Mirjam T. Epping
    •  & René Bernards
  2. Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

    • Mirjam T. Epping
    •  & Pier Paolo Pandolfi
  3. Department of Physiological Chemistry, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.

    • Lars A.T. Meijer
    •  & Johannes L. Bos
  4. Agendia BV, Science Park 406, 1098 XH Amsterdam, Netherlands.

    • Oscar Krijgsman
  5. Department of Pathology, VU Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.

    • Oscar Krijgsman

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Contributions

The experiments were conceived and designed by M.T.E., P.P.P. and R.B. Experiments were performed by M.T.E. Mass spectrometry was performed by L.A.T.M. and supervised by J.L.B. Statistical analysis of gene expression in breast cancer was performed by O.K. The paper was written by M.T.E., P.P.P. and R.B.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to René Bernards.

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DOI

https://doi.org/10.1038/ncb2142

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