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TSPYL5 suppresses p53 levels and function by physical interaction with USP7

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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Figure 1: TSPYL5 is a poor-prognosis marker in breast cancer and binds to USP7.
Figure 2: TSPYL5 increases p53 ubiquitylation and suppresses p53 protein levels.
Figure 3: TSPYL5 inhibits p53 transactivation and target gene transcription.
Figure 4: TSPYL5 inhibits oncogene-induced senescence and allows transformation.

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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.

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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.

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Correspondence to René Bernards.

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The authors declare no competing financial interests.

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Epping, M., Meijer, L., Krijgsman, O. et al. TSPYL5 suppresses p53 levels and function by physical interaction with USP7. Nat Cell Biol 13, 102–108 (2011). https://doi.org/10.1038/ncb2142

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