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A B56γ mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A

Oncogene volume 29, pages 3933–3941 (2010)Cite this article

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Abstract

Earlier studies have shown both p53-dependent and -independent tumor-suppressive functions of B56γ-specific protein phosphatase 2A (B56γ–PP2A). In the absence of p53, B56γ–PP2A can inhibit cell proliferation and cell transformation by an unknown mechanism. In the presence of p53, on DNA damage, a complex including B56γ–PP2A and p53 is formed, which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21 and inhibition of cell proliferation. In spite of its significance in inhibition of cell proliferation, no B56γ mutations have been linked to human cancer to date. In this study, we first differentiate between the p53-dependent and -independent functions of B56γ–PP2A by identifying a domain of the B56γ protein required for interaction with p53. Within this region, we identify a B56γ mutation, F395C, in lung cancer that disrupts the B56γ–p53 interaction. More importantly, we show that F395C is unable to promote p53 Thr55 dephosphorylation, transcriptional activation of p21 and the p53-dependent tumor-suppressive function of PP2A. This finding provides a mechanistic basis for the p53-dependent and -independent functions of B56γ–PP2A and establishes a critical link between B56γ–PP2A p53-dependent tumor-suppressive function and tumorigenesis.

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Acknowledgements

We are grateful to Dr B Shen at the City of Hope for assistance in searching public databases for mutations in the B56γ gene and to P Podlesny for generating B56γ mutant plasmid constructs. We thank all members of our laboratory for many helpful discussions. This work was supported by NIH grant CA075180 from the National Institute of Cancer.

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  1. Department of Biochemistry, University of California, Riverside, CA, USA

    G P Shouse, Y Nobumori & X Liu

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  1. G P Shouse
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  2. Y Nobumori
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Correspondence to X Liu.

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Shouse, G., Nobumori, Y. & Liu, X. A B56γ mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A. Oncogene 29, 3933–3941 (2010). https://doi.org/10.1038/onc.2010.161

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