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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References
Arnold H, Sears R . (2006). Protein phosphatase 2A regulatory subunit B56α associates with c-Myc and negatively regulates c-Myc accumulation. Mol Cell Biol 26: 2832–2844.
Bennin D, Don A, Brake T, McKenzie J, Rosenbaum H, Ortiz L et al. (2002). Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B’ subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest. J Biol Chem 277: 27449–27467.
Bode A, Dong Z . (2004). Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4: 793–805.
Chen W, Arroyo J, Timmons J, Possemato R, Hahn W . (2005). Cancer-associated PP2A Aα subunits induce functional haploinsufficiency and tumorigenicity. Cancer Res 85: 8183–8192.
Chen W, Possemato R, Campbell K, Plattner C, Pallas D, Hahn W . (2004). Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5: 127–136.
Cho U, Xu W . (2006). Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445: 53–57.
Eichorn P, Creyghton M, Bernards R . (2009). Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 1795: 1–15.
Esplin E, Ramos P, Martinez B, Tomlinson G, Mumby M, Evans G . (2006). The Glycine 90 to Aspartate alteration in the Aβ subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. Genes Chromosomes Cancer 45: 182–190.
Forester C, Maddox J, Louis J, Goris J, Virshup D . (2007). Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1. Proc Natl Acad Sci USA 104: 19867–19872.
Grochola L, Vazquez A, Bond E, Wurl P, Taubert H, Muller T et al. (2009). Recent natural selection identifies a genetic variant in a regulator subunit of protein phosphatase 2A that associates with altered cancer risk and survival. Clin Cancer Res 15: 6301–6308.
Janssens V, Goris J . (2001). Protein Phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signaling. Biochem J 353: 417–439.
Kruse J, Gu W . (2009). Modes of p53 regulation. Cell 137: 609–622.
Letourneux C, Rocher G, Porteu F . (2006). B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J 25: 727–738.
Li H, Cai X, Shouse G, Piluso L, Liu X . (2007). A specific PP2A regulatory subunit, B56γ, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO 26: 402–411.
Margolis S, Perry J, Forester C, Nutt L, Guo M, Jardim M et al. (2006). Role for the PP2A/B56δ phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis. Cell 127: 759–763.
Neto E, Correa R, Verjovski-Almeida S, Briones M, Nagai M, da Silva W et al. (2006). Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. Proc Natl Acad Sci USA 97: 3491–3496.
Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian S, Hainaut P et al. (2007). Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 6: 622–629.
Riedel C, Katis V, Katou Y, Mori S, Itoh T, Helmhart W et al. (2006). Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature 441: 53–61.
Ruediger R, Pham H, Walter G . (2001a). Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene. Oncogene 20: 1892–1899.
Ruediger R, Pham H, Walter G . (2001b). Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the Aα subunit gene. Oncogene 12: 10–15.
Schonthal A . (2001). Role of serine/threonine protein phosphatase 2A in cancer. Cancer Lett 170: 1–13.
Shouse G, Cai X, Liu X . (2008). Serine 15 phosphorylation of p53 directs its interaction with B56γ and the tumor suppressor activity of B56γ-specific protein phosphatase 2A. Mol Cell Biol 28: 448–456.
Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J et al. (2004). Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. Genome Res 14: 1711–1718.
Virshup D, Shenolikar S . (2009). From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 33: 537–545.
Vousden K, Prives C . (2009). Blinded by the light: the growing complexity of p53. Cell 137: 413–431.
Wang S, Esplin E, Li J, Huang L, Gazdar A, Minna J et al. (1998). Alterations of the PPP2R1B gene in human lung and colon cancer. Science 282: 284–287.
Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E et al. (2006). Structure of the protein phosphatase 2A holoenzyme. Cell 127: 1239–1251.
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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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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DOI: https://doi.org/10.1038/onc.2010.161
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