title: A B56gamma mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A.
abstract: Earlier studies have shown both p53-dependent and -independent tumor-suppressive functions of B56gamma-specific protein phosphatase 2A (B56gamma-PP2A). In the absence of p53, B56gamma-PP2A can inhibit cell proliferation and cell transformation by an unknown mechanism. In the presence of p53, on DNA damage, a complex including B56gamma-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 B56gamma mutations have been linked to human cancer to date. In this study, we first differentiate between the p53-dependent and -independent functions of B56gamma-PP2A by identifying a domain of the B56gamma protein required for interaction with p53. Within this region, we identify a B56gamma mutation, F395C, in lung cancer that disrupts the B56gamma-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 B56gamma-PP2A and establishes a critical link between B56gamma-PP2A p53-dependent tumor-suppressive function and tumorigenesis.
authors.affiliation: Department of Biochemistry, University of California, Riverside, CA 92521, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Shouse
authors.forename: Y
authors.initials: Y
authors.lastname: Nobumori
authors.forename: X
authors.initials: X
authors.lastname: Liu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010766:Phosphorylation / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C503981:PPP2R5C protein, human; D054648:Protein Phosphatase 2
references.citation: J Biol Chem. 2002 Jul 26;277(30):27449-67
references.pmid: 11956189
references.citation: Cell. 2006 Nov 17;127(4):759-73
references.pmid: 17110335
references.citation: Nat Rev Cancer. 2004 Oct;4(10):793-805
references.pmid: 15510160
references.citation: Biochem J. 2001 Feb 1;353(Pt 3):417-39
references.pmid: 11171037
references.citation: Hum Mutat. 2007 Jun;28(6):622-9
references.pmid: 17311302
references.citation: Cancer Lett. 2001 Sep 10;170(1):1-13
references.pmid: 11448528
references.citation: Nature. 2006 May 4;441(7089):53-61
references.pmid: 16541024
references.citation: Mol Cell. 2009 Mar 13;33(5):537-45
references.pmid: 19285938
references.citation: Oncogene. 2001 Apr 5;20(15):1892-9
references.pmid: 11313937
references.citation: Mol Cell Biol. 2006 Apr;26(7):2832-44
references.pmid: 16537924
references.citation: Nature. 2007 Jan 4;445(7123):53-7
references.pmid: 17086192
references.citation: Cell. 2009 May 15;137(4):609-22
references.pmid: 19450511
references.citation: Science. 1998 Oct 9;282(5387):284-7
references.pmid: 9765152
references.citation: Genes Chromosomes Cancer. 2006 Feb;45(2):182-90
references.pmid: 16276521
references.citation: Mol Cell Biol. 2008 Jan;28(1):448-56
references.pmid: 17967874
references.citation: Genome Res. 2004 Sep;14(9):1711-8
references.pmid: 15342556
references.citation: EMBO J. 2007 Jan 24;26(2):402-11
references.pmid: 17245430
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19867-72
references.pmid: 18056802
references.citation: Biochim Biophys Acta. 2009 Jan;1795(1):1-15
references.pmid: 18588945
references.citation: Cell. 2009 May 1;137(3):413-31
references.pmid: 19410540
references.citation: Clin Cancer Res. 2009 Oct 1;15(19):6301-8
references.pmid: 19773383
references.citation: EMBO J. 2006 Feb 22;25(4):727-38
references.pmid: 16456541
references.citation: Cancer Cell. 2004 Feb;5(2):127-36
references.pmid: 14998489
references.citation: Cell. 2006 Dec 15;127(6):1239-51
references.pmid: 17174897
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3491-6
references.pmid: 10737800
references.citation: Cancer Res. 2005 Sep 15;65(18):8183-92
references.pmid: 16166293
references.citation: Oncogene. 2001 Jan 4;20(1):10-5
references.pmid: 11244497