title: Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity.
abstract: Bcl-2 is frequently overexpressed in hematopoietic malignancies, and selective phosphorylation at ser70 enhances its antiapoptotic activity. Phospho-ser70 is dephosphorylated by specific heterotrimers of protein phosphatase 2A (PP2A). We report here that a mild pro-oxidant intracellular milieu induced by either pharmacological inhibition or genetic knockdown of superoxide dismutase 1 (SOD1) inhibits the functional holoenzyme assembly of PP2A and prevents Bcl-2 ser70 dephosphorylation. This redox-dependent regulation of Bcl-2 phosphorylation is due to nitrosative modification of B56δ, which we identify as the regulatory subunit mediating PP2A-dependent Bcl-2 dephosphorylation. Redox inhibition of PP2A results from peroxynitrite-mediated nitration of a conserved tyrosine residue within B56δ (B56δ(Y289)). Although nitrated B56δ(Y289) binds efficiently to ser70-phosphorylated Bcl-2, this specific modification inhibits the recruitment of the PP2A catalytic core (A and C subunits). Furthermore, inhibition of B56δ(Y289) nitration restores PP2A holoenzyme assembly, thereby permitting S70 dephosphorylation of Bcl-2 and inhibiting its antiapoptotic activity. More important, in primary cells derived from clinical lymphomas, Bcl-2 phosphorylation at S70 directly correlates with B56δ nitration and repression of SOD1, but inversely correlates with B56δ interaction with the PP2A-C catalytic subunit. These data underscore the role of a pro-oxidant milieu in chemoresistance of hematopoietic and other cancers via selective targeting of tumor suppressors such as PP2A.
authors.affiliation: Department of Physiology, National University of Singapore (NUS), NUS Graduate School of Integrative Sciences and Engineering.
authors.forename: Ivan Cherh Chiet
authors.initials: IC
authors.lastname: Low
authors.affiliation: Department of Otolaryngology, National University Healthcare System, Singapore;
authors.forename: Thomas
authors.initials: T
authors.lastname: Loh
authors.affiliation: Department of Otolaryngology, National University Healthcare System, Singapore;
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Huang
authors.affiliation: NUS Graduate School of Integrative Sciences and Engineering, Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: Department of Physiology, National University of Singapore (NUS), NUS Graduate School of Integrative Sciences and Engineering, Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; and Singapore-Massachusetts Institute of Technology Alliance, Singapore.
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
mesh_terms: D017209:Apoptosis; D002384:Catalysis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D009369:Neoplasms / Q000188:drug therapy; D009584:Nitrogen / Q000737:chemistry; D010084:Oxidation-Reduction; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012694:Serine / Q000737:chemistry*; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; C000606290:SOD1 protein, human; D014443:Tyrosine; D012694:Serine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C572369:PP2A-B56alpha protein, human; D054648:Protein Phosphatase 2; D009584:Nitrogen