Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity
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 induc...
| Main Authors: | , , , , |
|---|---|
| Format: | Journal Article |
| Published: |
American Society of Hematology
2014
|
| Online Access: | http://hdl.handle.net/20.500.11937/51027 |
| _version_ | 1848758596232282112 |
|---|---|
| author | Low, I. Loh, T. Huang, Y. Virshup, D. Pervaiz, Shazib |
| author_facet | Low, I. Loh, T. Huang, Y. Virshup, D. Pervaiz, Shazib |
| author_sort | Low, I. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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 geneticknockdownof 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 B56d, 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 B56d (B56dY289). Although nitrated B56dY289 binds efficiently to ser70-phosphorylated Bcl-2, this specific modification inhibits the recruitment of the PP2Acatalytic core (A andCsubunits). Furthermore, inhibitionofB56dY289 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 B56d nitration and repression of SOD1, but inversely correlates with B56d 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. (Blood. 2014;124(14):2223-2234). |
| first_indexed | 2025-11-14T09:46:30Z |
| format | Journal Article |
| id | curtin-20.500.11937-51027 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:46:30Z |
| publishDate | 2014 |
| publisher | American Society of Hematology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-510272017-09-13T15:41:42Z Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity Low, I. Loh, T. Huang, Y. Virshup, D. Pervaiz, Shazib 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 geneticknockdownof 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 B56d, 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 B56d (B56dY289). Although nitrated B56dY289 binds efficiently to ser70-phosphorylated Bcl-2, this specific modification inhibits the recruitment of the PP2Acatalytic core (A andCsubunits). Furthermore, inhibitionofB56dY289 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 B56d nitration and repression of SOD1, but inversely correlates with B56d 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. (Blood. 2014;124(14):2223-2234). 2014 Journal Article http://hdl.handle.net/20.500.11937/51027 10.1182/blood-2014-03-563296 American Society of Hematology unknown |
| spellingShingle | Low, I. Loh, T. Huang, Y. Virshup, D. Pervaiz, Shazib Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity |
| title | Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity |
| title_full | Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity |
| title_fullStr | Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity |
| title_full_unstemmed | Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity |
| title_short | Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56 d stabilizes its antiapoptotic activity |
| title_sort | ser70 phosphorylation of bcl-2 by selective tyrosine nitration of pp2a-b56 d stabilizes its antiapoptotic activity |
| url | http://hdl.handle.net/20.500.11937/51027 |