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Sustained Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of protein phosphatase 2A-B56delta stabilizes its anti-apoptotic activity

热1 阿平添加于 2014-8-7 18:25 | 7598 次阅读 | 3 个评论

作者
Low ICC, Loh T, Huang Y, Virshup DM, Pervaiz S
摘要
Bcl-2 is frequently overexpressed in haematopoietic malignancies, and selective phosphorylation at ser70 enhances its anti-apoptotic 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 B56delta, 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 B56delta (B56deltaY289). While nitrated-B56deltaY289 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 B56deltaY289 nitration restores PP2A holoenzyme assembly, thereby permitting S70 dephosphorylation of Bcl-2 and inhibiting its anti-apoptotic activity. More importantly, in primary cells derived from clinical lymphomas Bcl-2 phosphorylation at S70 directly correlates with B56delta nitration and repression of SOD1, but inversely correlates with B56delta interaction with PP2A-C catalytic subunit. These data underscore the role of a pro-oxidant milieu in chemoresistance of haematopoeitic and other cancers via selective targeting of tumor suppressors such as PP2A.
详细资料
- 文献种类: Journal Article
- 期刊名称: Blood
- 期刊缩写: Blood
- 期卷页: 2014年
- 地址: Department of Physiology, National University of Singapore (NUS), Singapore; phssp@nus.edu.sg
- ISBN: 0006-4971
学科领域生物医药 » 生物学
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阿平的文献笔记订阅

第一次看到PP2A还能被redox机制调控的

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发表评论评论(3 人)

!reply! centromere 2014-8-19 17:43: It is well known that phosphotase has -SH group, which can be regulated by redox signaling.

!reply! 阿平 2014-8-20 04:13: centromere: It is well known that phosphotase has -SH group, which can be regulated by redox signaling.
嗯，我之前确实有点孤陋寡闻

!reply! 阿平 2014-8-20 04:19: centromere: It is well known that phosphotase has -SH group, which can be regulated by redox signaling.
不对呀，这文章说的B56的Y289可被nitrated，和sh基团没啥关系吧