Protein phosphatase 2A promotes endothelial survival via stabilization of translational inhibitor 4E-BP1 following exposure to tumor necrosis factor-α.
Protein phosphatase 2A promotes endothelial survival via stabilization of translational inhibitor 4E-BP1 following exposure to tumor necrosis factor-α.
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DOI：
10.1161/atvbaha.111.230946
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
Chaudhuri G
中科院分区：
文献类型：
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作者：
Janzen C;Sen S;Cuevas J;Reddy ST;Chaudhuri G
当与环己亚胺（CHX）联合使用时，TNFα可能从内皮细胞（ECs）可逆活化的刺激物转变为杀手。内皮细胞通过何种途径进入存活或凋亡尚不完全清楚。我们研究了p38 MAPK和蛋白磷酸酶2A （PP2A）激活的作用及其对ECs 4E-BP1稳定性的调节，以确定该途径是否参与TNFα和CHX诱导的凋亡。TNFα联合环己亚胺（CHX） [TNFα/CHX]诱导人脐静脉内皮细胞（HUVECs）凋亡。在发生凋亡的huvec中，p38 MAPK的激活增加，这与eIF4E调节因子4E-BP1的降解有关，以p38 MAPK依赖的方式。CHX可以减弱tnf α刺激的PP2A表达和活性的增加。用siRNA转染沉默PP2A表达模拟chx致敏，通过TNFα刺激增加HUVEC凋亡，提示PP2A在凋亡过程中起保护作用。我们的数据表明，i) TNFα刺激PP2A， HUVECs通过PP2A依赖的p38 MAPK去磷酸化来避免凋亡；ii) chx诱导的PP2A抑制导致p38活性维持和4E-BP1降解，从而增强TNFα诱导的凋亡。
TNFα may change from a stimulator of reversible activation of endothelial cells (ECs) to a killer when combined with cycloheximide (CHX). The means by which endothelial cells are destined to either the survival or the apoptotic pathways are not fully understood. We investigated the role of p38 MAPK and protein phosphatase 2A (PP2A) activation and their regulation of 4E-BP1 stability in ECs to determine whether this pathway contributes to apoptosis induced by TNFα and CHX. Apoptosis was induced in human umbilical vein ECs (HUVECs) by treating them with a combination of TNFα and cycloheximide (CHX) [TNFα/CHX]. Activation of p38 MAPK was increased in HUVECs undergoing apoptosis, which was associated with degradation of eIF4E regulator, 4E-BP1, in a p38 MAPK-dependent manner. CHX attenuated a TNFα-stimulated increase in the expression and activity of PP2A. Silencing PP2A expression with siRNA transfection mimicked CHX-sensitization, increasing HUVEC apoptosis with TNFα stimulation, suggesting a protective role for PP2A in the apoptotic process. Our data suggest i) TNFα stimulates PP2A and that HUVECs elude apoptosis by PP2A-dependent de-phosphorylation of p38 MAPK and ii) CHX-induced inhibition of PP2A leads to maintenance of p38 activity and degradation of 4E-BP1, resulting in enhanced TNFα-induced apoptosis.