PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation.
PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation.
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DOI：
10.1083/jcb.201010051
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发表时间：
2011-05-30
期刊：
影响因子：
--
通讯作者：
Abe J
中科院分区：
文献类型：
--
作者：
Heo KS;Lee H;Nigro P;Thomas T;Le NT;Chang E;McClain C;Reinhart-King CA;King MR;Berk BC;Fujiwara K;Woo CH;Abe J
干扰的流动介导的PKC β-PIASy缔合对于p53 SUMO化至关重要，并诱导p53核输出和内皮细胞凋亡。动脉粥样硬化很容易在已知发生血流紊乱（d-流）的血管区域观察到。蛋白激酶C β（PKC β）激活与d-flow正相关，但d-flow介导的PKC β激活在动脉粥样硬化中的确切作用尚不清楚。我们测试了这样一个假设，即PKC β激活的d-流诱导内皮细胞（EC）凋亡，通过调节p53。我们发现，d-流介导的过氧亚硝酸盐（ONOO−）增加PKC β激活，随后诱导p53 SUMO化，p53-Bcl-2结合和EC凋亡。d-flow和ONOO−均通过PIASy的Siz/PIAS-RING结构域（氨基酸301-410）增加了PKC β与活化的STATy蛋白抑制剂（PIASy）的结合，PIASy的该结构域的过表达破坏了PKC β-PIASy相互作用和PKC β介导的p53 SUMO化。正面共聚焦显微镜显示，野生型小鼠位于d流区的主动脉EC中非核p53表达、硝基酪氨酸染色和凋亡增加，但这些作用在p53−/−小鼠中显著降低。我们提出了一种新的机制，p53 SUMO化介导的PKC β-PIASy相互作用在d-流量介导的EC凋亡，这与动脉粥样硬化的早期事件有潜在的相关性。
Disturbed flow-mediated PKCζ–PIASy association is critical for p53 SUMOylation and induces p53 nuclear export and endothelial cell apoptosis. Atherosclerosis is readily observed in regions of blood vessels where disturbed blood flow (d-flow) is known to occur. A positive correlation between protein kinase C ζ (PKCζ) activation and d-flow has been reported, but the exact role of d-flow–mediated PKCζ activation in atherosclerosis remains unclear. We tested the hypothesis that PKCζ activation by d-flow induces endothelial cell (EC) apoptosis by regulating p53. We found that d-flow–mediated peroxynitrite (ONOO−) increased PKCζ activation, which subsequently induced p53 SUMOylation, p53–Bcl-2 binding, and EC apoptosis. Both d-flow and ONOO− increased the association of PKCζ with protein inhibitor of activated STATy (PIASy) via the Siz/PIAS-RING domain (amino acids 301–410) of PIASy, and overexpression of this domain of PIASy disrupted the PKCζ–PIASy interaction and PKCζ-mediated p53 SUMOylation. En face confocal microscopy revealed increases in nonnuclear p53 expression, nitrotyrosine staining, and apoptosis in aortic EC located in d-flow areas in wild-type mice, but these effects were significantly decreased in p53−/− mice. We propose a novel mechanism for p53 SUMOylation mediated by the PKCζ–PIASy interaction during d-flow–mediated EC apoptosis, which has potential relevance to early events of atherosclerosis.
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影响因子：
20.3
作者：
Li, XC;Hahn, CN;Gamble, JR
通讯作者：
Gamble, JR
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
16
作者：
Bischof, Oliver;Schwamborn, Klaus;Dejean, Anne
通讯作者：
Dejean, Anne
DOI：
10.1152/ajpheart.1999.277.4.h1593
发表时间：
1999-10-01
影响因子：
4.8
作者：
Hu, YL;Li, S;Chien, S
通讯作者：
Chien, S
影响因子：
4.8
作者：
Levrand, S;Pesse, B;Liaudet, L
通讯作者：
Liaudet, L