Peroxynitrite-induced p38 MAPK pro-apoptotic signaling in enterocytes.
Peroxynitrite-induced p38 MAPK pro-apoptotic signaling in enterocytes.
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DOI：
10.1016/j.bbrc.2009.04.091
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发表时间：
2009-06-26
影响因子：
3.1
通讯作者：
Upperman, Jeffrey S.
中科院分区：
文献类型：
--
作者：
Guner, Yigit S.;Ochoa, Christian J.;Wang, Jin;Zhang, Xiaoru;Steinhauser, Sarah;Stephenson, Lydia;Grishin, Anatoly;Upperman, Jeffrey S.
坏死性小肠结肠炎的肠细胞凋亡部分是由于一氧化氮（NO）的毒性中间体的细化，如过氧亚硝酸盐（PN）。由于p38丝裂原活化蛋白激酶（MAPK）和丝氨酸-苏氨酸激酶（AKT）分别是具有良好特征的促凋亡和抗凋亡介质，我们假设PN可以通过激活p38和使AKT失活来诱导肠细胞凋亡。为了验证这一假设，我们用PN处理大鼠肠细胞系IEC-6。PN引起p38及其上游激活因子MKK3/6和下游效应因子ATF2的磷酸化。p38抑制剂SB202190和p38 siRNA可抑制pn诱导的细胞凋亡。PN降低AKT磷酸化；用SB202190或p38 siRNA预处理可以消除这种影响。PN暴露也增加了蛋白磷酸酶2A （PP2A）的活性。这些数据表明，pn介导的细胞凋亡依赖于p38通路，而p38可能通过PP2A的参与介导AKT存活通路的失活。
Enterocyte apoptosis in necrotizing enterocolitis is partly due the elaboration of toxic intermediates of nitric oxide (NO), such as peroxynitrite (PN). Because p38 mitogen-activated protein kinase (MAPK) and serine-threonine kinase (AKT) are well-characterized pro- and anti-apoptotic mediators respectively, we hypothesized that PN could induce enterocyte apoptosis via activation of p38 and deactivation of AKT. To test this hypothesis, the rat intestinal cell line, IEC-6, was treated with PN. PN caused phosphorylation of p38, its upstream activator, MKK3/6, and downstream effector, transcription factor ATF2. PN-induced apoptosis was inhibited by the p38 inhibitor, SB202190, and by p38 siRNA. PN decreased AKT phosphorylation; this effect was abrogated by pre-treatment with SB202190 or p38 siRNA. PN exposure also increased the activity of the protein phosphatase 2A (PP2A). These data demonstrate that PN-mediated apoptosis depends on the p38 pathway and that p38 mediates deactivation of AKT survival pathways possibly by the involvement of PP2A.
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