Bcl-2 protects endothelial cells against γ-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release
Bcl-2 protects endothelial cells against γ-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release
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DOI：
10.1158/0008-5472.can-06-2265
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Polverini, Peter J.
中科院分区：
文献类型：
--
作者：
Kumar, Pawan;Coltas, Ila K.;Polverini, Peter J.
Bcl-2癌蛋白是一种有效的细胞凋亡抑制剂，在多种恶性肿瘤中过度表达。直到最近，人们普遍认为Bcl-2主要通过调节线粒体释放细胞色素c来介导其抗凋亡功能。然而，最近的研究表明Bcl-2存在于几种细胞内膜上，线粒体可能不是Bcl-2行使其生存功能的唯一场所。在这项研究中，我们研究了Bcl-2是否可以通过细胞色素c非依赖性信号通路保护内皮细胞免受γ辐射。人皮肤微血管内皮细胞（HDMEC），当暴露于γ-辐射，表现出时间依赖性的激活caspase-3，这是与增加细胞色素c从线粒体释放。Bcl-2在内皮细胞中的表达（HDMEC-Bcl-2）显著抑制辐射诱导的caspase-3活化。然而，Bcl-2介导的caspase-3的抑制被Raf-mitogen-activated protein kinase（MAPK）/extracellular signal-regulated kinase（ERK）kinase（MEK）-ERK通路的抑制显著逆转。有趣的是，HDMEC-Bcl-2细胞中的caspase-3活化与细胞色素c释放无关。我们还观察到，内皮细胞Bcl-2的表达显着增加生存素和小鼠双分钟2（Mdm 2）通过Raf-MEK-ERK途径的表达。表达Bcl-2的内皮细胞也抑制γ辐射诱导的p38 MAPK激活和p53积累。HDMEC-Bcl-2中p53积累的抑制可能是由于这些细胞中Mdm 2的表达增强。总之，这些结果表明Bcl-2可能介导内皮细胞保护作用的三种机制，而不依赖于细胞色素c的释放：（a）增加生存素的表达，（B）抑制p53的积累，和（c）抑制p38 MAPK。
The Bcl-2 oncoprotein is a potent inhibitor of apoptosis and is overexpressed in a wide variety of malignancies. Until recently, it was generally accepted that Bcl-2 primarily mediates its antiapoptotic function by regulating cytochrome c release from mitochondria. However, more recent studies have shown that Bcl-2 is present on several intracellular membranes and mitochondria may not be the only site where Bcl-2 exercises its survival function. In this study, we investigated if Bcl-2 can protect endothelial cells against gamma-radiation by a cytochrome c-independent signaling pathway. Human dermal microvascular endothelial cells (HDMEC), when exposed to gamma-radiation, exhibited a time-dependent activation of caspase-3 that was associated with increased cytochrome c release from mitochondria. Bcl-2 expression in endothelial cells (HDMEC-Bcl-2) significantly inhibited irradiation-induced caspase-3 activation. However, Bcl-2-mediated inhibition of caspase-3 was significantly reversed by inhibition of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway. Interestingly, caspase-3 activation in HDMEC-Bcl-2 cells was not associated with cytochrome c release. We also observed that endothelial cell Bcl-2 expression significantly increased the expression of survivin and murine double minute-2 (Mdm2) via the Raf-MEK-ERK pathway. Endothelial cells expressing Bcl-2 also inhibited gamma-radiation-induced activation of p38 MAPK and p53 accumulation. Inhibition of p53 accumulation in HDMEC-Bcl-2 could be due to the enhanced expression of Mdm2 in these cells. Taken together, these results show three mechanisms by which Bcl-2 may mediate endothelial cell cytoprotection independently of cytochrome c release: (a) increased survivin expression, (b) inhibition of p53 accumulation, and (c) inhibition of p38 MAPK.