xIAP induces cell-cycle arrest and activates nuclear Factor-κB -: New survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells
xIAP induces cell-cycle arrest and activates nuclear Factor-κB -: New survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells
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DOI：
10.1161/01.res.88.3.282
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发表时间：
2001-02-16
影响因子：
20.1
通讯作者：
Breithardt, G
中科院分区：
文献类型：
--
作者：
Levkau, B;Garton, KJ;Breithardt, G
人类血管内皮细胞的存活取决于其激活转录因子核因子 - κB（NF - κB）的能力，NF - κB是抗凋亡基因的调节因子，比如X染色体连锁的凋亡抑制蛋白（xIAP）。在本研究中，我们证实了xIAP在正常人动脉和静脉内皮细胞中的表达，以及在高度恶性的人类内皮肿瘤中其水平升高。通过对人类内皮细胞进行逆转录病毒感染，我们确定了xIAP在内皮细胞中介导的两种新的存活机制。首先，xIAP能够激活转录因子NF - κB，而NF - κB是已知的人类内皮细胞存活因子。由xIAP诱导的这种正反馈回路是通过抑制蛋白（I）κBα的磷酸化和持续降解来介导的。其次，xIAP能够通过下调细胞周期蛋白A和D1以及诱导细胞周期蛋白依赖性激酶抑制剂p21（Cip1/Waf1）和p27（Kip1）来抑制细胞增殖。在内皮细胞凋亡过程中，半胱天冬酶对xIAP的切割使xIAP的这两种生物学功能丧失。因此，半胱天冬酶介导的xIAP切割中断了NF - κB和xIAP之间的正调控细胞保护回路，并通过使细胞从xIAP介导的静止状态中释放出来，增加了细胞对凋亡的易感性。
Survival of human vascular endothelial cells depends on their ability to activate the transcription factor nuclear factor-kappaB (NF-kappaB), a regulator of antiapoptotic genes, such as the X chromosome-linked inhibitor of apoptosis protein (xIAP). In the present study, we demonstrated expression of xIAP in the endothelial lining of normal human arteries and veins and elevated levels in highly malignant human endothelial tumors. Using retroviral infection of human endothelial cells, we identified two novel survival mechanisms mediated by xIAP in endothelial cells. First, xIAP can activate the transcription factor NF-kappaB, a known survival factor for human endothelial cells. This positive feedback loop induced by xIAP is mediated via phosphorylation and sustained degradation of inhibitor (I) kappaB alpha. Second, xIAP can inhibit cell. proliferation via downregulation of cyclins A and D1 and induction of the cyclin-dependent kinase inhibitors p21(Cip1/Waf1) and p27(Kip1). Cleavage of xIAP by caspases during endothelial cell apoptosis disables both of these biological functions of xIAP. Thus, caspase-mediated cleavage of xIAP interrupts a positive regulatory cytoprotective loop between NF-kappaB and xIAP and increases the vulnerability of the cell to apoptosis by releasing it from an xIAP-mediated quiescent state.