Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis
Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis
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DOI：
10.1074/jbc.m309479200
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发表时间：
2004-01-16
影响因子：
4.8
通讯作者：
Altieri, DC
中科院分区：
文献类型：
--
作者：
Beltrami, E;Plescia, J;Altieri, DC
存活素是凋亡抑制因子基因家族的成员，其与细胞分裂和凋亡抑制有关。在这里，我们表明，优先消融核池的生存素RNA干扰产生有丝分裂阻滞，然后重新进入细胞周期和多倍体。Survivin的去除会导致多个中心体缺陷、异常多极纺锤体形成和染色质错误分离，并且这些表型会因p21（-/-）细胞中细胞周期调节因子p21（Waf 1/Cip 1）的丢失而加剧。有丝分裂检查点激活的生存素的损失是介导的诱导p53和相关的表达增加，其下游目标，p21（Waf 1/Cip 1）。因此，与p53（+/+）对应物相比，p53（-/-）细胞在存活素消融后表现出减少的有丝分裂停滞和增强的多倍性。部分减少细胞溶质池的生存素的RNA干扰敏感的细胞紫外线B-介导的细胞凋亡，并在增强caspase-9蛋白水解裂解的结果，而完全消融的细胞溶质生存素的线粒体膜电位和自发凋亡的损失。这些数据表明，生存素在有丝分裂的多个阶段和细胞依赖性凋亡的控制中具有可分离的检查点功能。
Survivin is a member of the Inhibitor of Apoptosis gene family that has been implicated in cell division and suppression of apoptosis. Here, we show that preferential ablation of the nuclear pool of survivin by RNA interference produces a mitotic arrest followed by re-entry into the cell cycle and polyploidy. Survivin ablation causes multiple centrosomal defects, aberrant multipolar spindle formation, and chromatin missegregation, and these phenotypes are exacerbated by loss of the cell cycle regulator, p21(Waf1/Cip1) in p21(-/-) cells. The mitotic checkpoint activated by loss of survivin is mediated by induction of p53 and associated with increased expression of its downstream target, p21(Waf1/Cip1). Accordingly, p53(-/-) cells exhibit reduced mitotic arrest and enhanced polyploidy upon survivin ablation as compared with their p53(+/+) counterparts. Partial reduction of the cytosolic pool of survivin by RNA interference sensitizes cells to ultraviolet B-mediated apoptosis and results in enhanced caspase-9 proteolytic cleavage, whereas complete ablation of cytosolic survivin causes loss of mitochondrial membrane potential and spontaneous apoptosis. These data demonstrate that survivin has separable checkpoint functions at multiple phases of mitosis and in the control of mitochondrial-dependent apoptosis.