Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner
Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner
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DOI：
10.1073/pnas.94.12.6048
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发表时间：
1997-06-10
影响因子：
11.1
通讯作者：
Appella, E
中科院分区：
文献类型：
--
作者：
Fiscella, M;Zhang, HL;Appella, E
哺乳动物细胞暴露于电离辐射（IR）可诱导一系列复杂的细胞反应，包括细胞周期阻滞和/或细胞凋亡。IR诱导的GI阻滞依赖于肿瘤抑制因子p53的存在，而p53是几种基因的转录激活因子，p53在DNA损伤诱导细胞凋亡中也起作用，这一途径可以通过转录依赖和转录独立机制激活。在这里，我们报告了一种新的转录物，其表达以p53依赖的方式诱导IR的反应。这与2C型蛋白磷酸酶具有同源性。我们给这个新探员命名为wip1。在体外，重组Wip1表现出2C型磷酸酶的特征，包括Mg2+依赖性和对冈田酸的相对不敏感。在一些细胞系中进行的研究表明，IR后wip1的积累与野生型p53的存在相关，IR后wip1 mRNA的积累是快速而短暂的，并且该蛋白定位于细胞核，与waf1相似，人类细胞中wip1的异位表达抑制了集落的形成，这些结果表明wip1可能以p53依赖的方式激活了响应DNA损伤的生长抑制途径。
Exposure of mammalian cells to ionizing radiation (IR) induces a complex array of cellular responses including cell cycle arrest and/or apoptosis. IR-induced GI arrest has been shown to depend on the presence of the tumor suppressor p53, which acts as a transcriptional activator of several genes, p53 also plays a role in the induction of apoptosis in response to DNA damage, and this pathway can be activated by bath transcription-dependent and -independent mechanisms, Here we report the identification of a novel transcript whose expression is induced in response to IR in a p53-dependent manner, and that shows homology to the type 2C protein phosphatases. We have named this novel gent, wip1. In vitro, recombinant Wip1 displayed characteristics of a type 2C phosphatase, including Mg2+ dependence and relative insensitivity to okadaic acid. Studies performed in several cell lines revealed that wip1 accumulation following IR correlates with the presence of wild-type p53, The accumulation of wip1 mRNA following IR was rapid and transient, and the protein was localized to the nucleus, Similar to waf1, ectopic expression of wip1 in human cells suppressed colony formation, These results suggest that Wip1 might contribute to growth inhibitory pathways activated in response to DNA damage in a p53-dependent manner.