YB-1 is important for late-stage embryonic development, optimal cellular stress responses, and the prevention of premature senescence
YB-1 is important for late-stage embryonic development, optimal cellular stress responses, and the prevention of premature senescence
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DOI：
10.1128/mcb.25.11.4625-4637.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Ley, TJ
中科院分区：
文献类型：
--
作者：
Lu, ZH;Books, JT;Ley, TJ
含有“冷休克”结构域的蛋白质属于已知的细菌、植物和动物中进化上最保守的核酸结合蛋白家族。其中一种蛋白质YB-1在整个发育过程中广泛表达，并被认为是一种细胞存活因子，调节许多细胞生长和死亡相关基因的转录和/或翻译。由于这些原因，预计YB-1缺乏症与细胞存活不相容。然而，大多数YB-1（-/-）胚胎在胚胎第13.5天（E13.5）正常发育。在E13.5之后，YB-1（-/-）胚胎表现出严重的生长迟缓和进行性死亡，揭示了YB-1在胚胎晚期发育中的非冗余作用。来自YB-1（-/-）胚胎的成纤维细胞显示出正常的蛋白质合成率和转录组和蛋白质组的微小改变，但显示出对氧化、基因毒性和癌基因诱导的应激的反应能力降低。氧化应激下的YB-1（-/-）细胞表达高水平的G特异性CDK抑制剂p16Ink4a和p21Cip1，并提前衰老；这种缺陷是通过用特定的小干扰rna敲低CDK抑制剂水平来纠正的。这些数据表明，YB-1通常抑制CDK抑制剂的转录，使其成为细胞应激反应信号通路的重要组成部分。
Proteins containing "cold shock" domains belong to the most evolutionarily conserved family of nucleic acid-binding proteins known among bacteria, plants, and animals. One of these proteins, YB-1, is widely expressed throughout development and has been implicated as a cell survival factor that regulates the transcription and/or translation of many cellular growth and death-related genes. For these reasons, YB-1 deficiency has been predicted to be incompatible with cell survival. However, the majority of YB-1(-/-) embryos develop normally up to embryonic day 13.5 (E13.5). After E13.5, YB-1(-/-) embryos exhibit severe growth retardation and progressive mortality, revealing a nonredundant role of YB-1 in late embryonic development. Fibroblasts derived from YB-1(-/-) embryos displayed a normal rate of protein synthesis and minimal alterations in the transcriptome and proteome but demonstrated reduced abilities to respond to oxidative, genotoxic, and oncogene-induced stresses. YB-1(-/-) cells under oxidative stress expressed high levels of the G,specific CDK inhibitors p16Ink4a and p21Cip1 and senesced prematurely; this defect was corrected by knocking down CDK inhibitor levels with specific small interfering RNAs. These data suggest that YB-1 normally represses the transcription of CDK inhibitors, making it an important component of the cellular stress response signaling pathway.