The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice
The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice
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DOI：
10.1073/pnas.93.17.8919
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发表时间：
1996-08-20
影响因子：
11.1
通讯作者：
Curran, T
中科院分区：
文献类型：
--
作者：
Xanthoudakis, S;Smeyne, RJ;Curran, T
AP-1蛋白的DNA结合活性在体外通过翻译后机制进行调节，包括还原氧化，这种调节模式已被提出来控制Fos和Jun的转录活性和致癌潜力。先前的研究表明，细胞蛋白Ref-1还原氧化的Fos和Jun，刺激序列特异性AP-1 DNA结合活性，Ref-1，一种双功能蛋白质，也能够启动受损DNA中脱嘌呤/脱嘧啶位点的修复。Ref-1的氧化还原和DNA修复活性之间的关系是有趣的;这两种活性都被认为在细胞对氧化应激的反应中起重要作用。为了研究Ref-1的生理功能，我们使用基因靶向策略来产生缺乏功能性Ref-1基因的小鼠。我们在这里报告，杂合子突变小鼠发育到成年期没有任何明显的异常。相比之下，纯合突变小鼠，缺乏功能性ref-1基因，在胚胎发育期间死亡。详细的分析表明，死亡发生在胚泡形成后，植入后不久。突变体胚胎的退化在胚胎5.5天明显。这些发现表明Ref-I对于早期胚胎发育是必需的。
The DNA binding activity of AP-1 proteins is modulated, in vitro, by a posttranslational mechanism involving reduction oxidation, This mode of regulation has been proposed to control both the transcriptional activity and the oncogenic potential of Fos and Jun. Previous studies revealed that reduction of oxidized Fos and Jun by a cellular protein, Ref-l, stimulates sequence-specific AP-1 DNA-binding activity, Ref-l, a bifunctional protein, is also capable of initiating the repair of apurinic/apyrymidinic sites in damaged DNA, The relationship between the redox and DNA repair activities of Ref-l is intriguing; both activities have been suggested to play an important role in the cellular response to oxidative stress. To investigate the physiological function of Ref-1, we used a gene targeting strategy to generate mice lacking a functional ref-l gene. We report here that heterozygous mutant mice develop into adulthood without any apparent abnormalities. In contrast, homozygous mutant mice, Lacking a functional ref-l; gene, die during embryonic development, Detailed analysis indicates that death occurs following blastocyst formation, shortly after the time of implantation. Degeneration of the mutant embryos is clearly evident at embryonic day 5.5. These findings demonstrate that Ref-l is essential for early embryonic development.