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首页> 外文期刊>Cell Division >A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis
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A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis

机译：Cdc25A中易于致癌的人类多态性在小鼠中具有胚胎致死性，并促进ASK-1介导的细胞凋亡

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Background Failure to regulate the levels of Cdc25A phosphatase during the cell cycle or during a checkpoint response causes bypass of DNA damage and replication checkpoints resulting in genomic instability and cancer. During G1 and S and in cellular response to DNA damage, Cdc25A is targeted for degradation through the Skp1-cullin-β-TrCP (SCFβ-TrCP) complex. This complex binds to the Cdc25A DSG motif which contains serine residues at positions 82 and 88. Phosphorylation of one or both residues is necessary for the binding and degradation to occur. Results We now show that mutation of serine 88 to phenylalanine, which is a cancer-predisposing polymorphic variant in humans, leads to early embryonic lethality in mice. The mutant protein retains its phosphatase activity both in vitro and in cultured cells. It fails to interact with the apoptosis signal-regulating kinase 1 (ASK1), however, and therefore does not suppress ASK1-mediated apoptosis. Conclusions These data suggest that the DSG motif, in addition to its function in Cdc25A-mediated degradation, plays a role in cell survival during early embyogenesis through suppression of ASK1-mediated apoptosis.
机译：背景技术在细胞周期或检查点应答过程中未能调节Cdc25A磷酸酶水平会导致DNA损伤和复制检查点旁路，从而导致基因组不稳定和癌症。在G1和S期间以及细胞对DNA损伤的反应中，Cdc25A被靶向通过Skp1-cullin-β-TrCP（SCF β-TrCP）复合物降解。该复合物与Cdc25A DSG基序结合，后者在位置82和88处含有丝氨酸残基。一个或两个残基的磷酸化是发生结合和降解所必需的。结果我们现在表明，丝氨酸88突变为苯丙氨酸（苯丙氨酸是人类中易患癌症的多态性变体），可导致小鼠早期胚胎致死。突变蛋白在体外和培养的细胞中均保持其磷酸酶活性。它无法与细胞凋亡信号调节激酶1（ASK1）相互作用，因此，不能抑制ASK1介导的细胞凋亡。结论这些数据表明，DSG基序除了在Cdc25A介导的降解中起作用外，还通过抑制ASK1介导的凋亡在早期胚胎发生过程中在细胞存活中发挥作用。

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