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首页> 外文期刊>Molecular and Cellular Biology >Cdc25A Serine 123 Phosphorylation Couples Centrosome Duplication with DNA Replication and Regulates Tumorigenesis
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Cdc25A Serine 123 Phosphorylation Couples Centrosome Duplication with DNA Replication and Regulates Tumorigenesis

机译：Cdc25A丝氨酸123磷酸化耦合中心体复制与DNA复制并调节肿瘤发生。

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摘要

The cell division cycle 25A (Cdc25A) phosphatase is a critical regulator of cell cycle progression under normal conditions and after stress. Stress-induced degradation of Cdc25A has been proposed as a major way of delaying cell cycle progression. In vitro studies pointed toward serine 123 as a key site in regulation of Cdc25A stability after exposure to ionizing radiation (IR). To address the role of this phosphorylation site in vivo, we generated a knock-in mouse in which alanine was substituted for serine 123. The Cdc25 S123A knock-in mice appeared normal, and, unexpectedly, cells derived from them exhibited unperturbed cell cycle and DNA damage responses. In turn, we found that Cdc25A was present in centrosomes and that Cdc25A levels were not reduced after IR in knock-in cells. This resulted in centrosome amplification due to lack of induction of Cdk2 inhibitory phosphorylation after IR specifically in centrosomes. Further, Cdc25A knock-in animals appeared sensitive to IR-induced carcinogenesis. Our findings indicate that Cdc25A S123 phosphorylation is crucial for coupling centrosome duplication to DNA replication cycles after DNA damage and therefore is likely to play a role in the regulation of tumorigenesis.
机译：细胞分裂周期25A（Cdc25A）磷酸酶是正常条件下和应激后细胞周期进程的关键调节剂。已经提出应力诱导的Cdc25A降解是延迟细胞周期进程的主要方法。体外研究表明，丝氨酸123是电离辐射（IR）暴露后调控Cdc25A稳定性的关键部位。为了解决该磷酸化位点在体内的作用，我们生成了一种敲入小鼠，其中的丙氨酸取代了丝氨酸123。Cdc25S123A敲入小鼠表现正常，并且出乎意料的是，衍生自它们的细胞表现出不受干扰的细胞周期和DNA损伤反应。反过来，我们发现Cdc25A存在于中心体中，而敲除细胞中IR后Cdc25A水平并未降低。这导致中心体扩增，这是由于在中心体中进行IR后缺乏Cdk2抑制性磷酸化的诱导。此外，Cdc25A敲入动物似乎对IR诱导的致癌作用敏感。我们的发现表明，Cdc25A S123磷酸化对于DNA损伤后将中心体复制与DNA复制循环耦合至关重要，因此可能在调节肿瘤发生中发挥作用。

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