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首页> 外文期刊>American Journal of Physiology >Hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites.
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Hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites.

机译：高氧激活ATR-Chk1途径并在多个位点磷酸化p53。

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Hyperoxia has been shown to cause DNA damage resulting in growth arrest of cells in p53-dependent, as well as p53-independent, pathways. Although H2O2 and other peroxides have been shown to induce ataxia telangiectasia-mutated (ATM)-dependent p53 phosphorylation in response to DNA damage, the signal transduction mechanisms in response to hyperoxia are currently unknown. Here we demonstrate that hyperoxia phosphorylates the Ser15 residue of p53 independently of ATM. Hyperoxia phosphorylated p53 (Ser15) in DNA-dependent protein kinase null (DNA-PK-/-) cells, indicating that it may not depend on DNA-PK for phosphorylation of p53 (Ser15). We show that Ser37 and Ser392 residues of p53 are also phosphorylated in an ATM-independent manner in hyperoxia. In contrast, H2O2 did not phosphorylate Ser37 in either ATM+/+ or ATM-/- cells. Furthermore, H2O2 failed to phosphorylate Ser15 in ATM-/- cells. Additionally, overexpression of kinase-inactive ATM-and-Rad3-related (ATR) in HEK293T cells diminished Ser15, Ser37,and Ser392 phosphorylation compared with vector-only transfected cells. In contrast, wild-type ATR overexpression did not diminish Ser15, Ser37, or Ser392 phosphorylation. We also show that checkpoint kinase 1 (Chk1) is phosphorylated on Ser345 in response to hyperoxia, which could be inhibited by caffeine or wortmannin, potent inhibitors of phosphoinositide 3-kinase-related kinases. Hyperoxia also phosphorylated Chk1 in ATM+/+ as well as in ATM-/- cells, demonstrating an ATM-independent mechanism in Chk1 phosphorylation. Together, our data suggest that hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites in an ATM-independent manner, which is different from other forms of oxidative stress such as H2O2 or UV light.
机译：高氧血症已显示可引起DNA损伤，从而导致细胞以p53依赖性和p53依赖性途径生长停滞。尽管已显示过氧化氢和其他过氧化物可响应DNA损伤而诱导共济失调的毛细血管扩张突变（ATM）依赖性p53磷酸化，但目前尚不清楚响应高氧的信号转导机制。在这里，我们证明高氧独立于ATM磷酸化p53的Ser15残基。高氧血症使依赖于DNA的蛋白激酶无效（DNA-PK-/-）细胞中的p53（Ser15）磷酸化，表明它可能不依赖于DNA-PK来使p53（Ser15）磷酸化。我们显示p53的Ser37和Ser392残基也以高氧血症中的ATM独立方式被磷酸化。相反，H2O2在ATM + / +或ATM-/-细胞中均不会磷酸化Ser37。此外，H2O2无法使ATM-/-细胞中的Ser15磷酸化。此外，与仅转染载体的细胞相比，HEK293T细胞中激酶失活的ATM和Rad3相关（ATR）的过量表达减少了Ser15，Ser37和Ser392磷酸化。相反，野生型ATR过表达并没有减少Ser15，Ser37或Ser392磷酸化。我们还显示，对高氧的反应，检查点激酶1（Chk1）在Ser345上被磷酸化，可被咖啡因或渥曼青霉素（磷酸肌醇3激酶相关激酶的有效抑制剂）抑制。高氧还使ATM + / +以及ATM-/-细胞中的Chk1磷酸化，表明Chk1磷酸化的ATM独立机制。总之，我们的数据表明，高氧激活ATR-Chk1途径并以ATM独立方式在多个位点磷酸化p53，这不同于其他形式的氧化应激，例如H2O2或UV光。

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