ATR (ataxia telangiectasia mutated- and Rad3-related kinase) is activated by mild hypothermia in mammalian cells and subsequently activates p53
ATR (ataxia telangiectasia mutated- and Rad3-related kinase) is activated by mild hypothermia in mammalian cells and subsequently activates p53
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DOI：
10.1042/bj20101303
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发表时间：
2011-04-15
影响因子：
4.1
通讯作者：
Smales, C. Mark
中科院分区：
文献类型：
--
作者：
Roobol, Anne;Roobol, Jo;Smales, C. Mark
在体外培养的哺乳动物细胞对亚低温(27-33摄氏度)的反应是通过减弱细胞过程，减缓和阻止细胞周期。细胞周期在亚低温的上限范围(31-33摄氏度)的减慢和在较低范围(27-28摄氏度)的完全停滞是通过激活p53和随后的p21表达来实现的。然而，哺乳动物细胞感受到寒冷并随后激活P53的机制仍未确定。在本文中，我们报道了中国仓鼠卵巢K1细胞暴露于亚低温条件下，激活了ATR(共济失调毛细血管扩张突变和RAD3相关激酶)-P53-p21信号通路，因此是参与亚低温激活P53的关键途径。此外，我们还发现，尽管p38(MAPK)(p38丝裂原活化蛋白激酶)也参与了亚低温下P53的激活，但这可能是ATR激活p38(MAPK)的结果。此外，我们还发现，冷诱导的细胞膜脂质成分的变化与ATR-p53-p21通路的激活有关。因此，我们提供了在哺乳动物细胞中亚低温导致p53和p21激活的第一个细胞感应和信号机制细节，这被认为导致细胞周期停滞。
In vitro cultured mammalian cells respond to mild hypothermia (27-33 degrees C) by attenuating cellular processes and slowing and arresting the cell cycle. The slowing of the cell cycle at the upper range (31-33 degrees C) and its complete arrest at the lower range (27-28 degrees C) of mild hypothermia is effected by the activation of p53 and subsequent expression of p21. However, the mechanism by which cold is perceived in mammalian cells with the subsequent activation of p53 has remained undetermined. In the present paper, we report that the exposure of Chinese-hamster ovary-K1 cells to mildly hypothermic conditions activates the ATR (ataxia telangiectasia mutated- and Rad3-related kinase)-p53-p21 signalling pathway and is thus a key pathway involved in p53 activation upon mild hypothermia. In addition, we show that although p38(MAPK) (p38 mitogen-activated protein kinase) is also involved in activation of p53 upon mild hypothermia, this is probably the result of activation of p38(MAPK) by ATR. Furthermore, we show that cold-induced changes in cell membrane lipid composition are correlated with the activation of the ATR-p53-p21 pathway. Therefore we provide the first mechanistic detail of cell sensing and signalling upon mild hypothermia in mammalian cells leading to p53 and p21 activation, which is known to lead to cell cycle arrest.