Ataxia-telangiectasia mutated and Rad3-related kinase (ATR) is activated by mild hypothermia in mammalian cells and subsequently activates p53
Résumé
In vitro cultured mammalian cells respond to mild hypothermia (27-33oC) by attenuating cellular processes and slowing and arresting the cell cycle. The slowing of the cell cycle at the upper range (31-33oC) and its complete arrest at the lower range (27-28oC) 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. Here we report that the exposure of CHOK1 cells to mildly hypothermic conditions activates the Ataxia-telangiectasia mutated and Rad3-related kinase (ATR)-p53-p21 signalling pathway and is thus a key pathway involved in p53 activation upon mild hypothermia. In addition, we show that although p38MAPK is also involved in activation of p53 upon mild hypothermia, this is likely the result of activation of p38MAPK by ATR. Further, we show that cold-induced changes in cell membrane lipid composition are correlated with the activation of the ATR-p53-p21 pathway. We therefore 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.
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