title: ATR (ataxia telangiectasia mutated- and Rad3-related kinase) is activated by mild hypothermia in mammalian cells and subsequently activates p53.
abstract: In vitro cultured mammalian cells respond to mild hypothermia (27-33 °C) by attenuating cellular processes and slowing and arresting the cell cycle. The slowing of the cell cycle at the upper range (31-33 °C) and its complete arrest at the lower range (27-28 °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 p38MAPK (p38 mitogen-activated protein kinase) is also involved in activation of p53 upon mild hypothermia, this is probably the result of activation of p38MAPK 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.
authors.affiliation: Centre for Molecular Processing and Protein Science Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Roobol
authors.forename: Jo
authors.initials: J
authors.lastname: Roobol
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Carden
authors.forename: Amandine
authors.initials: A
authors.lastname: Bastide
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.forename: Warwick B
authors.initials: WB
authors.lastname: Dunn
authors.forename: Royston
authors.initials: R
authors.lastname: Goodacre
authors.forename: C Mark
authors.initials: CM
authors.lastname: Smales
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002477:Cells / Q000201:enzymology / Q000378:metabolism*; D003080:Cold Temperature; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007035:Hypothermia / Q000378:metabolism / Q000473:pathology; D008322:Mammals / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012720:Severity of Illness Index; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases