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.
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Research Article|
March 29 2011
ATR (ataxia telangiectasia mutated- and Rad3-related kinase) is activated by mild hypothermia in mammalian cells and subsequently activates p53
Anne Roobol;
Anne Roobol
*Centre for Molecular Processing and Protein Science Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, U.K.
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Jo Roobol;
Jo Roobol
*Centre for Molecular Processing and Protein Science Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, U.K.
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Martin J. Carden;
Martin J. Carden
*Centre for Molecular Processing and Protein Science Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, U.K.
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Amandine Bastide;
Amandine Bastide
†MRC Toxicology Unit, Hodgkin Building, P.O. Box 138, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Anne E. Willis;
Anne E. Willis
1
†MRC Toxicology Unit, Hodgkin Building, P.O. Box 138, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
1Correspondence may be addressed to either of these authors (email aew5@le.ac.uk or c.m.smales@kent.ac.uk).
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Warwick B. Dunn;
Warwick B. Dunn
‡School of Chemistry and Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, U.K.
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Royston Goodacre;
Royston Goodacre
‡School of Chemistry and Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, U.K.
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C. Mark Smales
C. Mark Smales
1
*Centre for Molecular Processing and Protein Science Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, U.K.
1Correspondence may be addressed to either of these authors (email aew5@le.ac.uk or c.m.smales@kent.ac.uk).
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Publisher: Portland Press Ltd
Received:
August 17 2010
Revision Received:
January 19 2011
Accepted:
February 02 2011
Accepted Manuscript online:
February 02 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 435 (2): 499–508.
Article history
Received:
August 17 2010
Revision Received:
January 19 2011
Accepted:
February 02 2011
Accepted Manuscript online:
February 02 2011
Citation
Anne Roobol, Jo Roobol, Martin J. Carden, Amandine Bastide, Anne E. Willis, Warwick B. Dunn, Royston Goodacre, C. Mark Smales; ATR (ataxia telangiectasia mutated- and Rad3-related kinase) is activated by mild hypothermia in mammalian cells and subsequently activates p53. Biochem J 15 April 2011; 435 (2): 499–508. doi: https://doi.org/10.1042/BJ20101303
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