The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress

Authors

  • Manel Joaquin,

    Corresponding author
    1. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Barcelona, Spain
    • Corresponding authors. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Dr Aiguader 88, Barcelona 08003, Spain. Tel.:+34 93 316 1820; Fax:+34 93 316 0901; E-mail: manel.joaquin@upf.edu or Tel.:+34 93 316 0849; Fax:+34 93 316 0901; E-mail: francesc.posas@upf.edu

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    • These authors contributed equally to this work.
  • Albert Gubern,

    1. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Barcelona, Spain
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    • These authors contributed equally to this work.
  • Daniel González-Nuñez,

    1. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Barcelona, Spain
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  • E Josué Ruiz,

    1. Signalling and Cell Cycle Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
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  • Isabel Ferreiro,

    1. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Barcelona, Spain
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  • Eulalia de Nadal,

    1. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Barcelona, Spain
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  • Angel R Nebreda,

    1. Signalling and Cell Cycle Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
    2. Institució Catalana de Recerca i Estudis Avançats (ICREA) and Signalling and Cell Cycle Laboratory, Institute for Research in Biomedicine, Barcelona, Spain
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  • Francesc Posas

    Corresponding author
    1. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Barcelona, Spain
    • Corresponding authors. Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Dr Aiguader 88, Barcelona 08003, Spain. Tel.:+34 93 316 1820; Fax:+34 93 316 0901; E-mail: manel.joaquin@upf.edu or Tel.:+34 93 316 0849; Fax:+34 93 316 0901; E-mail: francesc.posas@upf.edu

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Abstract

The p57Kip2 cyclin-dependent kinase inhibitor (CDKi) has been implicated in embryogenesis, stem-cell senescence and pathologies, but little is known of its role in cell cycle control. Here, we show that p57Kip2 is targeted by the p38 stress-activated protein kinase (SAPK). Phosphorylation of p57Kip2 at T143 by p38 enhances its association with and inhibition of Cdk2, which results in cell-cycle delay upon stress. Genetic inactivation of the SAPK or the CDKi abolishes cell-cycle delay upon osmostress and results in decreased cell viability. Oxidative stress and ionomycin also induce p38-mediated phosphorylation of p57 and cells lacking p38 or p57 display reduced viability to these stresses. Therefore, cell survival to various stresses depends on p57 phosphorylation by p38 that inhibits CDK activity. Together, these findings provide a novel molecular mechanism by which cells can delay cell cycle progression to maximize cell survival upon stress.

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