title: The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress.
abstract: The p57(Kip2) 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 p57(Kip2) is targeted by the p38 stress-activated protein kinase (SAPK). Phosphorylation of p57(Kip2) 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.
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Cell Signaling Research Group, Univeristat Pompeu Fabra, Barcelona, Spain. manel.joaquin@upf.edu
authors.forename: Manel
authors.initials: M
authors.lastname: Joaquin
authors.forename: Albert
authors.initials: A
authors.lastname: Gubern
authors.forename: Daniel
authors.initials: D
authors.lastname: González-Nuñez
authors.forename: E
authors.initials: E
authors.lastname: Josué Ruiz
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferreiro
authors.forename: Eulalia
authors.initials: E
authors.lastname: de Nadal
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
authors.forename: Francesc
authors.initials: F
authors.lastname: Posas
mesh_terms: D000818:Animals; D061207:Calcium Ionophores / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D009997:Osmotic Pressure / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C493964:CDKN1C protein, human; D061207:Calcium Ionophores; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D015759:Ionomycin; D048051:p38 Mitogen-Activated Protein Kinases