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The p57 CDKi integrates stress signals into cell‐cycle progression to promote cell survival upon stress
Author(s) -
Joaquin Manel,
Gubern Albert,
GonzálezNuñez Daniel,
Josué Ruiz E,
Ferreiro Isabel,
de Nadal Eulalia,
Nebreda Angel R,
Posas Francesc
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.122
Subject(s) - biology , stress (linguistics) , cell cycle , cell cycle progression , cell , microbiology and biotechnology , computational biology , genetics , philosophy , linguistics
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.