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Ferreiro I.,University Pompeu Fabra | Joaquin M.,University Pompeu Fabra | Islam A.,University Pompeu Fabra | Gomez-Lopez G.,Bioinformatics Unit | And 7 more authors.
BMC Genomics | Year: 2010

Background: Cells have the ability to respond and adapt to environmental changes through activation of stress-activated protein kinases (SAPKs). Although p38 SAPK signalling is known to participate in the regulation of gene expression little is known on the molecular mechanisms used by this SAPK to regulate stress-responsive genes and the overall set of genes regulated by p38 in response to different stimuli.Results: Here, we report a whole genome expression analyses on mouse embryonic fibroblasts (MEFs) treated with three different p38 SAPK activating-stimuli, namely osmostress, the cytokine TNFα and the protein synthesis inhibitor anisomycin. We have found that the activation kinetics of p38α SAPK in response to these insults is different and also leads to a complex gene pattern response specific for a given stress with a restricted set of overlapping genes. In addition, we have analysed the contribution of p38α the major p38 family member present in MEFs, to the overall stress-induced transcriptional response by using both a chemical inhibitor (SB203580) and p38α deficient (p38α-/-) MEFs. We show here that p38 SAPK dependency ranged between 60% and 88% depending on the treatments and that there is a very good overlap between the inhibitor treatment and the ko cells. Furthermore, we have found that the dependency of SAPK varies depending on the time the cells are subjected to osmostress.Conclusions: Our genome-wide transcriptional analyses shows a selective response to specific stimuli and a restricted common response of up to 20% of the stress up-regulated early genes that involves an important set of transcription factors, which might be critical for either cell adaptation or preparation for continuous extra-cellular changes. Interestingly, up to 85% of the up-regulated genes are under the transcriptional control of p38 SAPK. Thus, activation of p38 SAPK is critical to elicit the early gene expression program required for cell adaptation to stress. © 2010 Ferreiro et al; licensee BioMed Central Ltd.


Joaquin M.,University Pompeu Fabra | Gubern A.,University Pompeu Fabra | Gonzalez-Nunez D.,University Pompeu Fabra | Josue Ruiz E.,Signalling and Cell Cycle Group | And 5 more authors.
EMBO Journal | Year: 2012

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. ©2012 European Molecular Biology Organization.


Mouron S.,Signalling and Cell Cycle Group | De Carcer G.,Cell Division and Cancer Group | Seco E.,Signalling and Cell Cycle Group | Fernandez-Miranda G.,Cell Division and Cancer Group | And 3 more authors.
Journal of Cell Science | Year: 2010

RINGO/Speedy proteins are direct activators of Cdk1 and Cdk2 that have no sequence homology to cyclins. We have characterized the role in cell-cycle progression of a new human member of this protein family referred to as RINGO C. We show that siRNA-mediated knockdown of RINGO C results in premature mitotic exit with misaligned chromosomes, even in the presence of microtubule poisons. Time-lapse-microscopy experiments suggest that RINGO C is involved in the spindle-assembly checkpoint (SAC). Consistent with this idea, RINGO-C-depleted cells show impaired recruitment of the SAC components Mad2, Bub1 and BubR1. As the checkpoint is overridden, cells display defective chromosome segregation, which leads to an increased number of micronuclei and binucleated structures. Intriguingly, we found that RINGO C can associate with the mitotic kinase Aurora B, and downregulation of RINGO C produces mislocalization of the active form of Aurora B in prometaphase. Taken together, our results indicate a role for RINGO C in the mitotic checkpoint, which might be mediated by defective recruitment of SAC components and deregulation of the activity of Aurora kinase B.


PubMed | Signalling and Cell Cycle Group
Type: Journal Article | Journal: Journal of cell science | Year: 2010

RINGO/Speedy proteins are direct activators of Cdk1 and Cdk2 that have no sequence homology to cyclins. We have characterized the role in cell-cycle progression of a new human member of this protein family referred to as RINGO C. We show that siRNA-mediated knockdown of RINGO C results in premature mitotic exit with misaligned chromosomes, even in the presence of microtubule poisons. Time-lapse-microscopy experiments suggest that RINGO C is involved in the spindle-assembly checkpoint (SAC). Consistent with this idea, RINGO-C-depleted cells show impaired recruitment of the SAC components Mad2, Bub1 and BubR1. As the checkpoint is overridden, cells display defective chromosome segregation, which leads to an increased number of micronuclei and binucleated structures. Intriguingly, we found that RINGO C can associate with the mitotic kinase Aurora B, and downregulation of RINGO C produces mislocalization of the active form of Aurora B in prometaphase. Taken together, our results indicate a role for RINGO C in the mitotic checkpoint, which might be mediated by defective recruitment of SAC components and deregulation of the activity of Aurora kinase B.

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