The stress-activated protein kinases p38alpha/beta and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
Authors
Llopis, AlbaSalvador, Noelia
Ercilla, Amaia
Guaita-Esteruelas, Sandra
Barrantes, Ivan del Barco
Gupta, Jalaj
Gaestel, Matthias
Davis, Roger J.
Nebreda, Angel R.
Agell, Neus
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2012-10-01Keywords
AnimalsAphidicolin
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins
Cyclin B1
DNA
*DNA Replication
DNA-Binding Proteins
Embryo, Mammalian
Enzyme Activation
Fibroblasts
Hydroxyurea
JNK Mitogen-Activated Protein Kinases
Kinetics
MAP Kinase Kinase 3
MAP Kinase Kinase 6
Mice
Mitogen-Activated Protein Kinase 11
Mitogen-Activated Protein Kinase 14
*Mitosis
NIH 3T3 Cells
Protein Kinases
Protein-Serine-Threonine Kinases
S Phase
Tumor Suppressor Proteins
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G 2/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38alpha and p38beta isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, thereby preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA.Source
Cell Cycle. 2012 Oct 1;11(19):3627-37. doi: 10.4161/cc.21917. Epub 2012 Aug 30. Link to article on publisher's siteDOI
10.4161/cc.21917Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28289PubMed ID
22935704Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.4161/cc.21917
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Molecular determinants that mediate selective activation of p38 MAP kinase isoformsEnslen, Herve; Brancho, Deborah Marie; Davis, Roger J. (2000-03-16)The p38 mitogen-activated protein kinase (MAPK) group is represented by four isoforms in mammals (p38alpha, p38beta2, p38gamma and p38delta). These p38 MAPK isoforms appear to mediate distinct functions in vivo due, in part, to differences in substrate phosphorylation by individual p38 MAPKs and also to selective activation by MAPK kinases (MAPKKs). Here we report the identification of two factors that contribute to the specificity of p38 MAPK activation. One mechanism of specificity is the selective formation of functional complexes between MAPKK and different p38 MAPKs. The formation of these complexes requires the presence of a MAPK docking site in the N-terminus of the MAPKK. The second mechanism that confers signaling specificity is the selective recognition of the activation loop (T-loop) of p38 MAPK isoforms. Together, these processes provide a mechanism that enables the selective activation of p38 MAPK in response to activated MAPKK.
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Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6Enslen, Herve; Raingeaud, Joel; Davis, Roger J. (1998-01-27)The cellular response to treatment with proinflammatory cytokines or exposure to environmental stress is mediated, in part, by the p38 group of mitogen-activated protein (MAP) kinases. We report the molecular cloning of a novel isoform of p38 MAP kinase, p38 beta 2. This p38 MAP kinase, like p38 alpha, is inhibited by the pyridinyl imidazole drug SB203580. The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms, while MKK3 activates only p38 alpha and p38 gamma MAP kinase isoforms. The MKK3 and MKK6 signal transduction pathways are therefore coupled to distinct, but overlapping, groups of p38 MAP kinases.