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dc.contributor.authorBreitwieser, Wolfgang
dc.contributor.authorLyons, Steve
dc.contributor.authorFlenniken, Ann Marie
dc.contributor.authorAshton, Garry
dc.contributor.authorBruder, Gail
dc.contributor.authorWillington, Mark
dc.contributor.authorLacaud, Georges
dc.contributor.authorKouskoff, Valerie
dc.contributor.authorJones, Nic
dc.date.accessioned2009-06-12T13:57:27Z
dc.date.available2009-06-12T13:57:27Z
dc.date.issued2007-08-15
dc.identifier.citationFeedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. 2007, 21 (16):2069-82 Genes Dev.en
dc.identifier.issn0890-9369
dc.identifier.pmid17699753
dc.identifier.doi10.1101/gad.430207
dc.identifier.urihttp://hdl.handle.net/10541/70357
dc.description.abstractThe ATF2 transcription factor is phosphorylated by the stress-activated mitogen-activated protein kinases (MAPKs) JNK and p38. We show that this phosphorylation is essential for ATF2 function in vivo, since a mouse carrying mutations in the critical phosphorylation sites has a strong phenotype identical to that seen upon deletion of the DNA-binding domain. In addition, combining this mutant with a knockout of the ATF2 homolog, ATF7, results in embryonic lethality with severe abnormalities in the developing liver and heart. The mutant fetal liver is characterized by high levels of apoptosis in developing hepatocytes and haematopoietic cells. Furthermore, we observe a significant increase in active p38 due to loss of a negative feedback loop involving the ATF2-dependent transcriptional activation of MAPK phosphatases. In embryonic liver cells, this increase drives apoptosis, since it can be suppressed by chemical inhibition of p38. Our findings demonstrate the importance of finely regulating the activities of MAPKs during development.
dc.language.isoenen
dc.subject.meshActivating Transcription Factor 2
dc.subject.meshActivating Transcription Factors
dc.subject.meshAnimals
dc.subject.meshApoptosis
dc.subject.meshCell Survival
dc.subject.meshCells, Cultured
dc.subject.meshFeedback
dc.subject.meshFemale
dc.subject.meshHepatocytes
dc.subject.meshLiver
dc.subject.meshMAP Kinase Signaling System
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Knockout
dc.subject.meshMice, Mutant Strains
dc.subject.meshMice, Transgenic
dc.subject.meshModels, Biological
dc.subject.meshPregnancy
dc.subject.meshTranscriptional Activation
dc.subject.meshp38 Mitogen-Activated Protein Kinases
dc.titleFeedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells.en
dc.typeArticleen
dc.contributor.departmentCell Regulation Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom.en
dc.identifier.journalGenes & Developmenten
html.description.abstractThe ATF2 transcription factor is phosphorylated by the stress-activated mitogen-activated protein kinases (MAPKs) JNK and p38. We show that this phosphorylation is essential for ATF2 function in vivo, since a mouse carrying mutations in the critical phosphorylation sites has a strong phenotype identical to that seen upon deletion of the DNA-binding domain. In addition, combining this mutant with a knockout of the ATF2 homolog, ATF7, results in embryonic lethality with severe abnormalities in the developing liver and heart. The mutant fetal liver is characterized by high levels of apoptosis in developing hepatocytes and haematopoietic cells. Furthermore, we observe a significant increase in active p38 due to loss of a negative feedback loop involving the ATF2-dependent transcriptional activation of MAPK phosphatases. In embryonic liver cells, this increase drives apoptosis, since it can be suppressed by chemical inhibition of p38. Our findings demonstrate the importance of finely regulating the activities of MAPKs during development.


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