Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/70357
Title:
Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells.
Authors:
Breitwieser, Wolfgang; Lyons, Steve; Flenniken, Ann Marie; Ashton, Garry; Bruder, Gail; Willington, Mark; Lacaud, Georges; Kouskoff, Valerie; Jones, Nic
Abstract:
The 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.
Affiliation:
Cell Regulation Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom.
Citation:
Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. 2007, 21 (16):2069-82 Genes Dev.
Journal:
Genes & Development
Issue Date:
15-Aug-2007
URI:
http://hdl.handle.net/10541/70357
DOI:
10.1101/gad.430207
PubMed ID:
17699753
Type:
Article
Language:
en
ISSN:
0890-9369
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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

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