title: Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells.
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.
authors: Cell Regulation Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom.
authors: Wolfgang
authors: W
authors: Breitwieser
authors: Steve
authors: S
authors: Lyons
authors: Ann Marie
authors: AM
authors: Flenniken
authors: Garry
authors: G
authors: Ashton
authors: Gail
authors: G
authors: Bruder
authors: Mark
authors: M
authors: Willington
authors: Georges
authors: G
authors: Lacaud
authors: Valerie
authors: V
authors: Kouskoff
authors: Nic
authors: N
authors: Jones
mesh_terms: D051698:Activating Transcription Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051696:Activating Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005246:Feedback; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D011247:Pregnancy; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; D051696:Activating Transcription Factors; C497106:Atf2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
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