title: Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway.
abstract: To elucidate the physiological significance of MEK5 in vivo, we have examined the effect of mek5 gene elimination in mice. Heterozygous mice appear to be healthy and were fertile. However, mek5(-/-) embryos die at approximately embryonic day 10.5 (E10.5). The phenotype of the mek5(-/-) embryos includes abnormal cardiac development as well as a marked decrease in proliferation and an increase in apoptosis in the heart, head, and dorsal regions of the mutant embryos. The absence of MEK5 does not affect cell cycle progression but sensitizes mouse embryonic fibroblasts (MEFs) to the ability of sorbitol to enhance caspase 3 activity. Further studies with mek5(-/-) MEFs indicate that MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation and for the regulation of the transcriptional activity of myocyte enhancer factor 2. Overall, this is the first study to rigorously establish the role of MEK5 in vivo as an activator of ERK5 and as an essential regulator of cell survival that is required for normal embryonic development.
authors.affiliation: University of Manchester, The Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Merritt
authors.forename: Jan
authors.initials: J
authors.lastname: Seyfried
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.forename: Emmanouil S
authors.initials: ES
authors.lastname: Papadakis
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Finegan
authors.forename: Midori
authors.initials: M
authors.lastname: Kayahara
authors.forename: Jill
authors.initials: J
authors.lastname: Dixon
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mayer
authors.forename: Cathy
authors.initials: C
authors.lastname: Tournier
mesh_terms: D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D017930:Genes, Reporter; D005822:Genetic Vectors; D005838:Genotype; D006579:Heterozygote; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000235:genetics* / Q000502:physiology*; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D019076:Transgenes
chemical_list: D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D008156:Luciferases; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases