title: Mechanism of p38 MAP kinase activation in vivo.
abstract: The p38 mitogen-activated protein kinase (MAPK) is activated in vitro by three different protein kinases: MKK3, MKK4, and MKK6. To examine the relative roles of these protein kinases in the mechanism of p38 MAP kinase activation in vivo, we examined the effect of disruption of the murine Mkk3, Mkk4, and Mkk6 genes on the p38 MAPK signaling pathway. We show that MKK3 and MKK6are essential for tumor necrosis factor-stimulated p38 MAPK activation. In contrast, ultraviolet radiation-stimulated p38 MAPK activation was mediated by MKK3, MKK4, and MKK6. Loss of p38 MAPK activation in the mutant cells was associated with defects in growth arrest and increased tumorigenesis. These data indicate that p38 MAPK is regulated by the coordinated and selective actions of three different protein kinases in response to cytokines and exposure to environmental stress.
authors.affiliation: Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Brancho
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Anja
authors.initials: A
authors.lastname: Jaeschke
authors.forename: Juan-Jose
authors.initials: JJ
authors.lastname: Ventura
authors.forename: Nyaya
authors.initials: N
authors.lastname: Kelkar
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masanao
authors.initials: M
authors.lastname: Kyuuma
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Takeshita
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D009154:Mutation; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D020033:Protein Isoforms; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases