Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells.
The mitogen-activated protein (MAP) kinase p38 is a key component of stress response pathways and the target of cytokine-suppressing antiinflammatory drugs (CSAIDs). A genetic approach was employed to inactivate the gene encoding one p38 isoform, p38alpha. Mice null for the p38alpha allele die during embryonic development. p38alpha(1/)- embryonic stem (ES) cells grown in the presence of high neomycin concentrations demonstrated conversion of the wild-type allele to a targeted allele. p38alpha(-/)- ES cells lacked p38alpha protein and failed to activate MAP kinase-activated protein (MAPKAP) kinase 2 in response to chemical stress inducers. In contrast, p38alpha(1/+) ES cells and primary embryonic fibroblasts responded to stress stimuli and phosphorylated p38alpha, and activated MAPKAP kinase 2. After in vitro differentiation, both wild-type and p38alpha(-/)- ES cells yielded cells that expressed the interleukin 1 receptor (IL-1R). p38alpha(1/+) but not p38alpha(-/)- IL-1R-positive cells responded to IL-1 activation to produce IL-6. Comparison of chemical-induced apoptosis processes revealed no significant difference between the p38alpha(1/+) and p38alpha(-/)- ES cells. Therefore, these studies demonstrate that p38alpha is a major upstream activator of MAPKAP kinase 2 and a key component of the IL-1 signaling pathway. However, p38alpha does not serve an indispensable role in apoptosis.
Allen
M
M
Department of Respiratory, Allergy, Immunology, Inflammation, and Infectious Diseases, Central Research, Pfizer, Inc., Groton, CT 06340, USA.
Svensson
L
L
Roach
M
M
Hambor
J
J
McNeish
J
J
Gabel
C A
CA
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000893:Anti-Inflammatory Agents; D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D005804:Genes, Lethal; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D017670:Sodium Compounds / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D000841:Anisomycin; D000893:Anti-Inflammatory Agents; D018053:Arsenites; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017472:Receptors, Interleukin-1; D017670:Sodium Compounds; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C017947:sodium arsenite