Deficiency of the Stress Kinase p38 a 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, p38 a . Mice null for the p38 a allele die during embryonic development. p38 a 1 / 2 embryonic stem (ES) cells grown in the presence of high neomycin concentrations demonstrated conversion of the wild-type allele to a targeted allele. p38 a 2 / 2 ES cells lacked p38 a protein and failed to activate MAP kinase–activated protein (MAPKAP) kinase 2 in response to chemical stress inducers. In contrast, p38 a 1 / 1 ES cells and primary embryonic fibroblasts responded to stress stimuli and phosphorylated p38 a , and activated MAPKAP kinase 2. After in vitro differentiation, both wild-type and p38 a 2 / 2 ES cells yielded cells that expressed the interleukin 1 receptor (IL-1R). p38 a 1 / 1 but not p38 a 2 / 2 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 p38 a 1 / 1 and p38 a 2 / 2 ES cells. Therefore, these studies demonstrate that p38 a is a major upstream activator of MAPKAP kinase 2 and a key component of the IL-1 signaling pathway. However, p38 a does not serve an indispensable role in apoptosis.