Deficiency of the stress kinase p38α 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 alpha. Mice null for the p38 alpha allele die during embryonic development. p38 alpha(+/-) embryonic stem (ES) cells grown in the presence of high neomycin concentrations demonstrated conversion of the wild-type allele to a targeted allele. p38 alpha(-/-) ES cells lacked p38 alpha protein and failed to activate MAP kinase-activated protein (MAPKAP) kinase 2 in response to chemical stress inducers. In contrast, p38 alpha(+/+) ES cells and primary embryonic fibroblasts responded to stress stimuli and phosphorylated p38 alpha, and activated MAPKAP kinase 2. After in vitro differentiation, both wild-type and p38 alpha(-/-) ES cells yielded cells that expressed the interleukin 1 receptor (IL-1R). p38 alpha(+/+) but not p38 alpha(-/-) 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 alpha(+/+) and p38 alpha(-/-) ES cells, Therefore, these studies demonstrate that p38 alpha is a major upstream activator of MAPKAP kinase 2 and a key component of the IL-1 signaling pathway. However, p38 alpha does not serve an indispensable role in apoptosis.