Deficiency of the Stress Kinase p38 alpha 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 du...
Gespeichert in:
Veröffentlicht in: | The Journal of experimental medicine 2000-03, Vol.191 (5), p.859-870 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | 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 super(1/)-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 super(-/)- 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 super(1/+) 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 super(-/)- ES cells yielded cells that expressed the interleukin 1 receptor (IL-1R). p38 alpha super(1/+) but not p38 alpha super(-/)- 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 super(1/+) and p38 alpha super(-/)- 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. |
---|---|
ISSN: | 0022-1007 1540-9538 |
DOI: | 10.1084/jem.191.5.859 |