Activity of the p38alpha MAP kinase is stimulated by various stresses and hematopoietic growth factors. A role for p38alpha in mouse development and physiology was investigated by targeted disruption of the p38alpha locus. Whereas some p38alpha(-/-) embryos die between embryonic days 11.5 and 12.5, those that develop past this stage have normal morphology but are anemic owing to failed definitive erythropoiesis, caused by diminished erythropoietin (Epo) gene expression. As p38alpha-deficient hematopoietic stem cells reconstitute lethally irradiated hosts, p38alpha function is not required downstream of Epo receptor. Inhibition of p38 activity also interferes with stabilization of Epo mRNA in human hepatoma cells undergoing hypoxic stress. The p38alpha MAP kinase plays a critical role linking developmental and stress-induced erythropoiesis through regulation of Epo expression.
Anemia/enzymology Animals Embryonic and Fetal Development Erythropoiesis/physiology* Erythropoietin/genetics Female Gamma Rays Gene Expression Gene Targeting/methods Gestational Age Hematopoietic Stem Cells Humans Male Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases/genetics Mitogen-Activated Protein Kinases/metabolism Mitogen-Activated Protein Kinases/physiology* Stress, Physiological Tumor Cells, Cultured p38 Mitogen-Activated Protein Kinases