Requirement for p38α in erythropoietin expression:: A role for stress kinases in erythropoiesis

Activity of the p38 alpha MAP kinase is stimulated by various stresses and hematopoietic growth factors. A role for p38 alpha in mouse development and physiology was investigated by targeted disruption of the p38 alpha locus. Whereas some p38 alpha(-/-) 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 p38 alpha-deficient hematopoietic stem cells reconstitute lethally irradiated hosts, p38 alpha 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 p38a MAP kinase plays a critical role linking developmental and stress-induced erythropoiesis through regulation of Epo expression.