Requirement for p38α in Erythropoietin Expression: A Role for Stress Kinases in Erythropoiesis

Activity of the p38α MAP kinase is stimulated by various stresses and hematopoietic growth factors. A role for p38α in mouse development and physiology was investigated by targeted disruption of the p38α locus. Whereas some p38α−/− 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 p38α-deficient hematopoietic stem cells reconstitute lethally irradiated hosts, p38α 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 p38α MAP kinase plays a critical role linking developmental and stress-induced erythropoiesis through regulation of Epo expression.