ACTIVATION OF P38 MAP KINASE AND JNK BUT NOT ERK IS REQUIRED FOR ERYTHROPOIETIN-INDUCED ERYTHROID-DIFFERENTIATION

p38 MAP kinase (p38) and JNK have been described as playing a critical role in the response to a variety of environmental stresses and proin flammatory cytokines. It was recently reported that hematopoietic cyto kines activate not only classical MAP kinases (ERK), but also p38 and JNK. However, the physiological function of these kinases in hematopoi esis remains obscure. We found that all MAP kinases examined, ERK1, ER K2, p38, JNK1, and JNK2, were rapidly and transiently activated by ery thropoietin (Epo) stimulation in SKT6 cells, which can be induced to d ifferentiate into hemoglobinized cells in response to Epo. Furthermore , p38-specific inhibitor SB203580 but not MEK-specific inhibitor PD980 59 significantly suppressed Epo-induced differentiation and antisense oligonucleotides of p38, JNK1, and JNK2, but neither ERK1 nor ERK2 cle arly inhibited Epo-induced hemoglobinization. However, in Epo-dependen t FD-EPO cells, inhibition of either ERKs, p38, or JNKs suppressed cel l growth. Furthermore, forced expression of a gain-of-function MKK6 mu tant, which specifically activated p38, induced hemoglobinization of S KT6 cells without Epo. These results indicate that activation of p38 a nd JNKs but not of ERKs is required for Epo-induced erythroid differen tiation of SKT6 cells, whereas all of these kinases are involved in Ep o-induced mitogenesis of FD-EPO cells. (C) 1998 by The American Societ y of Hematology.