Distinct roles of JNKs/p38 MAP kinase and ERKs in apoptosis and survival of HCD-57 cells induced by withdrawal or addition of erythropoietin

Erythropoietin (EPO), a major regulator of erythroid progenitor cells, is e ssential for the survival, proliferation, and differentiation of immature e rythroid cells. To gain insight into the molecular mechanism by which EPO f unctions, we analyzed the activation of Jun N-terminal kinases (JNKs) and e xtracellular signal-regulated kinases (ERKs) in HCD-57 cells, a murine eryt hroid progenitor cell line that requires EPO for survival and proliferation . Withdrawal of EPO from the cell culture medium resulted in sustained acti vation of JNKs plus p38 MAP kinase, and inactivation of ERKs, preceding apo ptosis of the cells. Addition of EPO to the EPO-deprived cells caused activ ation of ERKs accompanied by inactivation of JNKs and p38 MAP kinase and re scued the cells from apoptosis. Phorbol 12-myristate 13-acetate, which acti vated ERKs by a different mechanism, also suppressed the activation of JNKs and significantly retarded apoptosis of the cells caused by withdrawal of EPO. Furthermore, MEK inhibitor PD98059, which inhibited activation of ERKs , caused activation of JNKs, whereas suppression of JNK expression by antis ense oligonucleotides and inhibition of p38 MAP kinase by SB203580 caused a ttenuation of the apoptosis that occurs upon withdrawal of EPO. Finally, th e activation of JNKs and p38 MAP kinase and concurrent inactivation of ERKs upon withdrawal of EPO were also observed in primary human erythroid colon y-forming cells. Taken together, the data suggest that activation of ERKs p romotes cell survival, whereas activation of JNKs and p38 MAP kinase leads to apoptosis and EPO functions by controlling the dynamic balance between E RKs and JNKs. (C) 1999 by The American Society of Hematology.