Mcl-1 is a common target of stem cell factor and interleukin-5 for apoptosis prevention activity via MEK/MAPK and PI-3K/Akt pathways

Stem cell factor (SCF) has been suggested as essential for optimal producti on of various hematopoietic lineages mainly because of its apoptosis preven tion function when it costimulates with other cytokines. However, the under lying mechanism of this synergism of apoptosis prevention is largely unknow n. The present study examined the expression of some Bcl-2 family members, including Bcl-2, Bcl-X-L, Mcl-1, and Bar, in response to cytokine stimulati on in TF-1 and JYTF-1 cells in which SCF costimulation is differentially re quired for optimal proliferation. The results revealed that only the expres sion of Mcl-1 highly correlated with the antiapoptotic activity of interleu kin-5 (IL-5) and the synergistic effect of SCF. In TF-1 cells, the defect o f IL-5 in apoptosis suppression and Mcl-1 induction was associated with the incapability to highly phosphorylate Janus kinases (JAK1, JAK2), signal tr ansducer and activator of transcription-5 (STAT5), mitogen-activated protei n kinase (MAPK), and Akt/PKB, whereas SCF costimulation restored the potent phosphorylation of MAPK and Akt/PKB, but not STATE. The importance of MAPK and Akt/PKB signaling pathways in regulating the expression of Mcl-1 and c ell survival was further supported by the observation that inhibition of ME K by PD98059 or phosphatidylinositol-3 kinase (PI-3K) by LY294002 independe ntly resulted in the reduction of Mcl-1 expression and loss of cell viabili ty. Therefore, the data suggest that Mcl-1 is a common antiapoptotic target of both early-stage cytokine SCF and late-stage cytokine IL-5. Both MEK/MA PK and PI-3K/Akt signaling pathways are essential in the regulation of Mcl- 1 expression and apoptosis prevention. (C) 2000 by The American Society of Hematology.