Downregulation of Bim, a proapoptotic relative of Bcl-2, is a pivotal stepin cytokine-initiated survival signaling in murine hematopoietic progenitors

Tw distinct signaling pathways regulate the survival of interleukin-3 (IL3) -dependent hematopoietic progenitors. One originates from the membrane-prox imal portion of the cytoplasmic domain of the IL-3 receptor (betac chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating facto r and is involved in the regulation of Bcl-x(L) through activation of STAT5 . The other pathway emanates from the distal region of the betac chain and overlaps with downstream signals from constitutively active Res proteins. A lthough the latter pathway is indispensable for cell survival, its downstre am targets remain largely undefined. Here we show that the expression of Bi m, a member of the BH3-only subfamily of cell death activators, is downregu lated by IL-3 signaling through either of two major Ras pathways: Raf/mitog en-activated protein kinase and the phosphatidylinositol 3-kinase/mammalian target of rapamycin. Akt/phosphokinase B does not appear to play a signifi cant role in this regulatory cascade. Bim downregulation has important impl ications for fell survival, since enforced expression of this death activat or at levels equivalent to those induced by cytokine withdrawal led to apop tosis even in the presence of IL-3, We conclude that Bim is a pivotal molec ule in cytokine regulation of hematopoietic cell survival.