Two distinct interleukin-3-mediated signal pathways, Ras-NFIL3 (E4BP4) andBcl-x(L), regulate the survival of murine pro-B lymphocytes

Hematopoietic cells require cytokine-initiated signals for survival as well as proliferation, The pathways that transduce these signals, ensuring time ly regulation of cell fate genes, remain largely undefined, The NFIL3 (E4BP 4) transcription factor, Bcl-x(L), and constitutively active mutants of com ponents in Ras signal transduction pathways have been identified as key reg ulation proteins affecting murine Interleukin-3 (IL-3)-dependent cell survi val. Here we show that expression of NFIL3 is regulated by oncogenic Ras mu tants through both the Raf-mitogen-activated protein kinase and phosphatidy linositol 3-kinase pathways. NFIL3 inhibits apoptosis without affecting Bcl -x(L) expression. By contrast, Bcl-x(L) levels are regulated through the me mbrane proximal portion in the cytoplasmic domain of the receptor (beta c c hain), which is shared by IL-3 and granulocyte-macrophage colony-stimulatin g factor. Activation of either pathway alone is insufficient to ensure cell survival, indicating that multiple independent signal transduction pathway s mediate the survival of developing B-lymphoid cells.