Two Distinct Interleukin-3-Mediated Signal Pathways, Ras-NFIL3 (E4BP4) and Bcl-x_L, Regulate the Survival of Murine Pro-B Lymphocytes

Abstract

Hematopoietic cells require cytokine-initiated signals for survival as well as proliferation. The pathways that transduce these signals, ensuring timely regulation of cell fate genes, remain largely undefined. The NFIL3 (E4BP4) transcription factor, Bcl-x_L, and constitutively active mutants of components in Ras signal transduction pathways have been identified as key regulation proteins affecting murine interleukin-3 (IL-3)-dependent cell survival. Here we show that expression of NFIL3 is regulated by oncogenic Ras mutants through both the Raf–mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. NFIL3 inhibits apoptosis without affecting Bcl-x_L expression. By contrast, Bcl-x_L levels are regulated through the membrane proximal portion in the cytoplasmic domain of the receptor (βc chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor. Activation of either pathway alone is insufficient to ensure cell survival, indicating that multiple independent signal transduction pathways mediate the survival of developing B-lymphoid cells.

ACKNOWLEDGMENTS

We are indebted to T. Kitamura for providing the pMX retrovirus vector, John Gilbert for editorial review, and John L. Cleveland for critical comments.

This research was supported by grants-in-aid from the Ministry of Education, Science and Culture of Japan; by the Senri Life Science Foundation; by grants from the National Cancer Institute (CA 59571 and Cancer Center Core CA 21765); and by the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children’s Research Hospital.