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 (␤c 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.

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

“…Recently, the IL-3 inducible Ras/NFIL3 pathway has been shown to partially protect Ba/F3 cells from apoptosis. The downstream survival e ectors are still not known but are clearly distinct from Bcl-xL (Kuribara et al, 1999).…”

“…The use of cytokine receptor mutants or dominant negative/constitutively active forms of components of these signaling pathways identi®es the phosphatidylinisitol 3-kinase (PI 3-kinase)/Akt, Ras/NFIL3, Ras/Raf/ MAP kinase (MAPK) and JAK/STAT pathways as crucial regulators of survival and/or proliferation of hematopoietic cells (Songyang et al, 1997;Kuribara et al, 1999;Kinoshita et al, 1997;Liu et al, 1997;Dumon et al, 1999). Coordinated activation of these signaling pathways is commonly induced by most cytokines.…”

MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis

“…Furthermore, while the effects on MCL1 are transduced through the membrane distal region of the GM-CSF/IL-3 beta c receptor subunit, induction of BCLX requires the membrane proximal region. 32,35 A speculative possibility to encompass these findings is that different growth factor-induced signal transduction pathways result in protein synthesis-independent up-regulation of MCL1 for short-term promotion of cell viability, as well as protein synthesis-dependent up-regulation of BCLX for the maintenance of this response. These findings thus agree with the model of MCL1 as a BCL2 family member that can be rapidly induced for short-term viability enhancement.…”

Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a BH3-only cell death activator

“…Immunoblot analysis was performed as described previously. 6,11 In each experiment, total cell extracts from 1 Â 10 5 glioma cells or from 1 Â 10 6 HL-60 cells were analyzed.…”

“…The expression or function of each member of this superfamily is known to be regulated in response to specific death triggers. For example, in hematopoietic cells, an antiapoptotic member, Bcl-x L , is downregulated by cytokine withdrawal through inactivation of JAK-STAT pathways, [6][7][8][9][10] while DNA damage induced by ionizing radiation (IR) usually does not alter its expression levels. 11 In contrast, IR induces a proapoptotic member, Bax, by activating p53-dependent pathways, 12 while cytokine withdrawal does not.…”