Cytokine receptors activate signals that regulate the transcription factor E2F-1, which then coordinates the expression of genes essential for DNA synthesis and cell cycle progression. Overexpression of E2F-1 most often induces S-phase entry followed by apoptosis, but in some cell types it leads to continuous proliferation and transformation. Here, it is shown that constitutive expression of E2F-1 promotes cytokine-independent proliferation in the murine pro-B cell line BaF-B03. There was no enhancement of apoptosis following cytokine withdrawal in these cells, despite the presence of intact p53-dependent apoptotic pathways. Notwithstanding the continuous presence of E2F-1, the cell cycle-dependent expression of cyclin A, cyclin B1, cyclin D1, cyclin E, and proliferating-cell nuclear antigen was restored with a pattern equivalent to that associated with cytokine stimulation. These findings provide evidence that, in the absence of cytokine, constitutive expression of E2F-1 can promote cell cycle progression and prevent apoptosis. (Blood. 2001;97:227-234)

IL-2 binding to its high-affinity receptor regulates signaling events that control both lymphocyte cell survival and cell cycle progression. Although many studies have examined the mechanisms by which IL-2 regulates cell growth, few studies have dissected the pathways involved in promoting cell survival or the coupling of these pathways to the receptor. In the present study, using the pre-B cell line Baf-B03 transfected with a truncated form of the IL-2 receptor (IL-2R) g chain, we demonstrate that IL-2-dependent cell survival requires only the N-terminal 350 amino acids of the IL-2R g chain. IL-2-dependent survival of cells expressing the truncated receptor correlates with increases in receptor-associated phosphatidylinositol 3-kinase (PI3K) activity and expression of Bcl-X L , but not with changes in c-Myc expression or proliferation. Inhibition of the PI3K pathway in these cells, but not in cells expressing the wild-type receptor, has a marked effect on the capacity of IL-2 to prevent cell death and diminishes the Bcl-X L response. The requirement for IL-2-induced PI3K activity in suppressing the onset of apoptotic cell death is discussed.

IL-2 binding to its high-affinity receptor regulates signaling events that control both lymphocyte cell survival and cell cycle progression. Although many studies have examined the mechanisms by which IL-2 regulates cell growth, few studies have dissected the pathways involved in promoting cell survival or the coupling of these pathways to the receptor. In the present study, using the pre-B cell line Baf-B03 transfected with a truncated form of the IL-2 receptor (IL-2R) g chain, we demonstrate that IL-2-dependent cell survival requires only the N-terminal 350 amino acids of the IL-2R g chain. IL-2-dependent survival of cells expressing the truncated receptor correlates with increases in receptor-associated phosphatidylinositol 3-kinase (PI3K) activity and expression of Bcl-X L , but not with changes in c-Myc expression or proliferation. Inhibition of the PI3K pathway in these cells, but not in cells expressing the wild-type receptor, has a marked effect on the capacity of IL-2 to prevent cell death and diminishes the Bcl-X L response. The requirement for IL-2-induced PI3K activity in suppressing the onset of apoptotic cell death is discussed.

T-cell chemotaxis constitutes an essential function of the immune response, since active secretion of chemokines controls homing and recruitment of leukocytes into tissues. Modification of chemotactic responses by HIV-1 may provide a mechanism to increase viral spread, and may be an important factor in HIV-1 disease progression and pathogenesis. One potent T-cell chemoattractant is SDF-1 alpha, the natural ligand for the HIV-1 co-receptor CXCR4. In addition, the HIV-1 gp120 molecule shares the chemotactic properties of several chemokines, including SDF-1 alpha. HIV-1 Nef is a pathogenic determinant and a virulence factor that has pleiotropic effects on immune cell processes and receptor signaling. In this study, the effects of Nef on T-cell migration to SDF-1 alpha, and on CXCR4 receptor signaling were examined. We report that disruption of the proline-rich region of Nef inhibits T-cell migration to SDF-1 alpha. This dominant negative effect indicates that Nef occupies a position in the CXCR4-mediated signaling pathway that is upstream of an SH3-dependent pathway. The results suggest that Nef may play an important role in homing of T cells during viral invasion in HIV-1 disease.