Ras activation leads to cell proliferation or apoptotic cell death upon interleukin‐2 stimulation or lymphokine deprivation, respectively

Abstract

Lymphokine-dependent cells undergo apoptosis upon lymphokine withdrawal. We describe that lymphokine deprivation of the interleukin (IL)-2- or IL-4-dependent mouse T cell line TS1 alpha beta induces Ras activation which plays a role in programmed cell death, since blocking Ras activity reduces the induction of apoptosis. Induction of apoptosis by lymphokine deprivation can be prevented by expression of the Bcl-2 protein. Rescue from cell death by IL-2 also promotes Ras activation, but, in contrast to lymphokine withdrawal, stimulates Bcl-2 expression. IL-4-induced cell survival is Ras- and Bcl-2 independent. These results are compatible with a model in which cell proliferation requires the simultaneous induction of at least two pathways which act in combination to prevent cell death.

Bcl-3 Expression Promotes Cell Survival following Interleukin-4 Deprivation and Is Controlled by AP1 and AP1-Like Transcription Factors

“…Stimulation of TS1␣␤ cells by IL-4, but not IL-2, induces Bcl-3 expression at the RNA and protein levels. The differential control of gene expression by IL-2 and IL-4 has been previously found in TS1␣␤ cells; IL-2 induces Bcl-2 and NFAT expression, whereas IL-4 does not (18,19). IL-9, GM-CSF, and Epo also induce Bcl-3 expression in T cells and erythroid cell precursors, as well as stimulating proliferation (35,46).…”

“…We have described that Bcl-2 is differentially regulated by IL-2 and IL-4 (19) and asked whether other genes might be differentially regulated by IL-2 and IL-4 in TS1␣␤ cells. Bcl-3 was recently shown to be induced by IL-9 and IL-4 in mouse T helper cells (35).…”

Bcl-2 Targets Protein Phosphatase 1α to Bad

“…Whereas up-or down-regulation of these proteins may account for the survival of certain cell types in response to extracellular stimuli, it also is possible that survival factors may use protein kinases or phosphatases to alter the ability of apoptotic proteins to promote cell survival or death. Bcl-2 is a positive regulator of cell survival, protecting various cell types from death induced by growth factor deprivation, heat shock, and viral agents (1,8). Several signal transducing proteins have been reported to directly or indirectly interact with Bcl-2.…”

Perillyl Alcohol Inhibits TCR-Mediated [Ca2+]i Signaling, Alters Cell Shape and Motility, and Induces Apoptosis in T Lymphocytes

“…4). Gómez et al studied the role of Ras in T cell proliferation and apoptosis and suggested that the cell proliferation is the consequence of a minimal number of molecular pathways involved in T cell activation (25). Incomplete signals may result in apoptotic cell death, instead of cell proliferation and effector functions.…”