Abstract
The products of the ras genes are known to regulate cell proliferation and differentiation; recently, they have been found to play a role in apoptosis. The expression of oncogenic p21(ras) in a number of cell types, including Jurkat (a human T lymphoblastoid cell line) and murine fibroblasts, makes the cells susceptible to apoptosis following suppression of protein kinase C (PKC) activity (PKC/Ras-mediated apoptosis). Engagement of Fas antigen, a potent effector of apoptosis, activates cellular p21(ras), which may be required for completion of the cell death program. To further investigate the role of p21(ras) in the regulation of apoptosis, the cellular mechanisms employed in these two apoptotic processes in which Ras activity is involved (PKC/Ras-related and Fas-triggered apoptosis), was explored. Increasing p21(ras) activity by expressing v-ras or by treatment with an antisense oligonucleotide to the GTPase-activating protein was found to accelerate the Fas-mediated apoptotic process in Jurkat and mouse LF cells. PKC/Ras-related apoptosis was associated with, and required, cell cycle progression, accompanied by the expression of the G1/S cyclins. In contrast, Fas engagement, although inducing a vigorous and PKC-independent activation of endogenous p21(ras), did not alter cell cycle progression, nor did it require such progression for apoptosis. Both the protein synthesis inhibitor cycloheximide and cyclin E antisense oligonucleotides partially abolished PKC/Ras-mediated apoptosis but had only a moderate effect on Fas-induced apoptosis. In contrast, the CED-3/interleukin-1beta-converting enzyme (ICE) protease inhibitor Z-VADfmk efficiently suppressed Fas-induced apoptosis and only marginally inhibited PKC/Ras-mediated apoptosis. Induction of both pathways resulted in activation of the Jun NH2-terminal kinase/JUN signaling system. These results suggest that different cell death programs, such as PKC/Ras-mediated and Fas-mediated apoptosis, may be interconnected via p21(ras) and perhaps Jun NH2-terminal kinase/JUN. In response to various death stimuli, p21(ras) may act as a common intermediate regulator in the transduction of apoptotic signals.
Highlights
The proteins encoded by the ras gene family participate in several seemingly opposed pathways of signal transduction
We have previously demonstrated that activated p21ras can cause human lymphoid Jurkat cells or mouse fibroblasts to undergo apoptosis under the condition of inhibition of protein kinase C (PKC) activity by chronic, high-dose phorbol myristyl acetate (PMA) treatment or PKC inhibitors
It has been shown that ceramides, which are generated at cell membrane through the activation of sphingomyelinases by Fas ligation, stimulate p21ras activity and induce cell death in T lymphocytes [35]
Summary
The proteins encoded by the ras gene family participate in several seemingly opposed pathways of signal transduction. At least some of the mechanisms mediating the mitogenic activities of Ras, including the involvement of molecules directly regulating cell cycle progression, have been elucidated. A synthesis of many data regarding signals leading either to mitosis or to cell death suggests, surprisingly, that common molecular mediators might be shared by pathways of proliferation and pathways of apoptosis. Such common second messengers appear to include protein kinase C (PKC), divalent cations, and p21ras proteins. The molecular mechanisms of Fas-induced apoptosis are not fully understood, it is clear that multiple pathways might be involved in Fas signaling, including those mediated by the CED-3 homolog ICE-like protease family, and the sphingomyelin/ceramide activation of p21ras signaling. The involvement of p21ras as a common mediator of both mitogenic and apoptotic signals might resolve these seemingly contradictory or opposing activities
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