The proto-oncogene bcl-2 inhibits apoptotic and necrotic neural cell death. Expression of Bcl-2 in the GT1-7 neural cell line prevented death as a result of glutathione depletion. Intracellular reactive oxygen species and lipid peroxides rose rapidly in control cells depleted of glutathione, whereas cells expressing Bcl-2 displayed a blunted increase and complete survival. Modulation of the increase in reactive oxygen species influenced the degree of cell death. Yeast mutants null for superoxide dismutase were partially rescued by expression of Bcl-2. Thus, Bcl-2 prevents cell death by decreasing the net cellular generation of reactive oxygen species.

Cell death has been described as either apoptotic, in which the cell actively participates, or necrotic, in which the cell is felt to be passive. The proto-oncogene bcl-2 has been shown to inhibit apoptosis in some hematopoietic and neural cells, by an unknown mechanism. We demonstrate that bcl-2 inhibits the necrosis of neural cells induced by glutathione depletion. This finding demonstrates that bcl-2 does not inhibit the cellular death program directly; rather, bcl-2 modulates a cellular process that leads to apoptosis under some conditions but necrosis under others.

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Extensive studies suggest a role for the myc protooncogene family in the control of cell proliferation and differentiation in vertebrates. Previously, deregulated expression of exogenous myc genes has been shown to inhibit induced differentiation in Friend erythroleukemia (MEL) cells and in human monoblastic U-937 cells. To examine the nature of the block of phorbol 12-myristate 13-acetate-induced differentiation in v-myc-expressing U-937 cells, we have studied the effect of other inducers utilizing signal pathways distinct from phorbol 12-myristate 13-acetate (i.e., la,25-dihydroxycholecalciferol and retinoic acid). We show that v-myc also inhibits differentiation associated with these inducers. However, the v-myc-associated block of phorbol 12-myristate 13-acetate-, 1a,25-dihydroxycholecalciferol-, and retinoic acid-induced differentiation can be overcome by adding interferon y as a costimulatory factor. Costimulation with interferon Y restores terminal differentiation, as shown by acquisition of a macrophage phenotype and an irreversible growth arrest in the GO/GI phase of the cell cycle, but induces only limited differentiation on its own. The differentiation is accomplished without altering the expression or nuclear localization of the v-myc protein. These results argue against the widely held view that down-regulation of myc expression is a general prerequisite for terminal differentiation of hematopoietic cells and suggests that interferon y induces a signal(s) that circumvents the v-myc activity.

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