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.

The protooncogene bcl-

Neuregulins

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.

Expression of the protooncogene bcl-2 inhibits both apoptotic and in some cases necrotic cell death in many cell types, including neural cells, and in response to a wide variety of inducers. The mechanism by which the Bcl-2 protein acts to prevent cell death remains elusive. One mechanism by which Bcl-2 has been proposed to act is by decreasing the net cellular generation of reactive oxygen species. To evaluate this proposal, we measured activities of antioxidant enzymes as well as levels of glutathione and pyridine nucleotides in control and bcl-2 transfectants in two different neural cell lines-rat pheochromocytoma P012 and the hypothalamic GnRH cell line GT1 -7. Both neural cell lines overexpressing bcl-2 had elevated total glutathione levels when compared with control transfectants. The ratios of oxidized glutathione to total glutathione in P012 and GT1 -7 cells overexpressing bcl-2 were significantly reduced. In addition, the NAD/NADH ratio of bcl-2-expressing P012 and GT1-7 cells was two-to threefold less than that of control cell lines. GT1-7 cells overexpressing bcl-2 had the same level of glutathione peroxidase, catalase, superoxide dismutase, and glutathione reductase activities as control cells. P012 cells overexpressing bcl-2 had a twofold increase in superoxide dismutase and catalase activity when compared with matched control transfected cells. The levels of glutathione peroxidase and glutathione reductase in P012 cells overexpressing bcl-2 were similar to those of control cells, These results indicate that the overexpression of bcl-2 shifts the cellular redox potential to a more reduced state, without consistently affecting the major cellular antioxidant enzymes.