Nerve growth factor determines survival and death of PC12 cells by regulation of the bcl-x, bax, and caspase-3 genes

We investigated the effects of nerve growth factor (NGF) and NGF withdrawal on expression of members of the bcl-2 family of genes and caspase-3 in PC1 2 cells. NGF regulated several members of the bcl-2 family and caspase-3 in a manner consistent with its effect on apoptosis in PC12 cells. Levels of bcl-xl, bcl-xs, and caspase-3 mRNAs were increased by NGF treatment. The in creases in caspase-3 and bcl-xs levels should have disposed the cells towar d apoptosis but were opposed by the simultaneous increase in bcl-xl level. NGF withdrawal resulted in abrupt down-regulation of bcl-xl and up-regulati on of bax, favoring apoptosis. Forced expression of bcl-xl after NGF withdr awal was sufficient to prevent cell death. Cell death was rapid when NGF wa s withdrawn after 5 days of treatment but relatively slow when NGF was with drawn after only 1 or 2 days of treatment. This was consistent with the red uced accumulation of caspase-3 mRNA with shorter NGF treatments. These resu lts indicate that Bcl-xl, Bcl-xs, Bar, and caspase-3 are important regulato rs of apoptosis in PC12 cells. Furthermore, regulation of their mRNA levels is implicated in the signal transduction of NGF.