ENHANCEMENT OF PEROXYNITRITE-INDUCED APOPTOSIS IN PC12 CELLS BY FIBROBLAST GROWTH-FACTOR-I AND NERVE GROWTH-FACTOR REQUIRES P21 RAS ACTIVATION AND IS SUPPRESSED BY BCL-2
N. Spear et al., ENHANCEMENT OF PEROXYNITRITE-INDUCED APOPTOSIS IN PC12 CELLS BY FIBROBLAST GROWTH-FACTOR-I AND NERVE GROWTH-FACTOR REQUIRES P21 RAS ACTIVATION AND IS SUPPRESSED BY BCL-2, Archives of biochemistry and biophysics (Print), 356(1), 1998, pp. 41-45
Extracellular trophic factors can regulate whether cells subjected to
oxidative stress will survive to proliferate or else undergo cell deat
h. We have previously shown that about 35% of undifferentiated PC12 ce
lls undergo apoptosis 18 h after exposure to peroxynitrite and that pr
etreatment with nerve growth factor (NGF) protects PC12 cells through
activation of phosphatidylinositol (PI) 3-kinase, In contrast, pretrea
tment with acidic fibroblast growth factor (FGF-1) approximately doubl
ed apoptosis, We report here that NGF added immediately after peroxyni
trite treatment no longer protected against apoptosis, but instead enh
anced apoptosis to the same extent as FGF, We further investigated whi
ch signaling pathways were involved in increasing the level of apoptos
is. Overexpression of Bcl-2 blocked the increased apoptosis caused by
NGF and FGF-1, but Bcl-2 did not prevent the induction of apoptosis by
peroxynitrite alone, The increase in apoptosis caused by the trophic
factors was also blocked by the expression of a dominant negative p21R
as mutant. Activation of PI 3-kinase by NGF pretreatment completely pr
otected against both the enhanced apoptosis induced by FGF-1 pretreatm
ent and NGF posttreatment and the apoptosis induced by peroxynitrite a
lone. Our results indicate that the enhancement of peroxynitrite-induc
ed apoptosis caused by NGF and FGF-1 is dependent on the stimulation o
f a proapoptotic pathway involving p21Ras that can be suppressed by Bc
l-2. (C) 1998 Academic Press.