NEDD2 IS REQUIRED FOR APOPTOSIS AFTER TROPHIC FACTOR WITHDRAWAL, BUT NOT SUPEROXIDE-DISMUTASE (SOD1) DOWN-REGULATION, IN SYMPATHETIC NEURONS AND PC12 CELLS
Cm. Troy et al., NEDD2 IS REQUIRED FOR APOPTOSIS AFTER TROPHIC FACTOR WITHDRAWAL, BUT NOT SUPEROXIDE-DISMUTASE (SOD1) DOWN-REGULATION, IN SYMPATHETIC NEURONS AND PC12 CELLS, The Journal of neuroscience, 17(6), 1997, pp. 1911-1918
Activation of cysteine aspartases (caspases) seems to be a required el
ement of apoptotic death in many paradigms. We have shown previously t
hat general inhibitors of cysteine aspartases block apoptosis of PC12
cells and sympathetic neurons evoked by either trophic factor (nerve g
rowth factor and/or serum) deprivation or superoxide dismutase (SOD1)
downregulation. Moreover, activation of a caspase family member simila
r or equivalent to the interleukin-1 beta-converting enzyme (ICE) was
implicated for death caused by SOD1 downregulation, but not withdrawal
of trophic support. The experiments presented here demonstrate that d
iminished expression of the cysteine aspartase Nedd2 in PC12 cells and
sympathetic neurons induced by an appropriate vector peptide-linked a
ntisense oligonucleotide rescues them from death caused by trophic fac
tor deprivation without inhibiting apoptosis in the same cell types ev
oked by SOD1 downregulation. Neither the level (as revealed by Western
immunoblotting) nor the cellular distribution (as revealed immunohist
ochemical ly) of Nedd2 was altered demonstrably by trophic factor depr
ivation. However, evidence for proteolytic processing of Nedd2 (consis
tent with commencement of activation) was observed in PC12 cells after
withdrawal of trophic support. These findings indicate that neuronal
death triggered by different initial causes may be mediated by distinc
t members of the cysteine aspartase family.