ORDERING THE CELL-DEATH PATHWAY - DIFFERENTIAL-EFFECTS OF BCL2, AN INTERLEUKIN-1-CONVERTING ENZYME FAMILY PROTEASE INHIBITOR, AND OTHER SURVIVAL AGENTS ON JNK ACTIVATION IN SERUM NERVE GROWTH FACTOR-DEPRIVED PC12 CELLS
Ds. Park et al., ORDERING THE CELL-DEATH PATHWAY - DIFFERENTIAL-EFFECTS OF BCL2, AN INTERLEUKIN-1-CONVERTING ENZYME FAMILY PROTEASE INHIBITOR, AND OTHER SURVIVAL AGENTS ON JNK ACTIVATION IN SERUM NERVE GROWTH FACTOR-DEPRIVED PC12 CELLS, The Journal of biological chemistry, 271(36), 1996, pp. 21898-21905
Previous studies indicate that activation of c-Jun kinase (JNK) is nec
essary for apoptosis of trophic factor-deprived PC12 cells and that de
ath in this system is suppressed by multiple agents, including BCL2, i
nhibitors of the interleukin-1-converting enzyme (ICE) family of prote
ases, blockers of transcription, and a variety of small molecules with
differing modes of action. Here, we determine the order in which thes
e agents block apoptosis relative to JNK activation. Overexpression of
BCL2 promotes PC12 cell survival and blocks JNK activation caused by
trophic factor withdrawal. Similarly, the survival-promoting agents au
rintricarboxylic acid, N-acetylcysteine, the nitric oxide generator di
ethylenetriamine nitric oxide, 8-bromo-cGMP, and 8-(4-chlorophenylthio
)-cAMP act upstream to inhibit JNK activation. In contrast, zVAD-fluor
omethylketone (a permeant ICE family inhibitor), actinomycin D, and th
e G(1)/S cell cycle inhibitor deferoxamine, all promote survival after
trophic factor withdrawal, but do not affect JNK activation. These fi
ndings are consistent with the presence of an ordered cell death pathw
ay triggered by trophic factor deprivation in which 1) BCL2 and a numb
er of survival-promoting agents act upstream of JNK, 2) ICE family pro
tease actions, regulated genes required for cell death, and certain ce
ll cycle blockers lie either downstream of JNK or on independent pathw
ays required for apoptotic death.