BAX-induced cell death may not require interleukin 1β-converting enzyme-like proteases

Abstract

Expression of BAX, without another death stimulus, proved sufficient to induce a common pathway of apoptosis. This included the activation of interleukin 1␤-converting enzyme (ICE)-like proteases with cleavage of the endogenous substrates poly(ADP ribose) polymerase and D4-GDI (GDP dissociation inhibitor for the rho family), as well as the f luorogenic peptide acetyl-Asp-Glu-Val-Aspaminotrif luoromethylcoumarin (DEVD-AFC). The inhibitor benzyloxycarbonyl-Val-Ala-Asp-f luoromethyl ketone (zVADfmk) successfully blocked this protease activity and prevented FAS-induced death but not BAX-induced death. Blocking ICE-like protease activity prevented the cleavage of nuclear and cytosolic substrates and the DNA degradation that followed BAX induction. However, the fall in mitochondrial membrane potential, production of reactive oxygen species, cytoplasmic vacuolation, and plasma membrane permeability that are downstream of BAX still occurred. Thus, BAXinduced alterations in mitochondrial function and subsequent cell death do not apparently require the known ICE-like proteases.

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

“…[19][20][21] Importantly, Bax is known to induce both caspase-independent anddependent cell death with cytoplasmic vacuolation when caspase activity is inhibited or absent. [26][27][28] These previous reports support our hypothesis that Bax is a key mediator of Q79C-induced cell death associated with cytoplasmic vacuolation. Recently, an elevated expression of Bax was reported in the brain of polyQ-transgenic mouse.…”

Proapoptotic genes BAX and CD40L are predictors of survival in transitional cell carcinoma of the bladder

“…BAX plays a central role in regulation and commitment to programmed cell death. BAX counteracts the apoptosis-preventing effect of BCL2 and may directly induce apoptosis (Xiang et al, 1996;Zha and Reed, 1997). The proapoptotic BAX is located in the outer mitochondrial membrane (Schlesinger et al, 1997).…”

Adenovirus-mediated transfer of Bax with caspase-8 controlled by myelin basic protein promoter exerts an enhanced cytotoxic effect in gliomas

“…Overexpression of Bax causes MPT, [22][23][24] which involves the formation of regulated megachannels in the contact site between the inner and outer mitochondrial membranes 39 and consequently leads to the release of cytochrome c and apoptosis-inducing factors from the mitochondrial intermembrane space. 21,40 -43 Cytochrome c forms a complex with Apaf-1 and caspase-9, and the activated caspase-9, in turn, cleaves and activates caspase-3, leading to apoptotic cell death.…”

“…Overexpression of Bax also induces MPT, which leads to apoptotic cell death. [22][23][24] Thus, MPT is a key event that causes enhanced cytotoxicity in cancer cells, regardless of whether it is induced through Bax overexpression, radiotherapy, chemotherapy, or a combination of these.…”