BAX complex

Abstract: Tumor necrosis factor alpha (TNF-α)-mediated death signaling causes the recruitment of monomeric pro- apoptotic Bax into a 500-kDa protein complex. The adenovirus Bcl-2 homologue, E1B 19K, inhibits TNF-α-mediated apoptosis, interacts with Bax, and blocked the formation of the 500-kDa Bax complex. TNF-α and truncated Bid induced Bax-Bax cross-linking, indicative of oligomerization, and E1B 19K expression during infection inhibited this TNF-α-mediated Bax oligomerization. TNF-α signaled conformation changes at the Bax amino and carboxy termini. Exposure of the Bax amino terminus facilitates E1B 19K-Bax binding, which prevented exposure of the carboxy-terminal Bax Bcl-2 homology region 2 epitope. Inhibition of Bax oligomerization by E1B 19K is an activity that bears striking similarity to the means by which bacterial immunity proteins block pore formation by bacterial toxins which have structural homology to Bax.

Abstract: Sympathetic premotor neurons for the maintenance of vasomotor tone are located in rostral ventrolateral medulla (RVLM) We demonstrated previously that overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in RVLM, leading to caspase 3-dependent apoptotic cell death, plays a pivotal role in cardiovascular depression during endotoxemia induced by intravenous administration of Escherichia coli lipopolysaccharide The interposing intracellular events remain unknown We evaluated the hypothesis that these events encompass protein kinase C (PKC) activation, which triggers activation and translocation of Bax that opens mitochondrial permeability transition pore by interacting with adenine nucleotide translocase (ANT) or voltage-dependent anion protein (VDAC), followed by cytosolic release of cytochrome c In Sprague-Dawley rats, coimmunoprecipitation and Western blot analyses revealed sequential manifestations during endotoxemia of membrane-bound translocation of PKC, dissociation of cytosolic PKC/Bax complex, mitochondrial translocation of activated Bax, augmented Bax/ANT or Bax/VDAC association, elevated cytosolic cytochrome c and caspase 3, and DNA fragmentation in ventrolateral medulla Microinjection of iNOS inhibitor into bilateral RVLM significantly retarded PKC and Bax activation The induced association of translocated Bax with ANT or VDAC and the triggered mitochondrial apoptotic signaling cascade were blunted by blockade in RVLM of PKC, mitochondrial translocation of Bax, Bax channels, ANT, or caspase 3, alongside significant amelioration of cardiovascular depression We conclude that formation of mitochondrial Bax/ANT or Bax/VDAC complex that initiates caspase 3-dependent apoptosis in the RVLM as a result of PKC-dependent mitochondrial translocation of activated Bax activated by iNOS-derived NO plays a pivotal role in the manifestation of endotoxin-induced cardiovascular depression

Abstract: Ku70, a DNA repair factor in the nucleus, also regulates cell death by binding to the apoptotic protein Bax in the cytoplasm. Acetylation of Ku70 triggers Bax release resulting in Bax dependent cell death. Thus dissociating Bax from Ku70, either by inhibiting histone deacetylase 6 (HDAC6) that deacetylates Ku70 or by increasing Ku70 acetylation induces cell death. Our results showed that in neuroblastoma cells, the depletion of Ku70 results in Bax-dependent cell death. This model provides a rationale for screening Ku70 acetylation modulators that can be tested in clinical trials, either alone or in combination with radiotherapy or DNA-damaging agents for the treatment of cancer.