Multistep and multitask Bax activation

Ghibelli, Lina; Diederich, Marc

doi:10.1016/j.mito.2010.08.003

Cited by 78 publications

(53 citation statements)

References 132 publications

(143 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, more than 75% of Bax colocalizes with mitochondria during apoptogenic insults, whereas the remaining Bax translocates to nuclei and endoplasmic reticulum or exists unbound in the cytosol (2). Bax lacks a mitochondrial localizing sequence, and a mitochondrial Bax receptor has yet to be identified (3,4), complicating efforts to dissect the molecular signals that drive intracellular Bax movement and toxicity. The possibility that a molecular chaperone facilitates mitochondrial Bax accumulation has been entertained recently (5,6).…”

mentioning

confidence: 99%

Nucleophosmin, a Critical Bax Cofactor in Ischemia-Induced Cell Death

Wang¹,

Gall

Bonegio

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

We hypothesized that nucleophosmin (NPM), a nucleolar phosphoprotein, is critical for Bax-mediated cell death. To test this hypothesis, Bax activation was induced by metabolic stress. During stress, nucleolar NPM translocated into the cytosol, NPMBax complexes formed, and both NPM and Bax accumulated in mitochondria. Expression of a cytosol-restricted NPM mutant (NPM-⌬NLS), but not a nucleus-restricted NPM mutant, increased NPM-Bax complex formation, mitochondrial NPM and Bax accumulation, mitochondrial membrane injury, caspase 3 activation, and ischemia-induced cell death. Coexpression of NPM-⌬NLS with constitutively active Bax mutants caused nearly universal cell death in the absence of metabolic stress, whereas expression of active Bax or NPM-⌬NLS alone did not. A Bax peptide that disrupts NPM-Bax interaction significantly reduced cell death caused by exposure to metabolic inhibitors in vitro and preserved kidney function after ischemia in vivo. Thus, NPM-Bax interaction enhances mitochondrial Bax accumulation, organelle injury, and cell death. NPM-Bax complex formation is a novel target for preventing ischemic tissue injury. Although Bax toxicity is well characterized, the events that signal Bax translocation to mitochondria, a major target of Baxmediated apoptosis, are unknown (1). Interestingly, more than 75% of Bax colocalizes with mitochondria during apoptogenic insults, whereas the remaining Bax translocates to nuclei and endoplasmic reticulum or exists unbound in the cytosol (2). Bax lacks a mitochondrial localizing sequence, and a mitochondrial Bax receptor has yet to be identified (3, 4), complicating efforts to dissect the molecular signals that drive intracellular Bax movement and toxicity. The possibility that a molecular chaperone facilitates mitochondrial Bax accumulation has been entertained recently (5, 6).Several Bax chaperones have been proposed (7), including humanin, Ku-70, Bax interacting factor 1 (bif-1), clusterin, specific 14-3-3 isoforms, and nucleophosmin (NPM; also called B23). NPM is an abundant, ubiquitously expressed, 35-kDa phosphoprotein that localizes to the nucleolar region of resting cells (8). In healthy cells, NPM promotes RNA metabolism, as well as the packaging and transport of cell proteins, by reversibly shuttling between the cytosol and the nucleolar region (9, 10). NPM also migrates into the cytosol during cell division to promote ribosomal protein synthesis and cell proliferation before returning to the nucleolar region (5,11,12). These NPM functions are essential, since its elimination causes embryonic death in NPM knockout mice (11).In cell-free systems, NPM interacts with Bax (6, 13). However, NPM only binds Bax that has undergone conformational change characterized by exposure of the amino-terminal 6A7 epitope (6, 14). The site responsible for binding NPM has been identified and localizes to the Bax carboxy-terminal domain (14). Furthermore, a synthetic, 21-amino-acid Bax peptide that includes this carboxyterminal NPM binding site disrupts NPM-Bax interaction in...

show abstract

mentioning

confidence: 99%

Nucleophosmin, a Critical Bax Cofactor in Ischemia-Induced Cell Death

Wang¹,

Gall

Bonegio

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Such sharing of these pathways reflects and explains the coexistence of apoptosis and necrosis in APAPinduced liver injury. Bax is a pro-apoptotic protein allowing apoptosis to occur through the intrinsic, damage-induced pathway, and amplifying one occurring via the extrinsic, receptor-mediated pathway [10]. Bax protein is activated and translocates from the cytosol to the outer mitochondrial membrane, forming high conductance channels [1,10].…”

Section: Resultsmentioning

confidence: 99%

“…For immunohistochemistry, mouse monoclonal antibodies for Bax (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, U.S.A.), PRL (prepared as described previously [10]), HEL (Nikken Seil Co., Ltd., Shizuoka, Japan), 4-HHE-histidine (NOF Corporation, Tokyo, Japan) and CRA-lysine (NOF Corporation, Tokyo, Japan) were used as the primary antibodies. All sections were dewaxed, rehydrated, rinsed with 0.05 M tris-buffered saline (TBS; pH 7.6), treated with 3% hydrogen peroxide, and then rinsed again with TBS.…”

Section: Methodsmentioning

confidence: 99%

Immunohistochemical Detection of Polyunsaturated Fatty Acid Oxidation Markers in Acetaminophen-Induced Liver Injury in Rats

Sun

Sugiyama

Hisaka

et al. 2012

The Journal of Veterinary Medical Science

View full text Add to dashboard Cite

ABSTRACT. To clarfity whether polyunsaturated fatty acid (PUFA) oxidation is involved in the mechanism of acetaminophen (APAP)-induced apoptotic cell death, the production and localization of PUFA oxidation markers N  -propanoyl-modified lysine, N  -hexanoylmodified lysine, 4-hydroxyhexenal-modified histidine and crotonaldehyde-modified lysine were evaluated in the development of APAPinduced liver injury. The immunoexpression of these markers in the liver was examined up to 24 hr post-APAP intraperitoneal injection in rats (1 g/kg body weight). The histopathological changes in the liver appeared 3 hr after APAP injection and became exacerbated with time. Proapoptotic protein Bax immunoreactivity was first detected in the degenerative hepatocytes 3 hr after the injection and areas positively immunostained for Bax reached a peak level at 6 hr, and then decreased at 12 and 24 hr. There was a significant increase in the TUNEL-positive rate at 12 and 24 hr. Immunohistological expression of all these oxidation markers was first detected in the degenerative hepatocytes 3 hr after the injection, and earlier than the occurrence of hepatocyte apoptosis. Immunohistochemical expression of these markers were observed in almost all degenerative hepatocytes 3-24 hr after APAP injection. Areas positively immunostained for these markers reached a peak level at 6 hr, and then decreased at 12 and 24 hr. The results thus suggest that the generation of PUFA oxidation markers may be the signature of early events preceding the induction of liver cell apoptosis and thus useful for early detection of oxidative stress-related liver cell injury.

show abstract

“…3) are the ones better characterized in molecular terms (Fulda & Debatin, 2006). The role of mitochondria as principal crossroad of the apoptotic process and emerged since 1990's, when it was shown that mitochondria of apoptosing cell death (Ghibelli & Diederich, 2010). The intrinsic pathway is characterized by the rapid release of cytochrome c from the mitochondrial inner membrane space into the cytosol.…”

Section: A Camphorata Regulates Apoptosis and Cell Survivalmentioning

confidence: 99%

“…During the stimulation, cytochrome c nucleates the assembly of a multi-protein complex, known as apoptosomes, functionally analog to the DISC, further recruits and activates the other upstream caspases, including caspase-9 and caspase-8. Caspase-8 and caspase-9 converge into proteolytic activation of caspase-3, results cells undergo execution phase of apoptosis and/or cell dismantling (Ghibelli & Diederich, 2010 (Yang et al, 2006;Yang et al, 2011). Meanwhile, the highest dose of A. camphorata (>100 µg/mL) was used to treat normal human endothelial cells for 24 hours, there was no cytotoxic effects were found.…”

Section: A Camphorata Regulates Apoptosis and Cell Survivalmentioning

confidence: 99%