Cholesterol Effects on BAX Pore Activation

Christenson, Eric T.; Merlin, Sean; Saito, Mitsuyoshi; Schlesinger, Paul H.

doi:10.1016/j.jmb.2008.06.037

Cited by 39 publications

(40 citation statements)

References 90 publications

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“…Liposomes with lipid composition of DOPC:DOPA:bovine heart cardiolipin (70:20:10 mol %) were prepared using the reverse-phase evaporation method (21) following the procedure described in detail in Ref. 22. The buffer was EB unless otherwise noted.…”

Section: Methodsmentioning

confidence: 99%

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Detergent-activated BAX Protein Is a Monomer

Ivashyna

García‐Sáez

Ries

et al. 2009

Journal of Biological Chemistry

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BAX is a pro-apoptotic member of the BCL-2 protein family. At the onset of apoptosis, monomeric, cytoplasmic BAX is activated and translocates to the outer mitochondrial membrane, where it forms an oligomeric pore. The chemical mechanism of BAX activation is controversial, and several in vitro and in vivo methods of its activation are known. One of the most commonly used in vitro methods is activation withdetergents,suchasn-octylglucoside.DuringBAXactivationwith n-octyl glucoside, it has been shown that BAX forms high molecular weight complexes that are larger than the combined molecular weight of BAX monomer and one detergent micelle. These large complexes have been ascribed to the oligomerization of BAX prior to its membrane insertion and pore formation. This is in contrast to the in vivo studies that suggest that active BAX inserts into the outer mitochondrial membrane as a monomer and then undergoes oligomerization. Here, to simultaneously determine the molecular weight and the number of BAX proteins per BAX-detergent micelle during detergent activation, we have used an approach that combines two single-molecule sensitivity technique, fluorescence correlation spectroscopy, and fluorescence-intensity distribution analysis. We have tested a range of detergents as follows: n-octyl glucoside, dodecyl maltoside, Triton X-100, Tween 20, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid, and cholic acid. With these detergents we observe that BAX is a monomer before, during, and after interaction with micelles. We conclude that detergent activation of BAX is not congruent with oligomerization and that in physiologic buffer conditions BAX can assume two stable monomeric conformations, one inactive and one active.

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Section: Methodsmentioning

confidence: 99%

“…The buffer was EB unless otherwise noted. The rest of the experimental conditions, experimental protocol, and data analysis were the same as described previously (22).…”

Section: Methodsmentioning

confidence: 99%

Detergent-activated BAX Protein Is a Monomer

Ivashyna

García‐Sáez

Ries

et al. 2009

Journal of Biological Chemistry

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“…Important growth-signaling complexes for pathways such as TGFb, EGFR/MAPK/ERK, AKT, and the AR reside within cholesterol-rich microdomains referred to as lipid rafts whose signaling integrity can be modulated by changes in cellular cholesterol levels that affect membrane fluidity, transport, and protein complex assembly and stability Freeman et al, 2007;Montero et al, 2008). Elevated mitochondrial cholesterol associated with different cancers has also been demonstrated to impair the BAX-mediated apoptotic permeability pore associated with apoptosis and provide an apoptotic escape mechanism (Zhuang et al, 2005;Li et al, 2006Li et al, , 2008MartinezAbundis et al, 2007;Oh et al, 2007;Christenson et al, 2008).…”

Section: Fredericks Et Almentioning

confidence: 99%

“…However, there is also a separate recognition that elevated intracellular cholesterol in non-hormone-dependent tumor cells can contribute to progression based on numerous reports of interference with multiple pathways of growth signaling and apoptosis (Zhuang et al, 2005;Li et al, 2006;Swinnen et al, 2006;Adam et al, 2007;Freeman et al, 2007;Martinez-Abundis et al, 2007;Oh et al, 2007;Christenson et al, 2008;Patra, 2008). The link between intracellular cholesterol and tumor progression has been found in hepatocellular carcinoma, colon, breast, head and neck, and melanoma cancers, either with tumor specimens and/or studies in cancer cell lines (Schabath et al, 2006;Baruthio et al, 2008;Montero et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

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Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

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“…However, while cholesterol content of up to 20% in liposomes impaired the tBid conformational change, this was not the case in the membrane with 8% cholesterol (Shamas-Din et al 2015). Bax activation and membrane insertion for permeabilization significantly reduced with high cholesterol content (Christenson et al 2008; . High levels of cholesterol in many tumor cells may be one of the mechanisms to prevent apoptosis and promote their survival and may also contribute to chemotherapy resistance in, for instance, hepatocellular carcinoma (Montero et al 2008).…”

Section: The Role Of Mitochondrial Membrane Lipids In Mompmentioning

confidence: 87%

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

et al. 2017

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Apoptosis is important in regulating cell death turnover and is mediated by the intrinsic and death receptor-based extrinsic pathways which converge at the mitochondrial outer membrane (MOM) leading to mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of apoptotic proteins that further activate the downstream pathway of apoptosis. Thus, tight regulation of MOMP is crucial in controlling apoptosis, and a lack of control may lead to tissue and organ malformation and the development of cancers. Despite a growing number of studies focusing on the structure and activity of the proteins involved in mediating MOMP, such as the Bcl-2 family proteins, the mechanism of MOMP is not well understood. In particular, the crucial role of the various structural properties and changes in lipid components of the MOM in mediating the recruitment and activation of different Bcl-2 proteins remains poorly understood. Furthermore, the factors that control the changes in mitochondrial membrane integrity from the initiation to the final disruption of MOM have yet to be clearly defined. In this review, we provide an overview of studies that focus on the mitochondrial membrane with a biophysical analysis of the interactions of the Bcl-2 proteins with the mitochondrial membrane.

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Cholesterol Effects on BAX Pore Activation

Cited by 39 publications

References 90 publications

Detergent-activated BAX Protein Is a Monomer

Detergent-activated BAX Protein Is a Monomer

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

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