Bax membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2

Murphy, Kathleen M.; Streips, Uldis N.; Lock, Richard B.

doi:10.1038/sj.onc.1203001

Cited by 85 publications

(63 citation statements)

References 48 publications

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“…For example, in the nanodisc cryo-EM study, Volkmann et al 78 found that BCL-XL abolished the integration of BAX into nanodisc membranes in the presence of BID BH3 peptides. This agrees with other work 10,34,95,[110][111][112] showing that BCL-XL or BCL-2 can block membrane recruitment and integration of BAX, even in the presence of a BAX-activating signal. In other studies, membrane integration of both BCL-XL and BAX (i.e.…”

Section: How Does Bcl-xl Protect Against Cell Death?supporting

confidence: 81%

The rheostat in the membrane: BCL-2 family proteins and apoptosis

et al. 2013

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Apoptosis, a mechanism for programmed cell death, has key roles in human health and disease. Many signals for cellular life and death are regulated by the BCL-2 family proteins and converge at mitochondria, where cell fate is ultimately decided. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX, BAK) proteins. Previously, it was thought that a balance between these opposing proteins, like a simple 'rheostat', could control the sensitivity of cells to apoptotic stresses. Later, this rheostat concept had to be extended, when it became clear that BCL-2 family proteins regulate each other through a complex network of bimolecular interactions, some transient and some relatively stable. Now, studies have shown that the apoptotic circuitry is even more sophisticated, in that BCL-2 family interactions are spatially dynamic, even in nonapoptotic cells. For example, BAX and BCL-XL can shuttle between the cytoplasm and the mitochondrial outer membrane (MOM). Upstream signaling pathways can regulate the cytoplasmic-MOM equilibrium of BAX and thereby adjust the sensitivity of cells to apoptotic stimuli. Thus, we can view the MOM as the central locale of a dynamic life-death rheostat. BAX invariably forms extensive homo-oligomers after activation in membranes. However, recent studies, showing that activated BAX monomers determine the kinetics of MOM permeabilization (MOMP), perturb the lipid bilayer and form nanometer size pores, pose questions about the role of the oligomerization. Other lingering questions concern the molecular mechanisms of BAX redistribution between MOM and cytoplasm and the details of BAX/BAK-membrane assemblies. Future studies need to delineate how BCL-2 family proteins regulate MOMP, in concert with auxiliary MOM proteins, in a dynamic membrane environment. Technologies aimed at elucidating the structure and function of the full-length proteins in membranes are needed to illuminate some of these critical issues.

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Section: How Does Bcl-xl Protect Against Cell Death?supporting

confidence: 81%

The rheostat in the membrane: BCL-2 family proteins and apoptosis

et al. 2013

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“…38 Consistent with a previous report, we have demonstrated that STP-induced Bax redistribution is independent of caspase activity. 32 However, Bax membrane translocation induced by Fas activation was caspase dependent, 39 indicating a differential requirement of caspase activity for this process depending on the apoptotic stimulus.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells

et al. 2000

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The pro-apoptotic protein, Bax, has been reported to translocate from cytosol to mitochondria following exposure of cells to apoptotic stresses including cytokine withdrawal and treatment with glucocorticoids and cytotoxic drugs. These observations, coupled with reports showing that Bax causes the release of mitochondrial cytochrome c, implicate Bax as a central mediator of the apoptotic process. In this report we demonstrate by subcellular fractionation a significant shift in Bax localization from cytosol to cellular membranes in two human tumor cell lines exposed to staurosporine or etoposide. Immunofluorescence studies confirmed that Bax specifically relocalized to the mitochondria. This redistribution of Bax occurred in concert with, or just prior to, proteolytic processing of procaspase-3, activation of DEVD-specific cleavage activity and degradation of poly(ADPribose) polymerase. However, Bax membrane translocation was independent of caspase activity as determined using the broad-range caspase inhibitor z-VAD-fmk. High level overexpression of the anti-apoptotic protein Bcl-2 prevented Bax redistribution to the mitochondria, caspase activation and apoptosis following exposure to staurosporine or etoposide. These data confirm the role of Bax in mitochondrial cytochrome c release, and indicate that prevention of Bax translocation to the mitochondrial membrane represents a novel mechanism by which Bcl-2 inhibits drug-induced apoptosis. Cell Death and Differentiation (2000) 7, 102 ± 111.

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“…Activation of caspase-8 could cleave its substrate Bid to generate 15 kD truncated Bid (tBid), which could be translocated to mitochondria to induce the release of cytochrome c thereby activating mitochondrial pathway of apoptosis [22]. Moreover, activation of caspase cascade might be correlated with migration of cytosolic Bax to the mitochondria where it could assist tBid in releasing cytochrome c into the cytosol [23]. We found that treatment with 4-HPR and IFN-γ caused significant increases in proteolytic cleavage of Bid to tBid in all glioblastoma cell lines (Fig.…”

Section: Activation Of Caspase-8 and Proteolytic Cleavage Of Bidmentioning

confidence: 99%

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

2008

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Glioblastoma is the most malignant and prevalent brain tumor in humans. It is composed of heterogenic abnormal astroglial cells that avoid differentiation, maintain proliferation, and reluctant to apoptosis. N-(4-Hydroxyphenyl) retinamide (4-HPR) induced astrocytic differentiation and increased sensitivity to interferon-gamma (IFN-γ) for apoptosis in human glioblastoma A172, LN18, and SNB19 cells. Combination of 4-HPR and IFN-γ significantly inhibited human telomerase reverse transcriptase (hTERT), cyclin dependent kinase 2 (CDK2), and survivin to upregulate caspase-8, caspase-9, and caspase-3 for increasing apoptosis in all glioblastoma cell lines. Hence, combination of 4-HPR and IFN-γ should be considered for controlling growth of different human glioblastoma cells.

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Bax membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2

Cited by 85 publications

References 48 publications

The rheostat in the membrane: BCL-2 family proteins and apoptosis

The rheostat in the membrane: BCL-2 family proteins and apoptosis

Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

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