Bax activation and translocation to mitochondria mediate EGF-induced programmed cell death

Tikhomirov, Oleg; Carpenter, Graham

doi:10.1242/jcs.02676

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…At present, it is still unclear why EGF can only initiate programmed cells death in these cells overexpressing its receptors [9,10] and that the overexpression of gene such as Bcl-xL prevent EGF-induced apoptosis [30]. From our investigation, we reasonably believe that, in cells like A431 overexpressing EGFR, maintaining an adequate quantity of mitochondrial EGFR is critical for cell survival, as EGFor etoposide-induced programmed cell death usually concurs a decline in mitochondrial EGFR.…”

Section: Discussionmentioning

confidence: 74%

“…Moreover, unlike HeLa cells, A431 cells were unable to prevent the cell death by increasing the expression of anti-apoptotic genes, such as Bcl-xL. On contrary, EGF treatment led to a decline in the Bcl-xL expression level and mitochondrial accumulation of Bax (a pro-apoptotic gene) in these cells [30]. In the case of Bcl-xL expression, the prevention of cell death may be due to the loss of mitochondrial EGFR, as we observed a decreased content of this subset of receptors upon transfection with Bcl-xL (data not shown).…”

Section: Discussionmentioning

confidence: 92%

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Mitochondrially localized EGFR is independent of its endocytosis and associates with cell viability

Yao¹,

Wang²,

Li³

et al. 2010

ABBS

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The molecular mechanism underlying epidermal growth factor receptor (EGFR) localization in mitochondria remains largely unknown. Using immune electron microscopy, we validated that EGFR could be localized on either the outer or the inner membrane of mitochondria. Mutant receptor lacked amino acids 646-660 was flawed in migration onto the organelles, whereas the mutated receptor with a defective endocytosis showed a greater capability of moving onto mitochondria upon stimulation of epidermal growth factor (EGF). Gefitinib, an inhibitor of EGFR kinase, inhibited the receptor endocytosis after short time of treatment, yet, only reduced cell viability as well as the amount of mitochondrial EGFR after longer time of exposure. Moreover, the content of mitochondrial EGFR transfer was decreased when the cells were exposed to the apoptotic inducer etoposide. EGF-induced programmed cell death usually coincided with a decline in mitochondrial EGFR. These data indicated that the mitochondrial-localized EGFR is independent of its internalization and may be correlated with cell survival and participate in the ligand-induced programmed cell death.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 92%

Mitochondrially localized EGFR is independent of its endocytosis and associates with cell viability

Yao¹,

Wang²,

Li³

et al. 2010

ABBS

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“…For instance, U937 lymphoma cells, HL60 leukemic cells, and PC3 epithelial cells treated with staurosporine released cytochrome c from the mitochondria into the cytosol, while no cytosolic cytochrome c accumulation was observed in the same cell types upon treatment with BMD188 (a potent apoptotic inducer) (Tang et al, 1998). Likewise, others (Tikhomirov and Carpenter, 2005) reported changes in mitochondrial membrane potential as well as apoptosis, but no significant release of cytochrome c from the mitochondria. Thus, it is possible for mitochondrial related apoptosis to occur in the absence of detectable cytochrome c release into the cytosol.…”

Section: Discussionmentioning

confidence: 97%

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Yadavilli¹,

Martinez‐Ceballos²,

Snowden-Aikens³

et al. 2007

Toxicology in Vitro

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Diepoxybutane (DEB) is the most potent metabolite of the environmental chemical 1, 3-butadiene (BD), which is prevalent in petrochemical industrial areas. BD is a known mutagen and human carcinogen, and possesses multi-systems organ toxicity. We recently reported that DEB-induced cell death in TK6 lymphoblasts was due to the occurrence of apoptosis, and not necrosis. In this study, we investigated the molecular mechanisms responsible for DEB-induced apoptosis in these cells. Bax and Bak were found to be over-expressed and activated, and the mitochondrial trans-membrane potential was attenuated in cells undergoing DEB-induced apoptosis. Cytochrome c was depleted from the mitochondria of TK6 cells undergoing apoptosis, and was released into the cytosol in Jurkat-T lymphoblasts exposed to the same concentrations of DEB. Executioner caspase 3 was deduced to be activated by initiator caspase 9. DEB induced reactive oxygen species (ROS) formation, and the ROS scavenger N-acetyl-L-cysteine effectively blocked DEB-induced apoptosis in TK6 cells.Collectively, these results demonstrate that the mitochondrial apoptotic pathway is activated to mediate DEB-induced apoptosis in human TK6 lymphoblasts. These results further demonstrate that DEB-induced apoptosis is also mediated by the DEB-induced generation of ROS. This is the first report to examine the mechanism of DEB-induced apoptosis in human lymphoblasts.

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“…These two proteins have pore-forming activities that mediate the release of apoptotic molecules, such as Smac and cytochrome c (10). BAX has been known as a cytosolic protein, which translocates to mitochondria during its activation (22). In contrast, BAK is expressed on the mitochondrial membrane and shows a conformational change during its activation, which is recognized by a specific antibody (23).…”

Section: Cr-induced Apoptosis Is Mediated Through the Activation Of Bmentioning

confidence: 99%

Coptidis Rhizoma induces intrinsic apoptosis through BAX and BAK activation in human melanoma

Yokoyama

Hayakawa

et al. 2017

Oncology Reports

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Abstract. Malignant melanoma has exhibited a rising incidence in recent years worldwide. Although various molecular targeted drugs are being researched and developed for melanoma patients, their efficacy appears to be unsatisfactory. Over the past few years, several reports have demonstrated that Coptidis Rhizoma water extracts (CR) or its major active chemical component, berberine, has anticancer activities in various types of cancer, including melanoma. However, their underlying mechanisms have not been well understood. In the present study, we determined that CR suppressed melanoma cell viability, which was mainly mediated through apoptosis. In addition, the expression levels of anti-apoptotic proteins, BCL2A1, MCL1 and BCL-w, were strongly suppressed by CR treatment. Furthermore, multi-domain pro-apoptotic proteins BAX and BAK were activated by CR treatment and were also required for the CR-induced apoptosis. Collectively, CR or some formulations containing CR, may be effective safe treatment strategies for human melanoma.

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Bax activation and translocation to mitochondria mediate EGF-induced programmed cell death

Cited by 25 publications

References 41 publications

Mitochondrially localized EGFR is independent of its endocytosis and associates with cell viability

Mitochondrially localized EGFR is independent of its endocytosis and associates with cell viability

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Coptidis Rhizoma induces intrinsic apoptosis through BAX and BAK activation in human melanoma

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