| Oligomerization of the mitochondrial protein voltage-dependent anion channel is coupled to the induction of apoptosis. | |
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MedLine Citation:
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PMID: 20937774 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Accumulating evidence implicates that the voltage-dependent anion channel (VDAC) functions in mitochondrion-mediated apoptosis and as a critical player in the release of apoptogenic proteins, such as cytochrome c, triggering caspase activation and apoptosis. The mechanisms regulating cytochrome c release and the molecular architecture of the cytochrome c-conducting channel remain unknown. Here the relationship between VDAC oligomerization and the induction of apoptosis was examined. We demonstrated that apoptosis induction by various stimuli was accompanied by highly increased VDAC oligomerization, as revealed by cross-linking and directly monitored in living cells using bioluminescence resonance energy transfer technology. VDAC oligomerization was induced in all cell types and with all apoptosis inducers used, including staurosporine, curcumin, As(2)O(3), etoposide, cisplatin, selenite, tumor necrosis factor alpha (TNF-α), H(2)O(2), and UV irradiation, all acting through different mechanisms yet all involving mitochondria. Moreover, correlation between the levels of VDAC oligomerization and apoptosis was observed. Furthermore, the apoptosis inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited VDAC oligomerization. Finally, a caspase inhibitor had no effect on VDAC oligomerization and cytochrome c release. We propose that VDAC oligomerization is involved in mitochondrion-mediated apoptosis and may represent a general mechanism common to numerous apoptogens acting via different initiating cascades. Thus, targeting the oligomeric status of VDAC, and hence apoptosis, offers a therapeutic strategy for combating cancers and neurodegenerative diseases. |
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Authors:
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Nurit Keinan; Dalia Tyomkin; Varda Shoshan-Barmatz |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-11 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 30 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2011-01-13 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 5698-709 Citation Subset: IM |
Affiliation:
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Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
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metabolism Animals Apoptosis / physiology* Caspases / antagonists & inhibitors, metabolism Fluorescence Resonance Energy Transfer / methods HEK293 Cells Hela Cells Humans Mitochondria / metabolism Mitochondrial Proteins / chemistry*, genetics, metabolism* Protein Multimerization* Protein Structure, Quaternary RNA, Small Interfering / genetics, metabolism Recombinant Fusion Proteins / genetics, metabolism Voltage-Dependent Anion Channel 1 / chemistry*, genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Mitochondrial Proteins; 0/RNA, Small Interfering; 0/Recombinant Fusion Proteins; 0/VDAC1 protein, human; 53005-05-3/4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; EC 1.6.-/Voltage-Dependent Anion Channel 1; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
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