| Attenuation of CD95-induced apoptosis by inorganic mercury: caspase-3 is not a direct target of low levels of Hg2+. | |
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MedLine Citation:
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PMID: 15585371 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Exposure to environmental mercury may be a factor that contributes to idiosyncratic autoimmune disease. Studies have demonstrated that inorganic, ionic mercury (i.e., Hg2+) modulates several lymphocyte signal transduction pathways, which may be a mechanism whereby Hg2+ dysregulates the immune response. The CD95/Fas apoptotic signaling pathway, which is of critical importance in regulating peripheral tolerance, is disrupted by low and environmentally relevant concentrations of Hg2+. Activation of the cysteine protease caspase-3 is a critical component of both CD95-mediated and TNF-alpha-induced apoptosis. The present work demonstrates that Hg2+ selectively disrupts death receptor mediated caspase-3 activation, where CD95-mediated caspase-3 activation is impaired in Hg2+ treated cells; whereas TNF-alpha-induced caspase-3 activation is not. Using the fluorogenic caspase-3 substrate, Ac-DEVD-7-amino-4-methyl coumarin, to measure caspase-3 enzyme activity as well as Western blotting to track processing of the caspase-3 proenzyme, we have considered the potential direct and indirect effects of Hg2+ on caspase-3. At relatively high concentrations and in a cell-free system, Hg2+ is capable of targeting the active site cysteinyl of caspase-3 resulting in enzyme inhibition. However, at more environmentally relevant exposures, Hg2+ does not gain access in appreciable quantities to the intracellular compartment where caspase-3 resides. Collectively, these data establish that Hg2+ impairs CD95-mediated apoptosis by targeting a plasma membrane proximal signaling event. By measuring the cellular Hg2+ content following various exposure conditions, we have determined that a cellular Hg2+ burden of approximately 50 ng/10(6) cells is sufficient to impair CD95-mediated caspase-3 activation. The present study furthers an understanding of the mechanism whereby relatively low and non-cytotoxic concentrations of Hg2+ may disrupt peripheral tolerance leading to sustained autoimmune disease. |
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Authors:
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Michael J McCabe; Kevin G Eckles; Margaret Langdon; Thomas W Clarkson; Michael J Whitekus; Allen J Rosenspire |
Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Toxicology letters Volume: 155 ISSN: 0378-4274 ISO Abbreviation: Toxicol. Lett. Publication Date: 2005 Jan |
Date Detail:
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Created Date: 2004-12-08 Completed Date: 2005-02-09 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 7709027 Medline TA: Toxicol Lett Country: Netherlands |
Other Details:
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Languages: eng Pagination: 161-70 Citation Subset: IM |
Affiliation:
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Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Box EHSC, 525 Elmwood Ave., Rochester, NY 14642, USA. michael_mccabe@urmc.rochester.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD95
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drug effects*,
metabolism Apoptosis / drug effects* Blotting, Western Caspase 3 Caspases / drug effects* Cysteine / metabolism Humans Indicators and Reagents Jurkat Cells Mercury / analysis, toxicity* Sulfhydryl Compounds / metabolism Tumor Necrosis Factor-alpha / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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P30 ES01247/ES/NIEHS NIH HHS; R01 ES012403/ES/NIEHS NIH HHS; R01 ES11000/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD95; 0/Indicators and Reagents; 0/Sulfhydryl Compounds; 0/Tumor Necrosis Factor-alpha; 52-90-4/Cysteine; 7439-97-6/Mercury; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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