| Binding of caspase-3 prodomain to heat shock protein 27 regulates monocyte apoptosis by inhibiting caspase-3 proteolytic activation. | |
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MedLine Citation:
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PMID: 17597071 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Caspase-3 is an essential executioner of apoptosis responsible for regulating many important cellular processes, among them the number of circulating monocytes, central players in the innate immune response. The activation of caspase-3 requires its processing from an inactive precursor. Here we show that the small heat shock protein 27 (Hsp27) associates with caspase-3 and protein-protein interaction experiments in vivo and with purified proteins demonstrate a direct interaction between Hsp27 and the amino-terminal prodomain of caspase-3. Using an in vitro caspase-3 activation assay, our results further establish that the interaction of Hsp27 with the caspase-3 prodomain inhibits the second proteolytic cleavage necessary for caspase-3 activation, revealing a novel mechanism for the regulation of this effector caspase. Hsp27 expression in monocytes is constitutive. Consistent with a central role of Hsp27 in blocking caspase-3 activation, Hsp27 down-regulation by double-stranded RNA interference induces apoptosis of macrophages, whereas Hsp27 overexpression increases the life span of monocytes by inhibiting apoptosis. Highlighting the importance of cell partitioning in the regulation of apoptosis, immunofluorescence, and subcellular fractionation studies revealed that whereas both caspase-3 and Hsp27 are cytoplasmic in fresh monocytes (i.e. not undergoing apoptosis), Hsp27 moves to the nucleus during apoptosis, a relocalization that can be blocked by promoting the differentiation of monocytes to macrophages or by inhibiting cell death. These results reveal a novel mechanism of caspase-3 regulation and underscore a novel and fundamental role of Hsp27 in the regulation of monocyte life span. |
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Authors:
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Oliver H Voss; Sanjay Batra; Sunny J Kolattukudy; M Elba Gonzalez-Mejia; Jeffrey B Smith; Andrea I Doseff |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2007-06-27 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 282 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-08-20 Completed Date: 2007-10-11 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 25088-99 Citation Subset: IM |
Affiliation:
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Heart and Lung Research Institute, Division of Pulmonary and Critical Care and Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD14
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biosynthesis Apoptosis Caspase 3 / metabolism* Cell Differentiation Enzyme Activation Enzyme Inhibitors / pharmacology* Heat-Shock Proteins / metabolism* Humans Models, Biological Monocytes / metabolism, pathology* Protein Binding Protein Structure, Tertiary RNA Interference Subcellular Fractions / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01HL075040/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD14; 0/Enzyme Inhibitors; 0/Heat-Shock Proteins; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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