| Fas-mediated apoptosis in mouse hepatocytes involves the processing and activation of caspases. | |
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MedLine Citation:
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PMID: 9620337 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mechanism of Fas antigen-induced hepatocyte apoptosis was investigated. Using a monoclonal antibody directed against the Fas antigen, apoptosis was induced in freshly isolated murine hepatocytes within 90 minutes of antibody addition as assessed by plasma membrane bleb formation, chromatin condensation, and DNA fragmentation. Pretreatment of the cells with the caspase inhibitors, N-acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-CHO), benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD-FMK), or Z-Asp-2,6-dichlorobenzoyloxymethylketone inhibited anti-Fas-mediated apoptosis. Likewise, the serine protease inhibitors, N-tosyl-L-phenyl chloromethyl ketone (TPCK) and 3,4-dichloroisocoumarin (DCI), prevented apoptosis, whereas N-tosyl-L-lysine chloromethyl ketone (TLCK), Ac-Leu-Leu-L-norleucinal, Ac-Leu-Leu-L-methional, and trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane were without effect. Examination of CED-3/caspase-3-related caspases revealed that pro-caspases-3 (CPP32) and -7 (Mch-3alpha) were rapidly processed after Fas antigen stimulation. Caspase-7 was further cleaved to form the catalytically active subunits. In contrast, the p17 subunit of caspase-3 was not detected, indicating slow formation or rapid degradation. The activation of CED-3-related caspases was further confirmed by an increase in the rate of Z-DEVD-7-amino-4-trifluoromethylcoumarin (Z-DEVD-AFC) hydrolysis that was sensitive to Ac-DEVD-CHO and was inhibited by pretreatment of the cells with TPCK but not by DCI. In contrast, no increase in the rates of hydrolysis of Z-YVAD-AFC, a substrate for caspase-1, was detected. Investigation of the in situ proteolytic cleavage of the CED-3 related caspases substrate, poly(ADP-ribose) polymerase, revealed that this protein was not degraded in hepatocytes undergoing Fas-mediated apoptosis. Taken together, our results show that processing of caspases, in particular, caspases-7 and -3, occurs during Fas-induced apoptosis of mouse hepatocytes and suggest a role of these proteases as well as serine protease(s) in the apoptotic response. |
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Authors:
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R A Jones; V L Johnson; N R Buck; M Dobrota; R H Hinton; S C Chow; G E Kass |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 27 ISSN: 0270-9139 ISO Abbreviation: Hepatology Publication Date: 1998 Jun |
Date Detail:
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Created Date: 1998-06-30 Completed Date: 1998-06-30 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1632-42 Citation Subset: IM |
Affiliation:
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School of Biological Sciences, University of Surrey, Guildford, England, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies / immunology, pharmacology Antigens, CD95 / immunology* Apoptosis / drug effects, immunology* Caspase 3 Caspase 7 Caspases* Cell Line Cysteine Endopeptidases / immunology* Enzyme Activation Humans Liver / immunology, pathology* Male Mice Mice, Inbred BALB C Signal Transduction / drug effects, immunology |
| Chemical | |
Reg. No./Substance:
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0/Antibodies; 0/Antigens, CD95; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP7 protein, human; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp7 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7; EC 3.4.22.-/Caspases; EC 3.4.22.-/Cysteine Endopeptidases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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