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Ionizing radiation-induced apoptosis in ataxia-telangiectasia fibroblasts. Roles of caspase-9 and cellular inhibitor of apoptosis protein-1.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2001 Aug 03; Vol. 276 (31), pp. 28842-8. Date of Electronic Publication: 2001 May 29. - Publication Year :
- 2001
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Abstract
- Ionizing radiation (IR) has been shown to induce apoptosis to a greater extent in a fibroblast cell line AT5BIVA derived from an individual with ataxia-telangiectasia (AT) than in control fibroblasts. However, the signaling pathway that underlies IR-induced apoptosis in AT cells has remained unknown. The mechanism of apoptosis in response to gamma-irradiation has now been examined in three AT fibroblast lines (AT3BIVA, AT4BIVA, and AT5BIVA) derived from different individuals with AT. The apoptotic indexes of these cell lines at 72 h after irradiation were 12, 31, and 35%, respectively, compared with a value of 2.3% for control fibroblasts. Immunoblot analysis and fluorometric assays revealed that the extents of IR-induced activation of caspase-3 and caspase-9 were markedly greater in AT4BIVA and AT5BIVA cells than in AT3BIVA and control cells. Furthermore, the basal abundance of the apoptotic inhibitor, a cellular inhibitor of apoptosis proteins (c-IAP-1), was markedly reduced in AT4BIVA and AT5BIVA cells compared with that in AT3BIVA and control cells. The overexpression of either caspase-9 mutant forms or recombinant c-IAP-1 in AT5BIVA cells inhibited the IR-induced activation of caspases-3 and 9 and reduced the apoptotic index of the irradiated cells. These results indicate that the extent of IR-induced apoptosis in different AT cell lines is inversely related to the abundance of c-IAP-1 and directly related to the extent of activation of caspases-3 and 9.
- Subjects :
- Amino Acid Substitution
Apoptosis physiology
Binding Sites
Caspase 3
Caspase 8
Caspase 9
Caspases chemistry
Caspases genetics
Cell Line
Enzyme Activation
Fibroblasts cytology
Fibroblasts pathology
Fibroblasts radiation effects
Gamma Rays
Humans
Inhibitor of Apoptosis Proteins
Kinetics
Mutagenesis, Site-Directed
Proteins genetics
Recombinant Proteins chemistry
Recombinant Proteins metabolism
Time Factors
Transfection
Apoptosis radiation effects
Ataxia Telangiectasia metabolism
Ataxia Telangiectasia pathology
Caspases metabolism
Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 276
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11382748
- Full Text :
- https://doi.org/10.1074/jbc.M010525200