p53 potentiation of tumor cell susceptibility to CTL involves Fas and mitochondrial pathways.
J Immunol
; 174(2): 871-8, 2005 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-15634909
ABSTRACT
In this study, we have investigated the mechanisms used by wild-type p53 (wtp53) to potentiate tumor cell susceptibility to CTL-mediated cell death. We report that wtp53 restoration in a human lung carcinoma cell line Institut Gustave Roussy (IGR)-Heu, displaying a mutated p53, resulted in up-regulation of Fas/CD95 receptor expression associated with an increase of tumor cell sensitivity to the autologous CTL clone, Heu127. However, when IGR-Heu cells were transfected with Fas cDNA, no potentiation to Heu127-mediated lysis was observed, indicating that induction of CD95 is not sufficient to sensitize target cells to CTL killing. Importantly, our data indicate that the effect of wtp53 on the Fas-mediated pathway involves a degradation of short cellular FLICE inhibitory protein resulting in subsequent caspase 8 activation. Furthermore, we demonstrate that wtp53 restoration also resulted in CTL-induced Bid translocation into mitochondria and a subsequent mitochondrial membrane permeabilization leading to cytochrome c release. These results indicate that tumor cell killing by autologous CTL can be enhanced by targeting degranulation-independent mechanisms via restoration of wtp53, a key determinant of apoptotic machinery regulation.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T Citotóxicos
/
Transdução de Sinais
/
Adjuvantes Imunológicos
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Proteína Supressora de Tumor p53
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Receptor fas
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Citotoxicidade Imunológica
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Mitocôndrias
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article