Bcl-xL and E1B-19K proteins inhibit p53-induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation.
J Biol Chem
; 279(17): 17765-71, 2004 Apr 23.
Article
em En
| MEDLINE
| ID: mdl-14764594
ABSTRACT
In this study, we describe novel functions of the anti-apoptotic Bcl-2 family proteins. Bcl-x(L) and E1B-19K were found to inhibit p53-induced irreversible growth arrest and senescence, but not to inhibit transient growth arrest, implying that Bcl-x(L) and E1B-19K are specifically involved in senescence without participating in growth arrest. We provide several lines of evidences showing that the functions of Bcl-x(L) and E1B-19K to prevent generation of reactive oxygen species (ROS) are important to inhibit senescence induction. First, we found that that ROS are increased during p53-induced senescence. Moreover, Bcl-x(L) and E1B-19K inhibit this p53-induced ROS generation. Second, antioxidants prevent the induction of senescence and ROS by p53, but not the persistence of the senescence phenotype. Third, the anti-senescence functions of Bcl-x(L) and E1B-19K were suppressed by adding exogenous ROS. These results suggest that Bcl-x(L) and E1B-19K inhibit senescence induction by preventing ROS generation. Furthermore, p38 kinase was found to be activated during p53-induced senescence, but not in cells expressing Bcl-x(L) or E1B-19K, or in cells treated with anti-oxidants. Consistently, a chemical inhibitor of p38 kinase, SB203580, was found to inhibit p53-induced senescence, but only when treated before the cellular commitment to senescence, implying that p38 kinase is necessary for senescence induction. Therefore, Bcl-x(L) and E1B-19K inhibit p53-induced senescence by preventing ROS generation, which in turn leads to the activation of p38 kinase. These results also suggest that the oncogenic potential of Bcl-2 is due to its ability to inhibit senescence as well as apoptosis.
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Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
/
Espécies Reativas de Oxigênio
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Proteínas E1B de Adenovirus
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Proteínas Proto-Oncogênicas c-bcl-2
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Proteínas Quinases Ativadas por Mitógeno
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2004
Tipo de documento:
Article