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Bcl-xL and E1B-19K Proteins Inhibit p53-induced Irreversible Growth Arrest and Senescence by Preventing Reactive Oxygen Species-dependent p38 Activation

Cited 49 time in Web of Science Cited 53 time in Scopus
Authors
Jung, Mun-Su; Jin, Dong-Hoon; Chae, Hee-Don; Kang, Seokwon; Kim, Sun-Chang; Bang, Yung-Jue; Choi, Tae-Saeng; Choi, Kyeong-sook; Shin, Deug Y.
Issue Date
2004-04
Citation
Journal of Biological Chemistry, Vol.279 No.17, pp.17765-17771
Abstract
In this study, we describe novel functions of the antiapoptotic 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.
ISSN
0021-9258
URI
https://hdl.handle.net/10371/173005
DOI
https://doi.org/10.1074/jbc.M305015200
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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