title: Bcl-xL and E1B-19K proteins inhibit p53-induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation.
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.
authors.affiliation: National Research Laboratory for Cell Cycle Control, Department of Microbiology, Dankook University College of Medicine, Cheonan, 330-714, Korea.
authors.forename: Mun-Su
authors.initials: MS
authors.lastname: Jung
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.forename: Hee-Don
authors.initials: HD
authors.lastname: Chae
authors.forename: Seokwon
authors.initials: S
authors.lastname: Kang
authors.forename: Sun-Chang
authors.initials: SC
authors.lastname: Kim
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Tae-Saeng
authors.initials: TS
authors.lastname: Choi
authors.forename: Kyeong-Sook
authors.initials: KS
authors.lastname: Choi
authors.forename: Deug Y
authors.initials: DY
authors.lastname: Shin
mesh_terms: D017501:Adenovirus E1B Proteins / Q000502:physiology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D004789:Enzyme Activation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051020:bcl-X Protein; D001616:beta-Galactosidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D017501:Adenovirus E1B Proteins; D000975:Antioxidants; C494811:BCL2L1 protein, human; D007093:Imidazoles; D016877:Oxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; D001973:Bromodeoxyuridine; C093642:SB 203580