Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

• Published in: Oncogene Vol. 29; no. 4; pp. 561 - 575
• Main Authors: Lee, J -J, Lee, J -H, Ko, Y -G, Hong, S I, Lee, J -S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.01.2010; Nature Publishing Group
• Subjects: Aging; Anthracenes - pharmacology; Apoptosis; Biological and medical sciences; Cell Biology; Cell Differentiation - drug effects; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cellular Senescence - drug effects; Cellular signal transduction; DNA Damage; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetics; Genotype & phenotype; Human Genetics; Humans; Internal Medicine; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; MAP Kinase Signaling System - drug effects; Medicine; Medicine & Public Health; Molecular and cellular biology; Oncology; original-article; Physiological aspects; Protein Kinase Inhibitors - pharmacology; Protein kinases; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; South Korea; premature senescence; JNK; Bcl-2; ROS; DNA damage; Premature; Bcl-2; Reactive oxygen species; Senescence; DNA damage; JNK; Carcinogenesis; premature senescence; Prevention; Regulation(control); DNA; C-Onc gene; ROS; Lesion; Protooncogene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.355

Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences show that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the mechanism for this regulation is not fully understood. Here, we examined the role of JNK in premature senescence of tumor cells. Treatment of cells with the JNK-specific inhibitor SP600125 caused phenotypical changes of senescence and triggered a rapid increase in mitochondrial reactive oxygen species (ROS) production and DNA-damage response (DDR) in MCF7 breast carcinoma cells. ROS generation was attributed to the suppression of B-cell lymphoma-2 (Bcl-2) phosphorylation, and resulted in DNA damage and p53 activation. Bax did not change their localization to the mitochondria, which is required for apoptosis. The essential roles of JNK and phosphorylated Bcl-2 in preventing premature senescence were confirmed using RNA interference and ectopic expression of mutants of Bcl-2, including phosphomimetic and nonphosphorylatable forms. These findings were evidenced in H460 lung carcinoma cells and primary human embryonic fibroblasts. Altogether, our results showed that loss of JNK activity triggers a Bcl-2/ROS/DDR signaling cascade that ultimately leads to premature senescence, indicating that basal JNK activity is essential in preventing premature senescence.