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

Oncogene volume 29, pages 561–575 (2010)Cite this article

Abstract

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.

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Acknowledgements

We thank Professor WS May of the University of Florida, USA for the kind gift of Bcl-2 mutant constructs and Professor J-Y Lee of the Hallym University, Korea for the kind supply of HEF cells. This work was supported by the Nuclear Research & Development Program of the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean government (MEST).

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Authors and Affiliations

  1. Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    J -J Lee & J -S Lee

  2. Graduate School of Life Sciences and Biotechnology, Korea University, Seoul, Korea

    J -J Lee & Y -G Ko

  3. Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea

    J -H Lee

  4. Department of Laboratory Medicine and Clinical Pathology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    S I Hong

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Lee, JJ., Lee, JH., Ko, YG. et al. Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species. Oncogene 29, 561–575 (2010). https://doi.org/10.1038/onc.2009.355

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Keywords

  • premature senescence; JNK; Bcl-2; ROS; DNA damage

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