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

J. J. Lee, J. H. Lee, Young-Gyu Ko, S. I. Hong, J. S. Lee

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)561-575
Number of pages15
JournalOncogene
Volume29
Issue number4
DOIs
Publication statusPublished - 2010 Jan 1

Fingerprint

JNK Mitogen-Activated Protein Kinases
B-Cell Lymphoma
Reactive Oxygen Species
DNA Damage
Cell Aging
RNA Interference
Mitochondria
Carcinogenesis
Fibroblasts
Phosphorylation
Apoptosis
Breast Neoplasms
Carcinoma
Lung
Neoplasms

Keywords

  • Bcl-2
  • DNA damage
  • JNK
  • Premature senescence
  • ROS

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species. / Lee, J. J.; Lee, J. H.; Ko, Young-Gyu; Hong, S. I.; Lee, J. S.

In: Oncogene, Vol. 29, No. 4, 01.01.2010, p. 561-575.

Research output: Contribution to journalArticle

Lee, J. J. ; Lee, J. H. ; Ko, Young-Gyu ; Hong, S. I. ; Lee, J. S. / Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species. In: Oncogene. 2010 ; Vol. 29, No. 4. pp. 561-575.
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