Ras signaling in tumor necrosis factor-induced apoptosis

Jonathan C. Trent, David J. McConkey, Susan M. Loughlin, Matthew T. Harbison, Antonio Fernandez, Honnavara N. Ananthaswamy

Research output: Contribution to journalArticle

Abstract

Tumor necrosis factor (TNF) exerts cytotoxicity on many types of tumor cells but not on normal cells. The molecular events leading to cell death triggered by TNF are still poorly understood. Our previous studies have shown that enforced expression of an activated H-ras oncogene converted non-tumorigenic, TNF-resistant C3H 10T1/2 fibroblasts into tumorigenic cells that also became very sensitive to TNF-induced apoptosis. This finding suggested that Ras activation may play a role in TNF-induced apoptosis. In this study we investigated whether Ras activation is an obligatory step in TNF-induced apoptosis. Introduction of two different molecular antagonists of Ras, the rap1A tumor suppressor gene or the dominant-negative rasN17 gene, into H-ras-transformed 10TEJ cells inhibited TNF-induced apoptosis. Similar results were obtained with L929 cells, a fibroblast cell line sensitive to TNF-induced apoptosis, which does not have a ras mutation. While Ras is constitutively activated in TNF-sensitive 10TEJ cells, TNF treatment increased Ras-bound GTP in TNF-sensitive L929 cells but not in TNF-resistant 10T1/2 cells. Moreover, RasN17 expression blocked TNF-induced Ras-GTP formation in L929 cells. These results demonstrate that Ras activation is required for TNF-induced apoptosis in mouse fibroblasts.

Original languageEnglish (US)
Pages (from-to)4497-4505
Number of pages9
JournalEMBO Journal
Volume15
Issue number17
StatePublished - Sep 2 1996

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Keywords

  • Apoptosis
  • Endogenous endonuclease
  • Ras activation
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Trent, J. C., McConkey, D. J., Loughlin, S. M., Harbison, M. T., Fernandez, A., & Ananthaswamy, H. N. (1996). Ras signaling in tumor necrosis factor-induced apoptosis. EMBO Journal, 15(17), 4497-4505.