Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis

L. Lin, Z. Su, I. V. Lebedeva, P. Gupta, H. Boukerche, T. Rai, G. N. Barber, P. Dent, D. Sarkar, P. B. Fisher

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Melanoma differentiation-associated gene-5 (mda-5) was the first molecule identified in nature whose encoded protein embodied the unique structural combination of an N-terminal caspase recruitment domain and a C-terminal DExD/H RNA helicase domain. As suggested by its structure, cumulative evidences documented that ectopic expression of mda-5 leads to growth inhibition and/or apoptosis in various cell lines. However, the signaling pathways involved in mda-5-mediated killing have not been elucidated. In this study, we utilized either genetically modified cloned rat embryo fibroblast cells overexpressing different functionally and structurally distinct oncogenes or human pancreatic and colorectal carcinoma cells containing mutant active ras to resolve the role of the Ras/Raf signaling pathway in mda-5-mediated growth inhibition/apoptosis induction. Rodent and human tumor cells containing constitutively activated Raf/Raf/MEK/ERK pathways were resistant to mda-5-induced killing and this protection was antagonized by intervening in this signal transduction cascade either by directly inhibiting ras activity using an antisense strategy or by targeting ras-downstream factors, such as MEK1/2, with the pharmacological inhibitor PD98059. The present findings provide a further example of potential cross-talk between growth-inhibitory and growth-promoting pathways in which the ultimate balance of these factors defines cellular homeostasis, leading to survival or induction of programmed cell death.

Original languageEnglish (US)
Pages (from-to)1982-1993
Number of pages12
JournalCell Death and Differentiation
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Lin, L., Su, Z., Lebedeva, I. V., Gupta, P., Boukerche, H., Rai, T., Barber, G. N., Dent, P., Sarkar, D., & Fisher, P. B. (2006). Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis. Cell Death and Differentiation, 13(11), 1982-1993. https://doi.org/10.1038/sj.cdd.4401899