Journal Article

<i>ras</i> oncogene expression determines sensitivity for intercellular induction of apoptosis

Agnes Schwieger, Lilian Bauer, Jörg Hanusch, Christine Sers, Reinhold Schäfer and Georg Bauer

in Carcinogenesis

Volume 22, issue 9, pages 1385-1392
Published in print September 2001 | ISSN: 0143-3334
Published online September 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.9.1385
ras oncogene expression determines sensitivity for intercellular induction of apoptosis

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Fibroblasts carrying an inducible ras oncogene acquire the transformed phenotype after oncogene induction. As a consequence, the transformed cells become sensitive to intercellular induction of apoptosis, a novel regulatory process directed by non-transformed fibroblasts against their transformed descendants. The causal relationship between oncogene expression and sensitivity to intercellular induction of apoptosis is based on extracellular superoxide anion production by oncogene-expressing cells. Superoxide anions (after dismutation to hydrogen peroxide) thereby foster HOCl synthesis and at the same time direct the selectivity of apoptosis induction through hydroxyl generation from HOCl. In parallel, ras expression enhances the sensitivity of fibroblasts for apoptosis-inducing stimuli like cycloheximide, ceramide and mitomycin C. This sensitization seems to be based on a decreased concentration of short lived endogenous apoptosis inhibitors. TGF-β, like ras induction, decreases the concentration of endogenous apoptosis inhibitors, but does not induce the transformed phenotype. Therefore, TGF-β treatment alone is not sufficient to render fibroblasts sensitive for intercellular induction of apoptosis, but TGF-β treatment in parallel with ras activation enhances intercellular induction of apoptosis. Our findings demonstrate that Ras-mediated superoxide anion production determines sensitivity to intercellular induction of apoptosis, whereas the parallel decrease in endogenous apoptosis inhibitors modulates the kinetics of apoptosis induction.

Keywords: CHX, cycloheximide; IPTG, isopropyl-β-d-thiogalactopyranoside; MEM, Eagle's minimal essential medium; SNP, sodium nitroprusside; SOD, superoxide dismutase.

Journal Article.  7198 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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