RAS SIGNALING IN TUMOR NECROSIS FACTOR-INDUCED APOPTOSIS

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