Tumor necrosis factor-alpha affects LTR-controlled oncogene expression in transformed mouse fibroblasts at the post-transcriptional level.
Potential mechanisms of TNF-alpha action on tumor cells have been investigated in a model of mouse fibroblasts transformed by distinct retroviral vectors carrying the v-mos, c-myc, and v-Ha-ras oncogene, respectively. Treatment of v-mos and c-myc transformed cells with murine rTNF-alpha in non-cytotoxic concentrations caused a strong inhibition of both proliferative capacity in monolayer culture and colony formation in soft agar. In contrast, v-Ha-ras transformed cells showed little sensitivity to TNF-alpha treatment. These changes in cell growth characteristics of v-mos and c-myc transformants was preceded by a selective reduction of oncogene-specific steady RNA levels, whereas no RNA down-regulation was observed for v-Ha-ras transformants. An unchanged transcriptional activity of the LTR-controlled v-mos and c-myc genes, but a decreased half-life of oncogene-specific mRNA suggests that TNF-alpha primarily affects stability of v-mos and c-myc RNA without influencing the activity of retroviral promoters. This is confirmed by an unchanged chloramphenicol acetyl transferase activity in TNF-treated LTR-chloramphenicol acetyl transferase transformants. Removal of TNF-alpha from cultures of reverted cells provoked a rapid retransformation, with full recovery of neoplastic growth characteristics 10 days after abrogation of TNF-alpha treatment. These data suggest that in cases of non-cytocidal action of TNF-alpha persistent suppression of tumor cell growth requires continuous TNF-alpha treatment.
Seliger
B
B
Clinical Research Group, Max-Planck-Society, Göttingen, Federal Republic of Germany.
Stark
G
G
Pfizenmaier
K
K
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D009052:Leukemia Virus, Murine / Q000235:genetics*; D051379:Mice; D009857:Oncogenes / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha