Selective effect of tumor necrosis factor on transformed versus nontransformed cells: nonselective signal recognition but differential target cell response.
TNF treatment causes oxidative down-modulation of endogenous survival factors in transformed as well as nontransformed fibroblasts. Endogenous survival factors are negative regulators of a constitutively expressed apoptosis machinery and have been defined in several cellular systems. As transformed cells harbour lower concentrations of endogenous survival factors than nontransformed parental cells, TNF-dependent down-modulation of endogenous survival factors in transformed cells is sufficient to release the apoptosis machinery from negative control and to cause cell death. In contrast, in nontransformed cells, due to their higher initial concentration of endogenous survival factors, down-modulation by TNF is not complete and therefore apoptosis is still prevented. Our data showed that perception of TNF signalling is not different between transformed and nontransformed cells, but that their differential response is due to quantitative differences in their regulatory setup. Furthermore, our data explained why application of low concentrations of cycloheximide can sensitize cells for apoptosis induction by TNF-alpha.
Schulz
A
A
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene Universität Freiburg, D-79104 Freiburg, Germany.
Bauer
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G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002273:Carcinogens; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008748:Methylcholanthrene; D051379:Mice; D008809:Mice, Inbred C3H; D017382:Reactive Oxygen Species / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002273:Carcinogens; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008748:Methylcholanthrene