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Published on: February 11, 2015
Selective effect of tumor necrosis factor on transformed versus nontransformed cells: nonselective signal recognition
1Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene Universität Freiburg, D-79104 Freiburg, Germany.
Abstract:
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.
Insights
Tumor necrosis factor (TNF) triggers cell death by reducing survival factors in transformed cells. Nontransformed cells resist TNF-induced apoptosis due to higher initial survival factor levels.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Endogenous survival factors regulate apoptosis.
- Transformed cells have lower survival factor levels than nontransformed cells.
- Tumor necrosis factor (TNF) can induce apoptosis.
Purpose of the Study:
- To investigate the differential response of transformed and nontransformed fibroblasts to TNF treatment.
- To elucidate the role of endogenous survival factors in TNF-induced apoptosis.
- To explain the sensitizing effect of cycloheximide on TNF-alpha-induced apoptosis.
Main Methods:
- Cell culture of transformed and nontransformed fibroblasts.
- Treatment with TNF and cycloheximide.
- Quantification of endogenous survival factors.
- Assessment of apoptosis induction.
Main Results:
- TNF treatment down-modulates endogenous survival factors in both cell types.
- Transformed cells undergo apoptosis due to sufficient down-modulation of survival factors.
- Nontransformed cells are protected from apoptosis by higher initial survival factor concentrations.
- TNF signaling perception is similar, but regulatory setup differs quantitatively.
Conclusions:
- Differential sensitivity to TNF-induced apoptosis is determined by the quantitative levels of endogenous survival factors.
- Lower initial survival factor concentrations in transformed cells predispose them to TNF-induced cell death.
- Cycloheximide sensitizes cells to TNF-alpha by further inhibiting survival factor production.
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