Down-regulation of tumor necrosis factor alpha expression by activating transcription factor 2 increases UVC-induced apoptosis of late-stage melanoma cells.
To identify mechanisms whereby activating transcription factor 2 (ATF2) alters the radiation resistance of human melanoma cells, we examined the possible role of ATF2 in UVC-induced apoptosis. Forced expression of full-length or truncated (Delta1-195 amino acids) forms of ATF2 in LU1205, a late-stage human melanoma cell line, elevated the levels of UVC-induced apoptosis. At the same time, either truncated or full-length forms of ATF2 reduced UVC-induced activation of the tumor necrosis factor-alpha (TNFalpha) promoter and decreased expression of TNFalpha. Forced expression of c-Jun in ATF2-expressing melanoma cells restored TNFalpha expression, suggesting that both forms of ATF2 sequestered transcription factors that positively regulate TNFalpha expression in response to UV irradiation. Antagonistic antibodies to Fas, but not to TNFR1, efficiently suppressed UVC-induced apoptosis, suggesting that the Fas pathway mediates the primary apoptotic signal in melanoma cells whereas the TNFR1 pathway elicits a survival signal. Indeed, treatment of melanoma cells with TNFalpha before UVC irradiation partially suppressed UVC-induced apoptosis, further supporting the protective role of TNFalpha in UVC-treated melanoma cells. Taken together, our findings suggest that ATF2 contributes to UVC-induced apoptosis through transcriptional silencing of TNFalpha, which balances Fas-mediated cell death in melanoma.
D051698:Activating Transcription Factor 2; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D016350:Leucine Zippers; D008545:Melanoma / Q000503:physiopathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D014466:Ultraviolet Rays