The c-Rel transcription factor can both induce and inhibit apoptosis in the same cells via the upregulation of MnSOD.
Rel/NF-kappaB transcription factors are involved in several physiological processes, including the regulation of apoptosis. These factors were shown to exhibit pro- or anti-apoptotic activities in different cellular models, but at present, the mechanisms underlying these opposite effects are poorly understood. In this study, we show that the constitutive expression of a transcriptionally active member of the Rel/NF-kappaB family, c-Rel, first induces a resistance against TNFalpha-induced apoptosis and later increases the level of spontaneous apoptosis of HeLa cells. Both the anti- and pro-apoptotic effects increase with the level of c-Rel overexpression. The up-regulation by c-Rel of the manganese superoxide dismutase (MnSOD) could explain both the rapid anti-apoptotic effect and the delayed pro-apoptotic one. Indeed, the enzymatic activity of MnSOD is to transform the toxic O(2)(*)(-) in H(2)O(2). Hence, on one hand, its induction helps cells to resist against the apoptogenic burst of O(2)(*)(-) produced upon TNFalpha stimulation, but on the other hand, it leads to a progressive H(2)O(2) accumulation that ultimately results in apoptosis. These results indicate that the anti- and pro-apoptotic effects of Rel/NF-kappaB factors are not necessarily alternative but can occur successively in the same cell, via the up-regulation of the same target gene.
Bernard
David
D
FRE 2353 CNRS/Institut Pasteur de Lille/Université Lille 2, Institut de Biologie de Lille, 1 rue Calmette, 59021 Lille Cedex, France.
Monte
Didier
D
Vandenbunder
Bernard
B
Abbadie
Corinne
C
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007202:Indicators and Reagents; D008164:Luminescent Proteins / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
D017304:Annexin A5; D003574:Cytochrome c Group; D017931:DNA Primers; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D016328:NF-kappa B; D011506:Proteins; D020569:Proto-Oncogene Proteins c-rel; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D049452:Green Fluorescent Proteins; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D020169:Caspases