The c-Rel transcription factor can both induce and inhibit apoptosis in the same cells via the upregulation of MnSOD

Oncogene. 2002 Jun 27;21(28):4392-402. doi: 10.1038/sj.onc.1205536.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / pharmacology
  • Adenoviridae / genetics
  • Annexin A5 / metabolism
  • Apoptosis*
  • Blotting, Western
  • Caspases / metabolism
  • Cell Division / physiology
  • Cytochrome c Group / metabolism
  • DNA Primers / chemistry
  • Fluorescent Antibody Technique
  • Green Fluorescent Proteins
  • HeLa Cells / enzymology
  • Humans
  • Hydrogen Peroxide / metabolism
  • Indicators and Reagents
  • Luminescent Proteins / metabolism
  • Mitochondria / physiology
  • NF-kappa B / physiology*
  • Polymerase Chain Reaction
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-rel / physiology*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Superoxides / metabolism
  • TNF Receptor-Associated Factor 1
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / physiology


  • Annexin A5
  • Cytochrome c Group
  • DNA Primers
  • Indicators and Reagents
  • Luminescent Proteins
  • NF-kappa B
  • Proteins
  • Proto-Oncogene Proteins c-rel
  • TNF Receptor-Associated Factor 1
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • Green Fluorescent Proteins
  • 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
  • Hydrogen Peroxide
  • Superoxide Dismutase
  • Caspases