IκBα (inhibitory κBα) identified as labile repressor of MnSOD (manganese superoxide dismutase) expression

Kelley K. Kiningham, Chotiros Daosukho, Daret K. St. Clair

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Cytokines, phorbol esters, radiation and chemotherapeutic drugs up-regulate the expression of MnSOD (manganese superoxide dismutase). Using the VA-13 cell line, we studied the regulation of SOD2 upon treatment with PMA. Pre-treatment with CHX (cycloheximide) followed by PMA led to significantly higher levels of MnSOD mRNA compared with those with either agent alone, suggesting de novo synthesis of an inhibitory protein. PMA treatment modulates redox-sensitive transcription factors, therefore we evaluated the effects of this combination treatment upon AP-1 (activator protein 1) and NF-κB (nuclear factor κB), two transacting factors suggested to play a role in SOD2 regulation. Coadministration of CHX and PMA led to a time-dependent increase in the binding activity of NF-κB. Therefore we evaluated IκBα (inhibitory κBα) and found that co-administration decreased its steady-state level compared with either agent alone, suggesting that enhanced NF-κB activation is due to inhibition of IκBα synthesis. PMA activates PKC (protein kinase C) enzymes which phosphorylate IκBα, leading to its degradation, therefore we used GF109203X to inhibit PKC activity. Stable transfection utilizing a PMA-responsive element in the human SOD2 gene, showed a concentration-dependent decrease in luciferase and NF-κB-binding activity with GF109203X. Western blot analysis indicated the presence of several PKC isoforms in the VA-13 cell line; however, PMA pre-treatment specifically down-regulated α and βI, suggesting a role for one or more of these proteins in SOD2 induction. Taken together, these results indicate that the PKC pathway leading to SOD2 induction proceeds at least in part through NF-κB and that inhibition of IκBα synthesis might serve as a potential pharmacological approach to up-regulate MnSOD.

Original languageEnglish
Pages (from-to)543-549
Number of pages7
JournalBiochemical Journal
Issue number3
StatePublished - Dec 15 2004


  • Cycloheximide
  • Gene regulation
  • Manganese superoxide dismutase (MnSOD)
  • Nuclear-factor-κB-binding protein (NF-κB-binding protein)
  • Phorbol ester
  • Protein kinase C (PKC)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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