NF-kappaB-associated MnSOD induction protects against beta-amyloid-induced neuronal apoptosis.
Expression of manganese superoxide dismutase (MnSOD), a nuclear-encoded mitochondrial primary antioxidant enzyme, is protective against various paradigms of oxidative stress-induced brain injury. We have shown previously that the presence of an intronic nuclear factor site, kappaB (NF-kappaB), in the MnSOD gene is essential for the induction of MnSOD by tumor necrosis factor alpha (TNF-alpha). However, whether activation of NF-kappaB is protective against oxidative stress-induced neuronal injury is unclear. In the present study, we demonstrate that TNF-alpha activates NF-kappaB activity in neuronal, SH-SY5Y, cells and preferentially enhances the binding of p50 and p65 to the promoter/enhancer regions of the MnSOD gene. Binding of NF-kappaB members to the MnSOD gene leads to the induction of MnSOD mRNA and protein levels. Consequently, induction of MnSOD by TNF-alpha primes neuronal cells to develop resistance against subsequent exposure to beta-amyloid and FeSO(4). Taken together, these results suggest that NF-kappaB might exert its protective function by induction of MnSOD leading to subsequent protection against oxidative stress-induced neuronal injury.
Sompol
Pradoldej
P
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Xu
Yong
Y
Ittarat
Wanida
W
Daosukho
Chotiros
C
St Clair
Daret
D
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000302:isolation & purification; D004742:Enhancer Elements, Genetic; D004790:Enzyme Induction; D005296:Ferrous Compounds / Q000633:toxicity; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D002843:Chromatin; D005296:Ferrous Compounds; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D010446:Peptide Fragments; C498143:RELA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C020748:ferrous sulfate; D013482:Superoxide Dismutase