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Afonso, V, Santos, G, Collin, P, Khatib, AM, Mitrovic, DR, Lomri, N, Leitman, DC and Lomri, A (2006) Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway. Free Radic. Biol. Med. 41:709-21


Overexpression of Cu/Zn superoxide dismutase 1 (SOD1) in monocytes blocks reactive oxygen species-induced inhibition of cell growth and apoptosis and renders cells resistant to the toxic effect of tumor necrosis factor (TNF)-alpha, suggesting that TNF-alpha represses the SOD1 gene in these cells. We herein show that TNF-alpha decreases SOD1 mRNA, protein, and promoter activity in U937 cells. Electrophoretic mobility-shift assays (EMSA) show that TNF-alpha decreased binding of three different complexes. Ectopic Sp1 overexpression markedly increased SOD1-basal promoter activity and partially antagonized the TNF-alpha inhibitory effect. In contrast, ectopic c-Jun overexpression mimics TNF-alpha inhibitory effects and antagonizes Sp1 stimulatory effects. In agreement with these findings, EMSA shows a TNF-alpha-induced increase in AP-1 and a decrease in Sp1 DNA binding. Disruption of the C/EBP site decreases, whereas mutation in the Sp1/Egr-1 site completely abolishes DNA-binding and promoter activity. A JNK inhibitor antagonized the negative effects of TNF-alpha on SOD1 promoter activity, suggesting that JNK signaling through c-Jun protein activation is critical for the TNF-alpha-dependent SOD1 repression. A greater understanding of the mechanisms of TNF-alpha-induced SOD1 repression could facilitate the design and development of novel therapeutic drugs for inflammatory conditions.


PubMed Online version:10.1016/j.freeradbiomed.2006.05.014


Base Sequence; Down-Regulation; Humans; MAP Kinase Kinase 4/metabolism; Molecular Sequence Data; Promoter Regions, Genetic; RNA, Messenger/metabolism; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase/genetics; Transcription Factor AP-1/metabolism; Transcription, Genetic; Transfection; Tumor Necrosis Factor-alpha/physiology; U937 Cells



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status



GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion


Seeded From UniProt


See also


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