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Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway.
Free Radic Biol Med. 2006 Sep 01; 41(5):709-21.FR

Abstract

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.

Authors+Show Affiliations

INSERM U606, Lariboisiere Hospital, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16895791

Citation

Afonso, Valéry, et al. "Tumor Necrosis Factor-alpha Down-regulates Human Cu/Zn Superoxide Dismutase 1 Promoter Via JNK/AP-1 Signaling Pathway." Free Radical Biology & Medicine, vol. 41, no. 5, 2006, pp. 709-21.
Afonso V, Santos G, Collin P, et al. Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway. Free Radic Biol Med. 2006;41(5):709-21.
Afonso, V., Santos, G., Collin, P., Khatib, A. M., Mitrovic, D. R., Lomri, N., Leitman, D. C., & Lomri, A. (2006). Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway. Free Radical Biology & Medicine, 41(5), 709-21.
Afonso V, et al. Tumor Necrosis Factor-alpha Down-regulates Human Cu/Zn Superoxide Dismutase 1 Promoter Via JNK/AP-1 Signaling Pathway. Free Radic Biol Med. 2006 Sep 1;41(5):709-21. PubMed PMID: 16895791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway. AU - Afonso,Valéry, AU - Santos,Guilherme, AU - Collin,Pascal, AU - Khatib,Abdel-Majid, AU - Mitrovic,Dragoslav R, AU - Lomri,Noureddine, AU - Leitman,Dale C, AU - Lomri,Abderrahim, Y1 - 2006/05/20/ PY - 2005/11/21/received PY - 2006/04/28/revised PY - 2006/05/12/accepted PY - 2006/8/10/pubmed PY - 2007/2/13/medline PY - 2006/8/10/entrez SP - 709 EP - 21 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 41 IS - 5 N2 - 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. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/16895791/Tumor_necrosis_factor_alpha_down_regulates_human_Cu/Zn_superoxide_dismutase_1_promoter_via_JNK/AP_1_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(06)00325-X DB - PRIME DP - Unbound Medicine ER -