title: Regulation of the Egr-1 gene by tumor necrosis factor and interferons in primary human fibroblasts.
abstract: Treatment of quiescent primary human fibroblasts with tumor necrosis factor (TNF) alpha, TNF-beta, interleukin-1, interferon (IFN) alpha, IFN beta, or IFN gamma induced Egr-1 mRNA. In primary human fibroblasts TNF-alpha and TNF-beta were mildly mitogenic and IFN alpha and IFN gamma were growth inhibitory. However, in HeLa cells TNF but not IFN induced the expression of Egr-1 mRNA, while both cytokines inhibited HeLa cell division. Kinetic measurements of Egr-1 gene expression showed that TNF-alpha, TNF-beta, and IFN gamma increased the cellular concentration of Egr-1 mRNA within 30 min. A maximum induction of Egr-1 mRNA was detected at approximately 60 min which dropped to basal level by 180 min. Induction was inhibited by H7 and staurosporine but not by HA1004, indicating the involvement of a functional protein kinase C. The Egr-1 message was translated and the cellular Egr-1 protein detected within 60 min of cytokine treatment. Despite similar Egr-1 mRNA induction, the amount of Egr-1 protein translated in IFN alpha- and IFN gamma-treated cells was lower than in those treated with TNF-alpha and TNF-beta, and highest in the EGF-treated primary human fibroblasts. Indeed, the level of Egr-1 protein translated in these cells correlated proportionally with both the phosphorylation of cap-binding protein (eukaryotic initiation factor) and the amount of cellular DNA synthesis in the variously treated fibroblasts. These results suggest that both growth stimulatory and inhibitory cytokines can regulate Egr-1 gene expression at the transcriptional and translational level. However, the combination of these regulatory controls may determine the cellular concentration of the Egr-1 gene product and hence, its effect on cell proliferation.
authors.affiliation: Signal Transduction Laboratory, National University of Singapore.
authors.forename: X M
authors.initials: XM
authors.lastname: Cao
authors.forename: G R
authors.initials: GR
authors.lastname: Guy
authors.forename: V P
authors.initials: VP
authors.lastname: Sukhatme
authors.forename: Y H
authors.initials: YH
authors.lastname: Tan
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D016475:3T3 Cells; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D019311:Staurosporine; D013449:Sulfonamides; D013936:Thymidine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D007546:Isoquinolines; D010879:Piperazines; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004247:DNA; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D019311:Staurosporine; D013936:Thymidine