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  • Title: Egr-1 mediates transcriptional repression of COL2A1 promoter activity by interleukin-1beta.
    Author: Tan L, Peng H, Osaki M, Choy BK, Auron PE, Sandell LJ, Goldring MB.
    Journal: J Biol Chem; 2003 May 16; 278(20):17688-700. PubMed ID: 12637574.
    Abstract:
    Following induction and activation of the early growth response (Egr)-1 transcription factor in human chondrocytes, interleukin-1beta (IL-1beta) suppresses the expression of the type II collagen gene (COL2A1), associated with induction of Egr-1 binding activity in nuclear extracts. The COL2A1 proximal promoter contains overlapping binding sites for Egr-1 and Sp1 family members at -119/-112 bp and -81/-74 bp. Mutations that block binding of Sp1 and Sp3 to either site markedly reduce constitutive expression of the core promoter. IL-1beta-induced Egr-1 binds strongly to the -119/-112 bp site, and mutations that block Egr-1 binding prevent inhibition by IL-1beta. Cotransfection with pCMV-Egr1 potentiates the inhibition of COL2A1 promoter activity by IL-1beta, whereas overexpression of dominant-negative Egr-1 mutant, Wilm's tumor-1 (WT1)/Egr1, Sp1, or Sp3 reverses the inhibition by IL-1beta. Cotransfection of pGL2-COL2/Gal4, in which we substituted the critical residue for Egr-1 binding with a Gal4 binding domain and a pCMV-Gal4-Egr1 chimera permits an inhibitory response to IL-1beta that is reversed by overexpression of Gal4-CBP. Our results indicate that IL-1beta-induced activation of Egr-1 binding is required for inhibition of COL2A1 proximal promoter activity and suggest that Egr-1 acts as a repressor of a constitutively expressed collagen gene by preventing interactions between Sp1 and the general transcriptional machinery.
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