CCAAT/enhancer binding proteins alpha and beta regulate the tumor necrosis factor receptor 1 gene promoter

Mol Immunol. 2009 Aug;46(13):2706-13. doi: 10.1016/j.molimm.2009.05.024. Epub 2009 Jun 11.


CCAAT/enhancer binding protein (C/EBP) transcription factors play essential roles in regulating an array of cellular processes, including differentiation, energy metabolism, and inflammation. In this report we demonstrate that both C/EBPalpha and C/EBPbeta activate the promoter driving transcription of the tumor necrosis factor receptor 1 (TNFR1). TNFR1 is the major receptor for tumor necrosis factor (TNF), a critical cytokine mediator of the inflammatory response. Although the TNFR1 protein has been shown to be regulated through post-translational modifications, very little is known about the transcriptional regulation of the TNFR1 gene. Here we have identified a specific C/EBP binding site within the TNFR1 promoter, and shown that this site is required for both C/EBPalpha and C/EBPbeta activation of the promoter in reporter gene assays. Furthermore, we show that both C/EBPalpha and C/EBPbeta are bound to the TNFR1 promoter in cells using chromatin immunoprecipitation assays. Finally, we demonstrate that reducing the level of C/EBPalpha and C/EBPbeta expression in cells using siRNA technology leads to decreased expression of the TNFR1 protein. These results suggest that the C/EBPalpha and C/EBPbeta transcription factors enhance expression of the TNFR1 protein in cells. Given that TNF and C/EBPbeta are known to activate each other's expression, C/EBPbeta may greatly amplify the initial TNF signal through a positive auto-regulatory mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Binding Sites / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Line
  • Chloramphenicol O-Acetyltransferase / genetics
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Mutagenesis, Site-Directed
  • Oligonucleotides / genetics
  • Oligonucleotides / metabolism
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • RNA, Small Interfering / genetics
  • Receptors, Tumor Necrosis Factor, Type I / genetics*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection


  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Protein-beta
  • Oligonucleotides
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • Chloramphenicol O-Acetyltransferase