Krüppel-like factor 6 is a co-activator of NF-κB that mediates p65-dependent transcription of selected downstream genes

J Biol Chem. 2014 May 2;289(18):12876-85. doi: 10.1074/jbc.M113.535831. Epub 2014 Mar 14.

Abstract

The transcription factor NF-κB plays a pivotal role in a broad range of physiological and pathological processes, including development, inflammation, and immunity. How NF-κB integrates activating signals to expression of specific sets of target genes is of great interest. Here, we identified Krüppel-like factor 6 (KLF6) as a co-activator of NF-κB after TNFα and IL-1β stimulation. Overexpression of KLF6 enhanced TNFα- and IL-1β-induced activation of NF-κB and transcription of a subset of downstream genes, whereas knockdown of KLF6 had opposite effects. KLF6 interacted with p65 in the nucleus and bound to the promoters of target genes. Upon IL-1β stimulation, KLF6 was recruited to promoters of a subset of NF-κB target genes in a p65-dependent manner, which was in turn required for the optimal binding of p65 to the target gene promoters. Our findings thus identified KLF6 as a previously unknown but essential co-activator of NF-κB and provided new insight into the molecular regulation of p65-dependent gene expression.

Keywords: DNA-binding Protein; Interleukin; Kruppel-like factor (KLF); NF-κB (NF-κB); Signal Transduction; Transcription; Tumor Necrosis Factor (TNF).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / genetics
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Gene Expression Regulation / drug effects
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Interleukin-1beta / pharmacology
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcription, Genetic*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Interleukin-1beta
  • KLF6 protein, human
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha