KLF6 and HSF4 transcriptionally regulate multidrug resistance transporters during inflammation

Biochem Biophys Res Commun. 2007 Feb 16;353(3):679-85. doi: 10.1016/j.bbrc.2006.12.090. Epub 2006 Dec 20.

Abstract

Endotoxin-induced inflammation alters the hepatic expression of the drug efflux transporter genes mdr1b (Abcb1b) and mrp3 (Abcc3) in rats. In this study, we identified a novel kruppel-like zinc finger protein 6 (KLF6) cis-element on the rat mdr1b promoter which is important for basal activity and IL-1beta and endotoxin-mediated induction in gene transcription. Interestingly, KLF6 also functioned as a negative transcriptional regulator, inhibiting TNF-alpha-mediated induction of mdr1b. Furthermore, novel CCAAT/enhancer binding protein beta (C/EBPbeta) and heat shock factor 4 (HSF4) transcription binding sites were identified on the rat mrp3 promoter. Deletion of the HSF4 element significantly increased transcriptional activity of the mrp3 gene when exposed to TNF-alpha. Endotoxin treatment significantly affected transcriptional activity only in C/EBPbeta and HSF4 double deletion mrp3 promoter constructs. In summary, KLF6 and HSF4 are stimuli-specific regulatory elements which may be important in the control of the rat mdr1b and mrp3 genes during health and disease.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics*
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / physiology*
  • Inflammation / chemically induced
  • Inflammation / physiopathology*
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors / physiology*
  • Lipopolysaccharides
  • Male
  • Multidrug Resistance-Associated Proteins / genetics*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcription, Genetic / physiology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • CCAAT-Enhancer-Binding Protein-beta
  • HSF4 protein, rat
  • Heat-Shock Proteins
  • Klf6 protein, rat
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors
  • Lipopolysaccharides
  • Multidrug Resistance-Associated Proteins
  • P-glycoprotein 2
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Chloramphenicol O-Acetyltransferase