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
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ATP Binding Cassette Transporter, Subfamily B / genetics*
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ATP-Binding Cassette Sub-Family B Member 4
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Animals
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CCAAT-Enhancer-Binding Protein-beta / genetics
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Chloramphenicol O-Acetyltransferase / metabolism
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Electrophoretic Mobility Shift Assay
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Gene Expression Regulation
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / physiology*
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Inflammation / chemically induced
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Inflammation / physiopathology*
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors / physiology*
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Lipopolysaccharides
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Male
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Multidrug Resistance-Associated Proteins / genetics*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / physiology*
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Rats
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Rats, Sprague-Dawley
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription, Genetic / physiology*
Substances
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ATP Binding Cassette Transporter, Subfamily B
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CCAAT-Enhancer-Binding Protein-beta
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HSF4 protein, rat
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Heat-Shock Proteins
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Klf6 protein, rat
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors
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Lipopolysaccharides
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Multidrug Resistance-Associated Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Chloramphenicol O-Acetyltransferase