KLF6 and HSF4 transcriptionally regulate multidrug resistance transporters during inflammation.
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.
Ho
Emmanuel A
EA
Department of Pharmaceutical Sciences, University of Toronto, Leslie Dan Faculty of Pharmacy, 144 College Street, Toronto, Ont., Canada M5S 3M2.
Piquette-Miller
Micheline
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008070:Lipopolysaccharides; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D022782:CCAAT-Enhancer-Binding Protein-beta; D015500:Chloramphenicol O-Acetyltransferase; D006360:Heat-Shock Proteins; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C517889:HSF4 protein, rat; C491357:Klf6 protein, rat