title: Involvement of ESE-3, epithelial-specific ETS factor family member 3, in transactivation of the ABCB1 gene via pregnane X receptor in intestine-derived LS180 cells but not in liver-derived HepG2 cells.
abstract: Pregnane X receptor (PXR) is involved in the transactivation of ABCB1 gene by rifampicin (RIF). However, we found that increase in ABCB1 mRNA by RIF was observed in LS180 cells but not in HepG2 cells. Since both cell lines expressed PXR equally, we hypothesized that a factor(s) other than PXR is responsible for PXR-mediated transactivation of the ABCB1 gene. Reporter activities of a distal enhancer module containing direct repeat 4 (DR4) motifs were increased by RIF in LS180 cells but not in HepG2 cells. Mutation of the DR4 motifs diminished the increase in reporter activities in LS180 cells. Gene subtraction showed that epithelial-specific ETS factor 3 (ESE-3) is a transcription factor enriched in LS180 cells compared to HepG2 cells. When ESE-3 and PXR were co-expressed in HepG2 cells, reporter activities were increased by RIF, which were completely abolished by mutation of DR4 motifs. Chromatin immunoprecipitation assays showed specific binding of ESE-3 to the region containing the DR4 motifs of the ABCB1 gene. Finally, knock-down of ESE-3 in LS180 cells resulted in a decrease in the induction of ABCB1 mRNA. These results suggest that ESE-3 is a factor responsible for PXR-mediated transactivation of the ABCB1 gene by RIF in LS180 cells.
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Naoya
authors: N
authors: Kameyama
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. Electronic address: kaoruk@faculty.chiba-u.jp.
authors: Kaoru
authors: K
authors: Kobayashi
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Shoko
authors: S
authors: Shimizu
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Yuki
authors: Y
authors: Yamasaki
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Mika
authors: M
authors: Endo
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Mari
authors: M
authors: Hashimoto
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Tomomi
authors: T
authors: Furihata
authors: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Kan
authors: K
authors: Chiba
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D045744:Cell Line, Tumor; D017930:Genes, Reporter / Q000235:genetics; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics*; D012293:Rifampin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C403306:EHF protein, human; D051557:Hepatocyte Nuclear Factor 4; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D014157:Transcription Factors; D012293:Rifampin
keywords: ABCB1; CYP3A4; Induction; Pregnane X receptor; Rifampicin; Transcription