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. Issue 5 (October 2016)

• Record Type: Journal Article
• Authors: Kameyama, Naoya; Kobayashi, Kaoru; Shimizu, Shoko; Yamasaki, Yuki; Endo, Mika; Hashimoto, Mari; Furihata, Tomomi; Chiba, Kan
• Is Part Of: Drug metabolism and pharmacokinetics. Volume 31:Issue 5(2016)
• Page Start: 340
• Page End: 348
• Publication Date: 2016-10
• Subjects: ABCB1 -- CYP3A4 -- Rifampicin -- Pregnane X receptor -- Transcription -- Induction; ABCB1 ATP-binding cassette B1 -- ChIP chromatin immunoprecipitation -- CYP3A4 cytochrome P450 3A4 -- DMSO dimethyl sulfoxide -- DR direct repeat -- ESE-3 epithelial-specific ETS factor family member 3 -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- PXR pregnane X receptor -- RIF rifampicin -- RXR retinoid X receptor; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; 615.7
• DOI: 10.1016/j.dmpk.2016.05.004
• Languages: English
• ISSNs: 1347-4367

Abstract

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. Graphical abstract: ESE-3 is a trans -regulatory factor responsible for PXR-mediated transactivation of the ABCB1 gene by rifampicin (RIF).