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

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• 作者：Naoya Kameyama ; Kaoru Kobayashi ; ^{kaoruk@faculty.chiba-u.jp" class="auth_mail" title="E-mail the corresponding author} ; Shoko Shimizu ; Yuki Yamasaki ; Mika Endo ; Mari Hashimoto ; Tomomi Furihata ; Kan Chiba
• 关键词：ABCB1 ; CYP3A4 ; Rifampicin ; Pregnane X receptor ; Transcription ; Induction
• 刊名：Drug Metabolism and Pharmacokinetics
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：31
• 期：5
• 页码：340-348
• 全文大小：1061 K

文摘

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.