title: Intestinal expression of mouse Abcg2/breast cancer resistance protein (BCRP) gene is under control of circadian clock-activating transcription factor-4 pathway.
abstract: ABCG2, encoding breast cancer resistance protein (BCRP), is a member of the ATP-binding cassette transporter family and is often associated with cancer chemotherapeutic resistance. BCRP is also expressed in a variety of normal cells and acts as a xenobiotic efflux transporter. Because intestinal BCRP limits systemic exposure to xenobiotics, alterations in the function and expression of this transporter could account for part of the variation in oral drug absorption. In this study, we show that ATF4, a molecular component of the circadian clock, induces circadian expression of the Abcg2 gene in mouse small intestine. Three types of leader exons (termed exons 1A, 1B, and 1C) are identified in the 5'-untranslated region of mouse Abcg2 transcripts. The exon 1B-containing Abcg2 transcript was the only isoform detected in mouse small intestine, and its mRNA levels oscillated in a circadian time-dependent manner. ATF4 bound time-dependently to the cAMP response element within the exon 1B promoter region of the Abcg2 gene, thereby causing the oscillation of BCRP protein abundance and its efflux pump function. The circadian clock-ATF4 pathway appears to enhance the function of BCRP during a specific time window and to modulate intestinal drug absorption. Our findings suggest a mechanism underlying circadian change in xenobiotic detoxification.
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Hamdan
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Wada
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kusunose
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: ohdo@phar.kyushu-u.ac.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D057906:Circadian Clocks / Q000187:drug effects / Q000502:physiology*; D005091:Exons / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D020218:Response Elements / Q000502:physiology; D015262:Xenobiotics / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; C081452:Atf4 protein, mouse; D015262:Xenobiotics; D051701:Activating Transcription Factor 4