title: Forkhead box A1 (FOXA1) and A2 (FOXA2) oppositely regulate human type 1 iodothyronine deiodinase gene in liver.
abstract: Type 1 iodothyronine deiodinase (D1), a selenoenzyme that catalyzes the bioactivation of thyroid hormone, is expressed mainly in the liver. Its expression and activity are modulated by several factors, but the precise mechanism of its transcriptional regulation remains unclear. In the present study, we have analyzed the promoter of human D1 gene (hDIO1) to identify factors that prevalently increase D1 activity in the human liver. Deletion and mutation analyses demonstrated that a forkhead box (FOX)A binding site and an E-box site within the region between nucleotides -187 and -132 are important for hDIO1 promoter activity in the liver. EMSA demonstrated that FOXA1 and FOXA2 specifically bind to the FOXA binding site and that upstream stimulatory factor (USF) specifically binds to the E-box element. Overexpression of FOXA2 decreased hDIO1 promoter activity, and short interfering RNA-mediated knockdown of FOXA2 increased the expression of hDIO1 mRNA. In contrast, overexpression of USF1/2 increased hDIO1 promoter activity. Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of hDIO1 mRNA, but knockdown of both FOXA1 and FOXA2 restored it. The response of the hDIO1 promoter to USF was greatly attenuated in the absence of FOXA1. Taken together, these results indicate that a balance of FOXA1 and FOXA2 expression modulates hDIO1 expression in the liver.
authors: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. kyotetsu@kuhp.kyoto-u.ac.jp
authors: Naotetsu
authors: N
authors: Kanamoto
authors: Tetsuya
authors: T
authors: Tagami
authors: Yoriko
authors: Y
authors: Ueda-Sakane
authors: Masakatsu
authors: M
authors: Sone
authors: Masako
authors: M
authors: Miura
authors: Akihiro
authors: A
authors: Yasoda
authors: Naohisa
authors: N
authors: Tamura
authors: Hiroshi
authors: H
authors: Arai
authors: Kazuwa
authors: K
authors: Nakao
mesh_terms: D024506:5' Flanking Region; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D024721:E-Box Elements; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C518584:DIDO1 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D034741:RNA, Small Interfering; C497181:USF1 protein, human; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; D051542:Hepatocyte Nuclear Factor 3-beta