title: Fibroblast growth factor 21 induction by activating transcription factor 4 is regulated through three amino acid response elements in its promoter region.
abstract: Fibroblast growth factor 21 (FGF21) is an endocrine growth factor, a regulator of fatty acids and glucose metabolism. Recently, it has been reported that FGF21 expression is regulated by activating transcription factor 4 (ATF4), a transcription factor activated by various stimuli such as endoplasmic reticulum (ER) stress. ATF4 binds to the amino acid response element (AARE), a binding site for ATF4, in the promoter region of the target genes. The two response elements for ATF4 (AARE1 and AARE2) have been reported in the promoter region of FGF21 gene. In this study, we found a novel response element, located upstream of AARE1 and AARE2, essential for a promoter activation of FGF21. When this DNA sequence, named AARE3, was mutated, the promoter activation by ATF4 or ER stress was strongly decreased. Our results showed that the FGF21 promoter contains three response elements for ATF4, suggesting that FGF21 is a sensitive target of ATF4.
authors.affiliation: a Department of Applied Biological Chemistry , Graduate School of Agricultural and Life Sciences, The University of Tokyo , Tokyo , Japan.
authors.forename: Ryuto
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: a Department of Applied Biological Chemistry , Graduate School of Agricultural and Life Sciences, The University of Tokyo , Tokyo , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: a Department of Applied Biological Chemistry , Graduate School of Agricultural and Life Sciences, The University of Tokyo , Tokyo , Japan.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: a Department of Applied Biological Chemistry , Graduate School of Agricultural and Life Sciences, The University of Tokyo , Tokyo , Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.affiliation: a Department of Applied Biological Chemistry , Graduate School of Agricultural and Life Sciences, The University of Tokyo , Tokyo , Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016415:Sequence Alignment; D015398:Signal Transduction; D014162:Transfection
chemical_list: C497109:ATF4 protein, human; C414620:fibroblast growth factor 21; D051701:Activating Transcription Factor 4; D005346:Fibroblast Growth Factors; D008156:Luciferases
keywords: Fibroblast growth factor 21 (FGF21); activating transcription factor 4 (ATF4); amino acid response element (AARE); endoplasmic reticulum (ER) stress; transcription