Maruyama Ryuto, Shimizu Makoto, Li Juan, Inoue Jun, Sato Ryuichiro
a Department of Applied Biological Chemistry , Graduate School of Agricultural and Life Sciences, The University of Tokyo , Tokyo , Japan.
Biosci Biotechnol Biochem. 2016 May;80(5):929-34. doi: 10.1080/09168451.2015.1135045. Epub 2016 Mar 24.
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.
成纤维细胞生长因子21（FGF21）是一种内分泌生长因子，是脂肪酸和葡萄糖代谢的调节剂。最近，有报道称FGF21的表达受激活转录因子4（ATF4）调控，ATF4是一种受内质网（ER）应激等多种刺激激活的转录因子。ATF4与靶基因启动子区域中的氨基酸反应元件（AARE）结合，AARE是ATF4的结合位点。在FGF21基因的启动子区域已报道了两个ATF4反应元件（AARE1和AARE2）。在本研究中，我们发现了一个位于AARE1和AARE2上游的新型反应元件，它对FGF21启动子激活至关重要。当这个名为AARE3的DNA序列发生突变时，ATF4或内质网应激引起的启动子激活会大幅降低。我们的结果表明，FGF21启动子包含三个ATF4反应元件，这表明FGF21是ATF4的一个敏感靶点。
