Journal
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
Volume 80, Issue 5, Pages 929-934Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/09168451.2015.1135045
Keywords
activating transcription factor 4 (ATF4); Fibroblast growth factor 21 (FGF21); endoplasmic reticulum (ER) stress; transcription; amino acid response element (AARE)
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [25504003]
- Grants-in-Aid for Scientific Research [15H05781, 14J10497, 25504003] Funding Source: KAKEN
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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.
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