Identification and characterization of functional antioxidant response elements in the promoter of the aldo-keto reductase AKR1B10 gene. (1st October 2017)

• Record Type: Journal Article
• Authors: Nishinaka, Toru; Miura, Takeshi; Shimizu, Kahori; Terada, Tomoyuki
• Is Part Of: Chemico-biological interactions. Volume 276(2017)
• Page Start: 160
• Page End: 166
• Publication Date: 2017-10-01
• Subjects: Aldo-keto reductase -- Nrf2 -- AP-1 -- Antioxidant response element -- Transcription -- Lung -- H23 -- A549 -- c-Jun; AKR aldo-keto reductase -- Nrf2 NF-E2-related factor 2 -- ARE antioxidant response element; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2017.02.008
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: AKR1B10 is a human-type aldo-keto reductase. The up-regulation of AKR1B10 has been associated with various cancers including non-small cell lung carcinoma, viral and bacterial infections, and skin diseases. However, the mechanisms underlying AKR1B10 gene regulation are not fully understood. We previously indicated the involvement of the transcription factor Nrf2 in AKR1B10 gene regulation. There are at least five potential Nrf2-responsive consensus sequences, so-called antioxidant response elements (AREs), and several ARE-like sequences in the 5'-flanking region up to −3282 bp of the AKR1B10 gene. In the present study, we attempted to identify functional AREs by luciferase reporter analyses using various mutants for each ARE. And we found that only those between −530 and −520 bp (ARE-A), which is the closest location to the translation start site, were functional among the five ARE consensus sites examined. Furthermore, ARE-A functioned co-operatively with the neighboring AP-1 site. Since the AP-1 site resembles ARE, the tandem arrangement of these two elements may be essential for augmented responsiveness to Nrf2 and plays an important role in AKR1B10 gene regulation by various Nrf2-mediating stimuli. Highlights: Functional AREs responsible for Nrf2 on the AKR1B10 gene promoter were identified. Only the ARE-A is functional among the five potential ARE-like sequences. The AP-1 site also functions as ARE. The AP-1 site forms a tandem repeat with ARE-A to augment responsiveness to Nrf2. c -Jun is not involved in the regulation through this tandem repeat of ARE.