Down-regulation of EPHX2 gene transcription by Sp1 under high-glucose conditions

The Biochemical Journal
Ami OguroSusumu Imaoka

Abstract

sEH (soluble epoxide hydrolase), which is encoded by the EPHX2 gene, regulates the actions of bioactive lipids, EETs (epoxyeicosatrienoic acids). Previously, we found that high-glucose-induced oxidative stress suppressed sEH levels in a hepatocarcinoma cell line (Hep3B) and sEH was decreased in streptozotocin-induced diabetic mice in vivo. In the present study, we investigated the regulatory mechanisms underlying EPHX2 transcriptional suppression under high-glucose conditions. The decrease in sEH was prevented by an Sp1 (specificity protein 1) inhibitor, mithramycin A, and overexpression or knockdown of Sp1 revealed that Sp1 suppressively regulated sEH expression, in contrast with the general role of Sp1 on transcriptional activation. In addition, we found that AP2α (activating protein 2α) promoted EPHX2 transcription. The nuclear transport of Sp1, but not that of AP2α, was increased under high glucose concomitantly with the decrease in sEH. Within the EPHX2 promoter -56/+32, five Sp1-binding sites were identified, and the mutation of each of these sites showed that the first one (SP1_1) was important in both suppression by Sp1 and activation by AP2α. Furthermore, overexpression of Sp1 diminished the binding of AP2α by DNA-affi...Continue Reading

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Citations

Jul 28, 2016·Prostaglandins & Other Lipid Mediators·James M Luther, Nancy J Brown
Jan 4, 2021·Prostaglandins, Leukotrienes, and Essential Fatty Acids·Laura KalveramChristian A Hudert
Dec 2, 2020·Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (GMS)·Long-Yan RanZhi-Zhong Guan
Apr 26, 2021·The Journal of Biological Chemistry·Ferbian Milas SiswantoSusumu Imaoka

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