Functional antioxidant responsive elements

Abstract

Exposure of human and rodent cells to a wide variety of chemoprotective compounds confers resistance against a broad set of carcinogens. For a subset of the chemoprotective compounds, protection is generated by an increase in the abundance of protective enzymes like glutathione S-transferases (GST). Antioxidant responsive elements (AREs) mediate the transcriptional induction of a battery of genes which comprise much of this chemoprotective response system. Past studies identified a necessary ARE ''core'' sequence of RTGACnnnGC, but this sequence alone is insufficient to mediate induction. In this study, the additional sequences necessary to define a sufficient, functional ARE are identified through systematic mutational analysis of the murine GST Ya ARE. Introduction of the newly identified necessary nucleotides into the regions flanking a nonresponsive, ARE-like, GST-Mu promoter sequence produced an inducible element. A screen of the GenBank database with the newly identified ARE consensus identified 16 genes which contained the functional ARE consensus sequence in their promoters. Included within this group was an ARE sequence from the murine ferritin-L promoter that mediated induction when tested. In an electrophoretic mobility-shift assay, the ferritin-L ARE was bound by ARE-binding protein 1, a protein previously identified as the likely mediator of the chemoprotective response. A three-level ARE classification system is presented to account for the distinct induction strengths observed in our mutagenesis studies. A model of the ARE as a composite regulatory site, where multiple transcription factors interact, is presented to account for the complex characteristics of AREmediated chemoprotective gene expression.

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

“…Studies on the role of the GC box in constitutive gene expression, however, are controversial. Similarly to what was observed here with rat GGT promoter 5, deletion of the GC box abrogated EpRE-mediated basal expression of the rat GSH S-transferase Ya [55] and cystine/glutamate exchange transporter [56]; however, deletion of the GC box had no effect on the constitutive expression of hGCLm and mice heme oxygenase-1 (HO-1) [54,57].…”

Transcriptional expression analysis of ABC efflux transporters and xenobiotic-metabolizing enzymes in the Chinese rare minnow

“…In line with this, the role of Nrf2 in mediating the co-regulation of the phase II enzymes and ABC transporters was further confirmed by the discovery of AREs (antioxidant response elements) in many of these genes. For example, the AREs have been detected in many genes of the phase II enzymes including the GST (Wasserman and Fahl, 1997;Kwak et al, 2003), GCLC (Kwak et al, 2003), and UGT1A1 genes (Yueh and Tukey, 2007); ARE-like sequences were also identified in the mouse ABCCs (Vollrath et al, 2006). These finding suggest that a common regulatory mechanism is possible for the GST, GCLC and ABCC genes (Meijerman et al, 2008).…”

Polymorphisms in xenobiotic‐metabolizing genes and the risk of chronic lymphocytic leukemia and non‐Hodgkin's lymphoma in adult Russian patients

“…It is known from the literature, that estrogens can regulate the expression of phase II enzymes via cis-active DNA elements, so-called antioxidant/electrophile response element ARE, which are located in promoter regions of corresponding genes [44]. For instance, it was described, that 17b-estradiol [E2] administration induced the decrease of catalytic activity of GSTs in cervical cells using ARE-mediated mechanism.…”