Functional antioxidant responsive elements

WW Wasserman, WE Fahl - Proceedings of the National …, 1997 - National Acad Sciences
WW Wasserman, WE Fahl
Proceedings of the National Academy of Sciences, 1997National Acad Sciences
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 …
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 ARE-mediated chemoprotective gene expression.
National Acad Sciences