Virtually all eukaryotic cells respond to oxidative stress with coordinate up-regulation of an array of protective genes, including those encoding the rate limiting enzyme in glutathione (GSH) synthesis, gamma-glutamylcysteine synthetase (GCS). The resulting increase in GSH and other protective mechanisms reduces the cell's susceptibility to damage following subsequent exposures. This stress response is thought to involve a regulatory cis-element known as the electrophile response element (EpRE) present in the promoters of oxidant-induced genes. The EpRE consensus sequence resembles the DNA binding sequence for hetero-dimers of small maf proteins and CNC family proteins (Nrf2, Mrfl, Nrf3, p45) and Nrf2: maf heterodimers appear to be involved in EpRE-mediated transactivation of the GCS subunit genes. Preliminary data suggest that expression of the small maf genes (mafF, mafG, mafK) is up-regulated following oxidant exposure. Despite high amino acid sequence homology among the small maf proteins, temporal and quantitative differences in their induction argues against complete functional redundancy. This proposal is designed to determine patterns of expression of small maf genes following oxidant exposure, demonstrate Nrf2: maf and maf: maf binding to EpRE sites in the GCS subunit genes, and identify cis-elements which mediate induction of small maf genes by oxidative inducers of GCS. The proposed studies will not only elucidate the role of small maf proteins in GCS induction, but will also have broader implications for oxidative stress response.
| Moran, Julie A; Dahl, Erica L; Mulcahy, R Timothy (2002) Differential induction of mafF, mafG and mafK expression by electrophile-response-element activators. Biochem J 361:371-7 |
