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Glyoxalase-I is a glutathione-binding protein involved in the detoxification of methylglyoxal, a by-product of glycolysis. Aberrations in the expression of human glyoxalase in cancer and diabetes have been reported. To gain a better understanding of the glyoxalase-I regulation under normal physiological conditions and in disease processes, we have cloned 12kb of genomic sequence, comprising five exons, separated by four introns. A fragment comprising 982bp of 5′ flanking region was used in the pSEAP reporter system to identify the minimal promoter and to locate any cis-acting functional elements. This region contained a minimal promoter between -20 and -160bp. Cells transfected with a construct containing the 5′ flanking sequence exhibited a 45-fold higher activity over vector transfected cells. A twofold reproducible increase in reporter activity was seen with insulin and ZnCl(2) treatments, indicating a functionally operative insulin response element (IRE) and metal response element (MRE). Knowledge regarding the regulation of glyoxalase-I may provide insights into the importance of this enzyme in human diseases.