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Regulation of the Rat Glutathione S-Transferase A2 Gene by Glucocorticoids: Crosstalk Through C/EBPs

Regulation of the rat glutathione S-transferase A2 (GSTA2) gene by glucocorticoids is biphasic in its concentration dependence to glucocorticoids, with concentrations of 10–100 nM repressing gene activity (GR-dependent), and concentrations above 1 μM increasing transactivation (PXR-dependent) in adult rat hepatocytes or transient transfection assays. Over-expression of either C/EBPα or β negatively regulates basal and inducible expression of a 1.65 Kb GSTA2 luciferase reporter, and synergizes the response to glucocorticoids (GC). C/EBP responsive elements have been identified in the GSTA2 5′-flanking sequence, associated with the palindrominic Glucocorticoid Responsive Element (GRE), the Ah receptor response elements, and the antioxidant response element. In reporters lacking the palindromic GRE, negative regulation by GC is observed only when C/EBPα is co-expressed. Co-transfection of C/EBPα/β induced gene expression of the GSTA2 XRE reporter, but negatively regulated the GSTA2 ARE-reporter. In contrast, the ARE from the rat NAD(P)H quinone oxidoreductase gene was induced by co-transfection of C/EBPs, but was still negatively regulated by GC. PXR-induction of the GSTA2 reporter was partially ablated by co-transfection of C/EBPα and enhanced by co-transfection of C/EBPβ. We conclude that C/EBPα and β are involved in GC-dependent repression of GSTA2 gene expression and ARE sequences that bind C/EBPs appears to be critical for these responses.