Estrogen-related receptors-stimulated monoamine oxidase B promoter activity is down-regulated by estrogen receptors

Although there are studies published about the neuroprotective effect of estrogen, little is known about the mechanisms and cellular targets of the hormone. Recent reports demonstrate that estrogen down-regulates the expression of monoamine oxidase A and B (MAO-A and MAO-B) in the hypothalamus of the Macaques monkey, both of which are key isoenzymes in the neurotransmitter degradation pathway. Additionally, estrogen-related receptor alpha(ERR alpha) up-regulates MAO-B gene expression in breast cancer cells. ERR alpha recognizes a variety of estrogen response elements and shares many target genes and coactivators with estrogen receptor alpha (ER alpha). In this study, we investigate the interplay of ERs and ERRs in the regulation of MAO-B promoter activity. We demonstrate that ERR alpha and ERR alpha up-regulate MAO-B gene activity, whereas ER alpha and ER beta decrease stimulation in both a ligand-dependent and -independent manner. Ectopically expressed ERR alpha and ERR beta stimulate the expression of MAO- B mRNA and protein as well as increase the MAO-B enzymatic activity in ER-negative HeLa cells. The ability of ERRs to stimulate MAO-B promoter activity was reduced in ER-positive MCF-7 and T47D cells. Several AGGTCA motifs of the MAO- B promoter are responsible for up-regulation by ERRs. Interestingly, ER alpha or ER beta alone have no effect on MAO-B promoter activity but can down-regulate the activation function of ERRs, whereas glucocorticoid receptor does not. By using chromatin immunoprecipitation assay, we demonstrate that ERs compete with ERRs for binding to the MAO-B promoter at selective AGGTCA motifs, thereby changing the chromatin status and cofactor recruitment to a repressed state. These studies provide new insight into the relationship between ER alpha, ER beta, ERR gamma, and ERR gamma in modulation of MAO-B gene activity.