TY - JOUR T1 - Transcription Factor EAPP, R1 and Sp1 Cooperatively Regulate Glucocorticoid Activation of Monoamine Oxidase B JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.067439 SP - mol.110.067439 AU - Kevin Chen AU - Xiao-Ming Ou AU - Jason Boyang Wu AU - Jean C Shih Y1 - 2010/01/01 UR - http://molpharm.aspetjournals.org/content/early/2010/10/27/mol.110.067439.abstract N2 - Glucocorticoid steroid hormones play important roles in many neurophysiological processes such as responses to stress, behavioral adaption and mood. One mechanism by which glucocorticoids exert functions in the brain is via the modulation of neurotransmission systems. Glucocorticoids are capable of inducing the activities of monoamine oxidases (MAOs), which degrade monoamine neurotransmitters including serotonin, norepinephrine, phenylethylamine and dopamine. However, the molecular mechanisms for such induction are not yet fully understood. Here, we report that dexamethasone, a synthetic glucocorticoid hormone, stimulates MAO B (an isoform of MAOs) promoter and catalytic activities via both the fourth glucocorticoid response element (GRE) and Sp1-binding sites in MAO B promoter. Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) analyses demonstrated that glucocorticoid receptor binds to the fourth GRE in vitro and in vivo. Using Sp1-binding motifs as bait in a yeast one-hybrid system, we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), which down-regulates MAO B via MAO B core promoter that contains Sp1 sites. EMSA suggested that EAPP and R1 competed with Sp1 for binding to the Sp1 site in vitro. Moreover, EAPP and R1 reduced Sp1-activated glucocorticoid activation of MAO B promoter. In response to dexamethasone, lower occupancy by EAPP and R1 and higher occupancy by Sp1 were shown at the natural MAO B core promoter. Collectively, this study uncovers for the first time the molecular mechanisms for glucocorticoid activation of MAO B gene and provides new insights into the hormonal regulation of MAO. ER -