Abstract
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 simian virus 40 promoter factor 1 (Sp1) binding sites in MAO B promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation analysis 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), that down-regulate MAO B via MAO B core promoter, which 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. Together, 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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Mental Health [Grants R01-MH67968, R01-MH39085]; and the Boyd and Elsie Welin Professorship; the Public Health Service [Grant P20 RR 017701]; and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.067439.
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ABBREVIATIONS:
- MAO
- monoamine oxidase
- ChIP
- chromatin immunoprecipitation
- EAPP
- E2F-associated phosphoprotein
- GR
- glucocorticoid receptor
- GRE
- glucocorticoid response element
- luc
- luciferase
- WT
- wild type
- EMSA
- electrophoretic mobility shift assay
- 5-HT
- 5-hydroxytryptamine
- NE
- norepinephrine
- DA
- dopamine
- PEA
- phenylethylamine
- KO
- knockout
- MPTP
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- bp
- base pair(s)
- PBS
- phosphate-buffered saline
- DTT
- dithiothreitol
- PMSF
- phenylmethylsulfonyl fluoride
- PCR
- polymerase chain reaction
- IP
- immunoprecipitation
- HA
- hemagglutinin
- Sp1
- simian virus 40 promoter factor 1.
- Received July 7, 2010.
- Accepted October 26, 2010.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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