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Molecular Pharmacology

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Research ArticleArticle

Transcription Factor E2F-Associated Phosphoprotein (EAPP), RAM2/CDCA7L/JPO2 (R1), and Simian Virus 40 Promoter Factor 1 (Sp1) Cooperatively Regulate Glucocorticoid Activation of Monoamine Oxidase B

Kevin Chen, Xiao-Ming Ou, Jason Boyang Wu and Jean C. Shih
Molecular Pharmacology February 2011, 79 (2) 308-317; DOI: https://doi.org/10.1124/mol.110.067439
Kevin Chen
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Xiao-Ming Ou
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Jason Boyang Wu
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Jean C. Shih
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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.

  • 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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Molecular Pharmacology: 79 (2)
Molecular Pharmacology
Vol. 79, Issue 2
1 Feb 2011
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Research ArticleArticle

Transcription Factor E2F-Associated Phosphoprotein (EAPP), RAM2/CDCA7L/JPO2 (R1), and Simian Virus 40 Promoter Factor 1 (Sp1) Cooperatively Regulate Glucocorticoid Activation of Monoamine Oxidase B

Kevin Chen, Xiao-Ming Ou, Jason Boyang Wu and Jean C. Shih
Molecular Pharmacology February 1, 2011, 79 (2) 308-317; DOI: https://doi.org/10.1124/mol.110.067439

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Research ArticleArticle

Transcription Factor E2F-Associated Phosphoprotein (EAPP), RAM2/CDCA7L/JPO2 (R1), and Simian Virus 40 Promoter Factor 1 (Sp1) Cooperatively Regulate Glucocorticoid Activation of Monoamine Oxidase B

Kevin Chen, Xiao-Ming Ou, Jason Boyang Wu and Jean C. Shih
Molecular Pharmacology February 1, 2011, 79 (2) 308-317; DOI: https://doi.org/10.1124/mol.110.067439
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