title: Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1.
abstract: Monoamine oxidase (MAO) A is a key enzyme for the degradation of neurotransmitters serotonin, norepinephrine, and dopamine. There are three consensus glucocorticoid/androgen response elements and four Sp1-binding sites in the human monoamine oxidase A 2-kb promoter. A novel transcription factor R1 (RAM2/CDCA7L) interacts with Sp1-binding sites and represses MAO A gene expression. Luciferase assays show that glucocorticoid (dexamethasone) and androgen (R1881) increase MAO A promoter and catalytic activities in human neuroblastoma and glioblastoma cells. Gel-shift analysis demonstrates that glucocorticoid/androgen receptors interact directly with the third glucocorticoid/androgen response element. Glucocorticoid/androgen receptors also interact with Sp1-binding sites indirectly via transcription factor Sp1. In addition, dexamethasone induces R1 translocation from the cytosol to the nucleus in a time-dependent manner in both the neuroblastoma and wild-type UW228 cell lines but not in R1 knock-down UW228 cells. In summary, this study shows that glucocorticoid enhances monoamine oxidase A gene expression by 1) regulation of R1 translocation; 2) direct interaction of the glucocorticoid receptor with the third glucocorticoid/androgen response element; and 3) indirect interaction of glucocorticoid receptor with the Sp1 or R1 transcription factor on Sp1-binding sites of the MAO A promoter. Androgen also up-regulates MAO A gene expression by direct interaction of androgen receptor with the third glucocorticoid/androgen response element. Androgen receptor indirectly interacts with the Sp1, but not R1 transcription factor, on Sp1-binding sites. This study provides new insights on the differential regulation of MAO A by glucocorticoid and androgen.
authors.affiliation: Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Ou
authors.affiliation: Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033; Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033. Electronic address: jcshih@usc.edu.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
mesh_terms: D000728:Androgens / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D005909:Glioblastoma / Q000378:metabolism; D005938:Glucocorticoids / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D008995:Monoamine Oxidase / Q000737:chemistry*; D009447:Neuroblastoma / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry*
chemical_list: D000728:Androgens; C513450:CDCA7L protein, human; D005938:Glucocorticoids; D011944:Receptors, Androgen; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D008995:Monoamine Oxidase