Ou Xiao-Ming, Chen Kevin, Shih Jean C
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033.
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.
J Biol Chem. 2006 Jul 28;281(30):21512-21525. doi: 10.1074/jbc.M600250200. Epub 2006 May 25.
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.
单胺氧化酶（MAO）A是降解神经递质5-羟色胺、去甲肾上腺素和多巴胺的关键酶。人类单胺氧化酶A 2-kb启动子中有三个共有糖皮质激素/雄激素反应元件和四个Sp1结合位点。一种新型转录因子R1（RAM2/CDCA7L）与Sp1结合位点相互作用并抑制MAO A基因表达。荧光素酶分析表明，糖皮质激素（地塞米松）和雄激素（R1881）可增加人神经母细胞瘤和胶质母细胞瘤细胞中MAO A启动子活性和催化活性。凝胶迁移分析表明，糖皮质激素/雄激素受体直接与第三个糖皮质激素/雄激素反应元件相互作用。糖皮质激素/雄激素受体还通过转录因子Sp1间接与Sp1结合位点相互作用。此外，地塞米松在神经母细胞瘤和野生型UW228细胞系中均以时间依赖性方式诱导R1从细胞质转移至细胞核，但在R1敲低的UW228细胞中则不然。总之，本研究表明，糖皮质激素通过以下方式增强单胺氧化酶A基因表达：1）调节R1的转位；2）糖皮质激素受体与第三个糖皮质激素/雄激素反应元件直接相互作用；3）糖皮质激素受体与MAO A启动子Sp1结合位点上的Sp1或R1转录因子间接相互作用。雄激素也通过雄激素受体与第三个糖皮质激素/雄激素反应元件直接相互作用上调MAO A基因表达。雄激素受体在Sp1结合位点上间接与Sp1而非R1转录因子相互作用。本研究为糖皮质激素和雄激素对MAO A的差异调节提供了新见解。
