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Estrogen Regulates KiSS1 Gene Expression through Estrogen Receptor and SP Protein Complexes

Institute of Biosciences and Technology (D.L., D.M., J.L., Z.Y., S.-G.C., J.G., M.L.), and Department of Molecular and Cellular Medicine, Texas A&M University System Health Science Center, Houston, Texas 77030; Endocrine and Metabolic Division (X.L., G.N., M.L.), E-Institutes of Shanghai Universities, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Jiaotong University Medical School, Shanghai 200025, China; and College of Life Sciences (D.L., J.L., X.W., M.L.), Hunan Normal University, Changsha, Hunan 410081, China

Address all correspondence and requests for reprints to: Mingyao Liu, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 West Holcombe Boulevard, Houston, Texas 77030. E-mail: mliu{at}ibt.tamhsc.edu.

Kisspeptins are natural ligands of G protein-coupled receptor-54. Activation of KiSS1/G protein-coupled receptor-54 signaling pathways results in potent activation of the hypothalamus-pituitary-gonadal axis and initiates puberty. Recent data have shown that in female mice, KiSS1 is positively regulated by estradiol (E₂) in the anteroventral periventricular nucleus, an important reproductive neuroendocrine brain region, but negatively regulated in the arcuate nucleus. However, little is known about the molecular mechanisms governing E₂-modulated KiSS1 expression. Here, we demonstrate that the expression level of the KiSS1 gene was up-regulated with the administration of E₂ in estrogen receptor (ER)-positive hypothalamic GT1–7 cells. Using transient transfection of human KiSS1 gene promoter coupled to a luciferase reporter, E₂ increases promoter activity in the presence of ER. Deletion analysis of KiSS1 promoter indicates that the E₂-regulated increase in promoter activity depends on the Sp1 sites of the proximal promoter region. Using both EMSAs and chromatin immunoprecipitation analysis, we determined that both Sp1 and Sp3 proteins constitutively associate with the four putative Sp1 sites in vitro, whereas the association of ER with the KiSS1 promoter is dependent on E₂ exposure. Sp1 and ER form a complex in vivo to mediate the E₂-induced activation of KiSS1 promoter. Interestingly, Sp1 transactivates KiSS1 promoter activity, whereas Sp3 functions as a transcriptional repressor. Together, these results demonstrate that E₂-dependent transcriptional activation of KiSS1 gene is mediated by ER through the interaction of Sp1/Sp3 proteins with the GC-rich motifs of KiSS1 promoter, providing a molecular mechanism of how steroid hormone feedback regulates KiSS1 expression.

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