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Identification of a Hormone-Responsive Promoter Immediately Upstream of Exon 1c in the Human Vitamin D Receptor Gene¹

Department of Biological Sciences (I.M.B., L.F., M.P.R.T., J.W.), University of Notre Dame, Notre Dame, Indiana 46556; and Departments of Zoology (I.M.B.), and Botany (L.F.), University College Dublin, Belfield, Ireland

Address all correspondence and requests for reprints to: Dr. JoEllen Welsh, Department of Biology, University of Notre Dame, Notre Dame, Indiana 46556. E-mail: jwelsh3{at}nd.edu

To gain insight into the molecular regulation of the human vitamin D₃ receptor (hVDR), we have cloned and sequenced the 5' flanking region of exon 1c and examined promoter activity of this region in breast cancer cells. Sequence analysis of the first 1300 bp upstream of exon 1c reveals several characteristics of a class II promoter, including GC-rich regions and the presence of a TATA box at -29 bp. Putative transcription factor binding sites identified in this potential hVDR promoter include AP-2, Sp-1, and glucocorticoid response elements. No consensus vitamin D₃ (VDRE) or estrogen (ERE) responsive elements were identified in the promoter sequence. Primer extension analysis performed with a primer specific for exon 1c confirms that transcription initiated in the 5' flanking region of exon 1c occurs in MCF-7 cells. Transient transfection of MCF-7 cells with this putative promoter region cloned into the pRLnull luciferase reporter vector generates significant reporter gene activity that is enhanced by treatment with forskolin, retinoic acid, and 17ß-estradiol. The enhancement of exon 1c promoter activity by 17ß-estradiol is blocked by the selective estrogen response modifier (SERM) tamoxifen and is not observed in estrogen receptor-negative breast cancer cells. In summary, we have cloned and characterized a TATA containing promoter upstream of exon 1c of the hVDR and provide evidence that this region represents a hormonally regulated hVDR promoter.

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