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A Composite Hormone Response Element Regulates Transcription of the Rat GHRH Receptor Gene

Department of Neuroendocrinology (H.N., K.M., S.H.), Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan; Departments of Anatomy (Y.H., S.A., K.K.) and Neurosurgery (M.K.), School of Medicine, Keio University, Tokyo 160-8582, Japan; Laboratory of Functional Anatomy (M.M., E.N., T.H.), Faculty of Agriculture, Meiji University, Kanagawa 214-0071; Japan; Second Department of Internal Medicine (N.H.), National Defense Medical College, Saitama 359-8513, Japan; and Shonan Kamakura General Hospital (S.K.), Kamakura 247-8533, Japan

Address all correspondence and requests for reprints to: Haruo Nogami, Ph.D., Laboratory of Neuroendocrinology, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. E-mail: . hnogami{at}md.tsukuba.ac.jp

To further elucidate the molecular mechanisms underlying the transcriptional regulation of the GHRH receptor (GHRH-R) gene, hormonal regulation of the promoter activity of this gene was examined. An approximately 3-kb genomic fragment spanning the promoter region of the gene was sequenced and the transcription start site was determined by RT-PCR and RNase protection assay. A major start site was localized at -105 (relative to the translation initiation codon, ATG), and a pit-1 binding sequence characteristic of pituitary specific genes was found at -155 to -146. Deletion and mutation studies demonstrated this site to be functional. In the presence of dexamethasone, the GHRH-R promoter (from -2935 to -11) directed luciferase expression in MtT-S cells, a somatotropic cell line, but not in the PC12 cells that normally do not express GHRH-R. While T₃, all trans-RA, and 9cis-RA alone weakly enhanced the reporter gene expression, each of these substances was found to act as a synergistic enhancer in the presence of dexamethasone. Additional deletion and mutation analyses demonstrated a functional RA response element at -1090 to -1074. Two functional glucocorticoid response elements and a T₃ response element were found in an 80-bp 5'-flanking sequence of the pit-1 site. Interestingly, it is suggested that the 6-bp half-site AGGACA (from -209 to -204) functions as a 3'-half-site of T₃ response element as well as a 5'-half-site of one of the glucocorticoid response elements.

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