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Submitted on December 18, 2003
Accepted on May 6, 2004
Department of Medicine and Clinical Science (N.K., T.A., Y.H., K.M., K.N.), Kyoto University Graduate School of Medicine, Kyoto, Japan, 606-8507; Ghrelin Research Project, Department of Experimental Therapeutics (T.A., K.T., H.H., K.K.), Translational Research Center, Kyoto University Hospital, Kyoto University School of Medicine, Kyoto, Japan, 606-8507; Clinical Research Institute, Center for Endocrine and Metabolic Diseases (T.T.), Kyoto National Hospital, Kyoto, Japan, 612-8555; Department of Biochemistry (H.H., M.K., K.K.), National Cardiovascular Center Research Institute, Osaka, Japan, 565-8565; and Institute of Life Science (M.K.), Kurume University, Fukuoka, Japan, 839-0861
* To whom correspondence should be addressed. E-mail: akataka{at}kuhp.kyoto-u.ac.jp.
Ghrelin, an endogenous ligand for the growth hormone secretatogue receptor, induces growth hormone secretion, food intake, and positive energy balance. While ghrelin exhibits a variety of hormonal actions, the mechanisms regulating ghrelin expression and secretion remain unclear. To understand the regulation of the human ghrelin gene expression, we examined the genomic structure of approximately 5,000 base pairs of the 5'-flanking region of the human ghrelin gene. We performed rapid amplification of cDNA ends to estimate transcriptional start sites, indicating that there are two transcriptional initiation sites within the human ghrelin gene. Both transcripts were equally expressed in the human stomach whereas the longer transcript was mainly expressed in a human medullary thyroid carcinoma (TT) cell line. Functional analysis using promoter-reporter constructs containing the 5'-flanking region of the gene indicated that the sequence residing within the -349 to -193 region is necessary for human ghrelin promoter function in TT cells. Within this region existed several consensus sequences for a number of trans-activating regulatory proteins, including an E-box site. Destruction of this site decreased to 40% of the promoter activity. The upstream region of the promoter has two additional putative E-box sites and site-directed mutagenesis suggested that these are also involved in the promoter activation. Electrophoretic mobility shift assays demonstrated that the upstream stimulatory factor (USF) specifically bound to these E-box elements. These results suggest a potential role for USF transcription factors in the regulation of human ghrelin expression.
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