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Structure and Activity of the Human Growth Hormone Receptor (hGHR) Gene V2 Promoter

Departments of Experimental Medicine (Y.W., C.G.G.) and Pediatrics (C.G.G.), McGill University, and Endocrine Research Laboratory (Y.W., S.P., C.G.G.), McGill University Health Centre-Montreal Children’s Hospital Research Institute, Montreal, Quebec, Canada H3Z 2Z3; and Division of Pediatric Endocrinology and Diabetes (M.W.), Department of Pediatrics and Adolescent Medicine, University of Ulm, 89075 Ulm, Germany

Address all correspondence and requests for reprints to: Cynthia Gates Goodyer, Ph.D., McGill University Health Centre, Montreal Children’s Hospital Research Institute, 4060 St. Catherine West, Room 415-1, Montreal, Quebec, Canada H3Z 2Z3. E-mail: cindy.goodyer{at}muhc.mcgill.ca.

Human GH (hGH) has important effects on growth as well as carbohydrate, fat, and protein metabolism. These actions require the presence of normal levels of a functional hGH receptor (hGHR) on the surface of target cells. hGHR gene expression is characterized by the use of several 5'-noncoding exons and alternative splicing, resulting in the generation of multiple mRNA isoforms. The hGHR V2 transcript is predominant in most tissues, including human fat. However, factors regulating its ubiquitous expression have remained unidentified. The present study was aimed at characterizing the mechanisms regulating hGHR V2 transcription. Two major V2 transcriptional start sites were identified by primer extension assays. The V2 proximal promoter is TATA-less, with several characteristics of a housekeeping gene promoter. Transient transfection analyses of 2.6 kb of the 5'-flanking region of V2 confirmed its promoter activity in multiple primate cell lines. Similar promoter activity patterns were observed in human SGBS preadipocytes and mature adipocytes but with much higher V2 promoter activity in mature adipocytes, suggesting that changes in the availability of specific factors during adipocyte differentiation play a role in V2 promoter regulation. Serial deletion and mutation analyses revealed that transcription of hGHR V2 in different cell types, including adipocytes, is determined by a core promoter and distinct inhibitory and activation domains in the 5'-promoter region as well as within the V2 exon. Our data suggest that V2 transcription is the result of a complex interplay involving multiple factors, to ensure appropriate expression of hGHR in different hGH target cells.

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				Y. Wei, S. Puzhko, M. Wabitsch, and C. G. Goodyer Transcriptional Regulation of the Human Growth Hormone Receptor (hGHR) Gene V2 Promoter by Transcriptional Activators and Repressor Mol. Endocrinol., March 1, 2009; 23(3): 373 - 387. [Abstract] [Full Text] [PDF]