Human growth hormone receptor gene expression is regulated by Gfi-1/1b and GAGA cis-elements

Human growth hormone receptor (hGHR) gene regulation is complex: mRNAs are transcribed from multiple variant (V) 5′UTR exons, several ubiquitously while others only in the postnatal hepatocyte. The liver-specific V1 exon promoter contains Gfi-1/1b repressor sites adjacent to a GAGA box, a GH response element (GHRE) in several mammalian genes. GAGA boxes are also present in the ubiquitously expressing V3 exon promoter. Heterologous sites in bovine, ovine and murine GHR genes suggest conserved roles. GAGA factor stimulated V1 and V3 promoters while Gfi-1/1b repressed basal and GAF-stimulated V1 transcription. HGH treatment of HepG2 cells resulted in a new complex forming with V3 GAGA elements, suggesting a functional GHRE. Data suggest liver-specific V1 transcription is regulated by inhibitory Gfi-1/1b and stimulatory GAGA cis-elements and Gfi-1/1b may control the lack of V1 expression in fetal liver, hepatic tumours and non-hepatic tissues. In addition, hGH may regulate hGHR expression through V3 GAGA boxes.