Growth hormone suppression of insulin-like growth factor binding protein-1 promoter activity

Abstract

Hepatic transcription of insulin-like growth factor binding protein-1 (IGFBP-1) is rapidly downregulated by growth hormone (GH) which is also known to induce expression of c-fos and c-jun. Co-expression of c-fos or c-jun in rat hepatocytes, individually or together, suppresses IGFBP-1 promoter activity by ≈60%. When hepatic nuclear extracts from sham-operated, hypophysectomized (hypox) and GH-treated hypox rats were analyzed by DNase-1 footprinting, differences in the protection pattern were identified in three regions of the IGFBP-1 promoter. F1 corresponding to −660 to −640 bp showed acute changes in response to GH administration. In additional regions, F2 and F3, representing −758 to −748 bp and −477 to −447 bp, respectively, differences were apparent between nuclear extracts from the hypox and sham-operated rats. When F1 and F2 were removed by deletion of the region from −824 to−557 bp, the GH response was lost but suppression by co-expression of c-fos and c-jun was preserved. A putative AP-1 binding site was present in the F3 footprint region, however removal of F3 did not affect the GH responsiveness. These data indicate that several distinct sequences, other than the putative AP-1 site are involved in mediating the GH effects on IGFBP-1 transcription.