STRUCTURE AND LOCALIZATION OF THE IGFBP-1 GENE AND ITS EXPRESSION DURING LIVER-REGENERATION

Insulin-like growth factor-binding protein-1s are important modulators of the insulin-like growth factors that may have both positive and negative effects on the ability of insulin-like growth factors to stimulate cell growth. The IGFBP-1 gene is one of the most highly induced immediate-early genes after partial hepatectomy. The IGFBP-1 gene is also expressed at a high level during fetal liver development and in response to nutritional changes and diabetes. Therefore it may have important roles in liver growth and metabolism. To begin to examine the regulation of this gene, we cloned and sequenced the entire mouse IGFBP-1 gene. Its structure is highly similar to that of the human gene, and, in addition to the exonic regions, the two genes are highly conserved in specific regions in the promoter and first intron. Analysis of this conservation allows us to predict important regulatory sites that define the tissue specific and insulin-mediated regulation of the gene and identify potential sites that might be important for the transcriptional induction during liver regeneration. The mouse gene is located on mouse chromosome 11; it is found at the boundary between regions in the mouse genome homologous to human chromosomes 22 and 7. We found IGFBP-1 mRNA in both parenchymal and nonparenchymal RNA after partial hepatectomy. Using in situ hybridization of IGFBP-1 mRNA in regenerating rat liver tissue, we demonstrated IGFBP-1 transcripts in several cell types. We found that IGFBP-1 gene induction after partial hepatectomy is paralleled by protein expression. However, on immunohistochemical study, insulin-like growth factor-binding protein-1 protein is found only in hepatocytes after hepatectomy. Unlike IGFBP-1 mRNA, serum levels of insulinlike growth factor-binding protein-1 are increased for a relatively short time with a peak at 2 to 3 hr after hepatectomy. Increased levels of insulinlike growth factor-binding protein-1 could be important in modulating insulinlike growth factor-1 effects on metabolism and growth during liver regeneration.