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 ne gative effects on the ability of insulin-like growth factors to stimul ate cell growth. The IGFBP-1 gene is one of the most highly induced im mediate-early genes after partial hepatectomy. The IGFBP-1 gene is als o expressed at a high level during fetal liver development and in resp onse to nutritional changes and diabetes. Therefore it may have import ant roles in liver growth and metabolism. To begin to examine the regu lation 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 def ine the tissue specific and insulin-mediated regulation of the gene an d identify potential sites that might be important for the transcripti onal induction during liver regeneration. The mouse gene is located on mouse chromosome 11; it is found at the boundary between regions in t he mouse genome homologous to human chromosomes 22 and 7. We found IGF BP-1 mRNA in both parenchymal and nonparenchymal RNA after partial hep atectomy. 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 s tudy, insulin-like growth factor-binding protein-1 protein is found on ly in hepatocytes after hepatectomy. Unlike IGFBP-1 mRNA, serum levels of insulinlike growth factor-binding protein-1 are increased for a re latively short time with a peak at 2 to 3 hr after hepatectomy. Increa sed levels of insulinlike growth factor-binding protein-1 could be imp ortant in modulating insulinlike growth factor-1 effects on metabolism and growth during liver regeneration.