Book Description

Insulin-like growth factor I (IGF-I) gene expression is under developmental control, however, molecular mechanisms governing its regulation remain poorly defined. Growth hormone (GH), whose action is mediated by the GH receptor (GHR), is a major regulator of IGF-I gene expression. The expression of IGF-I and GHR mRNA is widely distributed, with the liver being the primary site of expression of both genes. Mechanisms of GH action are known, however signal transduction pathways that mediate GH activation of the IGF-I gene are undefined. In this series of studies, we investigated what factors determine IGF-I gene expression during development. RNase protection assays and Western blot analysis demonstrated that the expression of the IGF-I gene correlates with GHR expression in all the rat tissues we examined such as liver, testis, skeletal muscle, heart, kidney, lung and brain. Further, with the exception of insulin receptor substrate 1 (IRS-1), GH signaling molecules were expressed at all stages of development. In addition, levels of hepatic and brain nuclear protein binding to IGF-I foot print I (IGFI-FPI), a protein binding site in the major promoter of the rat IGF-I gene that is important for basal promoter activity in vitro, were similar throughout development, demonstrating that the IGFI-FPI is likely not involved in the developmental regulation of IGF-I gene expression. These data indicated a critical role of GHR in determining levels of IGF-I gene expression during development. However, increasing the level of GHR expression in fetal rat hepatocytes did not induce GH-dependent IGF-I gene expression, despite inducing GH-dependent activation of genes with defined GH responsive elements such as c-fos and spi 2.1 in these cells. This indicated that in addition to GHR expression, regulation of factors operating at a post-receptor level is likely to be important for inducing GH-mediated IGF-I gene expression. This led us to begin to define the signal transduction pathways that are utilized by GH to mediate IGF-I gene expression. We show that PI3-kinase and the ERKs are important for GH dependent regulation of IGF-I gene expression in rat hepatocytes, with PI3-kinase having a more robust effect.