Growth hormone (GH) is an important regulator of growth and metabolism. Little is known about how the intracellular GH signaling pathways, that utilizes several Stat of transcription factors, interact with the similar signaling pathways of other hormones and cytokines, such as interleukin 6 (IL-6). In addition to the Jak/Stat pathway, we present evidence that other intracellular signaling pathways, several of the MAP kinase pathways, are induced by GH or IL-6. One of the primary target organs for both GH and IL-6 is the liver. However, only a few hepatic genes have been found to be directly regulated by GH and have been studied in detail since most hepatic GH-responsive genes are not expressed or not regulated by GH in cultured hepatoma cell lines. Thus, much of our knowledge on GH-regulated gene expression has been derived from the use of cultured adipocyte cell lines, or by use of rat and mouse models of GH deficiency and replacement, especially hypophysectomized rats. We have selected cDNAs specific for the mRNAs of 13 new GH-Inducible Genes (GIGs) from the liver of a GH- treated hypophysectomized male rat. Partial sequence analysis indicates that several of the cDNAs are specific for hemopexin (Hx). A major physiologic role of Hx is to avidly bind heme, transport it back to the liver where it can be reused thereby depriving bacteria of needed iron and reducing bacterial division, reducing heme-catalyzed oxygen radical formation and decreased oxygen radical damage. Hx is also the major hepatic hyaluronidase and may contribute to a number of cellular processes including wound repair. Of primary importance for this application, there are major gaps in our understanding of the signaling mechanisms by which GH regulates hepatic gene expression. Our preliminary data indicates GH and IL-6 can synergize in the regulation of the Hx gene. A goal of this proposal is to delineate the intracellular signaling pathways used by GH in regulating gene expression in the liver and to determine how the signaling pathways of GH and IL-6 may interact. We hypothesize that in certain circumstances GH may be important in the physiologic response to bacterial infection, injury and surgical stress, and in certain circumstances wounds and recovery from various injury and trauma. Our goal is to understand the interactions between the multiple signaling pathways used by GH and IL-6 in the regulation of hepatic gene expression. We now have a new model system that can allow us to dissect this regulation.
|Stred, Susan E; Messina, Joseph L (2003) Identification of hemopexin as a GH-regulated gene. Mol Cell Endocrinol 204:101-10|
|Stred, Susan E; Cote, Deborah; Weinstock, Ruth S et al. (2003) Regulation of hemopexin transcription by calcium ionophores and phorbol ester in hepatoma cells. Mol Cell Endocrinol 204:111-6|