This proposal addresses the molecular basis of growth hormone action in the liver through examination of the rat Spi I (serine protease inhibitor) 2 locus. Three hypotheses will be tested. The first is that regulation of the Stat 2.1 gene is mediated by binding of Stat5 in a cooperative fashion to two sites within the GHRE. The second is that additional proteins interact with Stat5 to mediate regulation. The third is that specificity of GH regulation through the Stat5 pathway is achieved through the unique architecture of the GHRE in the Spi 2.1 gene and these Stat5-protein interactions.
Three specific aims are proposed to test these hypotheses. 1. The investigator will further define the nuclear proteins critical for GH action in the Spi 2.1 model, establishing proof that Stat5 is necessary for Spi 2.1 gene activation, examining the role of YY1 in GH action, determining the role of glucocorticoid receptor, and evaluating the role of serine phosphorylation of Stat5. 2. The investigator will examine the functional architecture of the GHRE, exploring the significance of paired GAS-like elements in the response to GH, distinguishing characteristics of DNA elements structurally related to the Spi 2.1 GHRE but not responsive to GH, and defining other elements in the Spi 2.1 promoter important in the response to GH. 3. The investigator will compare the actions of GH and IL-6 in Spi 2.1 gene expression, defining the IL-6 response element and the nuclear factors binding to Spi 2.1 in response to IL-6 with comparison to the GH response, thereby furthering understanding of the specificity of the Spi 2.1 response to GH.
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