): In response to interferon, growth hormone, erythropoeitin, epidermal growth factor and over 50 other extracellular signaling proteins, the STATs (signal transducers and activators of transcription) become activated, accumulate in the nucleus, bind DNA and participate in regulating gene expression. A great many decisive physiologic events during development and in adulthood depend upon these signaling pathways. For example, Stati is not only required in the first line of host defense against bacterial and viral infection but also in growth restraint. In contrast, Stat3 has recently been implicated in preventing apoptosis in human cancers and a constitutively active Stat3 (Stat3-C) has been found to be able to transform cultured cells into cancer cells. Understanding the biochemical details of how Stat3 in cooperation with other specific nuclear proteins in structures called enhanceosomes governs gene expression is a major goal of this research. We will explore and further expand current knowledge of how Stat3 interacts with itself as a tetramer, with c-Jun, with the glucocorticoid receptor and with an HMG-box protein to effect immediately increased transcription. We will extend previous crystallographic structure studies to include Stat:c-Jun complexes. The genes that Stat3 and Stat3-C activate in transformed cells and the specific residues required for transformation within known structural domains of Stat3 will be determined. Cell-based transformation assays, protein:protein association assays, crystallographic analysis of appropriate pairwise interactions, in .vivo and in vitro transcription analysis and mouse genetics of Stat3 mutants will all be used in these studies. The detailed knowledge of Stat3 as a transcriptional activator and its role in cell transformation, will greatly aid in the discovery of drugs that inhibit persistently active Stat3 and possibly inhibit cancer.
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