In contrast to well characterized primary glucocorticoid hormone responses where the glucocorticoid receptor interacts directly with viral and cellular target genes to increase transcription, secondary glucocorticoid responses remain poorly defined. A hallmark of the secondary response is the requirement for ongoing protein synthesis in order for increased transcription of the secondary response gene to occur. Secondary responses are presumed to be medicated by as yet unidentified transcription factors (transactivators) that are themselves induced or activated by glucocorticoids. Dr. Norris and colleagues have cloned and characterized a glucocorticoid regulated secondary response gene, hGSTYBX, from a hormonally induced leiomyosarcoma cell line, an have found it to be a nuclear glutathione S-transferase (GST). This class of gene is directly involved in xenobiotic drug metabolism and multidrug resistance, and is suspected to play a role in hormonal carcinogenesis. Therefore, understanding its regulation may also reveal important information about its role in the neoplastic process. This application has three specific aims that will address the role of this important GST molecules in hormonal carcinogenesis. In the first aim Dr. Norris will continue characterization of the transactivator proteins that regulate transcription of the gene. This characterization will be largely biochemical and will involve EMSA, western blotting and the use of phosphatase and kinase inhibitors. These studies will result in a detailed biochemical characterization and further identification of the transactivating factors, including potential putative secondary response factors that alter transcription of the gene. The second specific aim will ask direct questions about the role of this gene in hormonal carcinogenesis and who both androgen and estrogen are required to induce leiomyosarcomas in Syrian hamsters. The final specific aim will investigate the mechanics and ultimately regulation of hGSTYBX nuclear localization. Understanding the biology and function of this class of gene has the potential to yield great insight into the mechanism of hormonal carcinogenesis in the Syrian hamster, a 100% reproducible model for steroid induced solid tumor formation. The long term goal of this grant is to characterize the genes and their related cellular control mechanism involved in hormonal carcinogenesis. It is Dr. Norris' belief that understanding these pathways will ultimately allow definition of novel interventional protocols for the control of cancer.
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