Zinc finger proteins are key regulators of normal morphogenesisi and can also act as either oncogenes or tumor suppressors. The investigators laboratory has been focused on studying the role of these proteins in the regulation of pancreatic gene expression, cell growth, and the modulation of neoplastic transformation. Pancreatic cancer currently ranks fifth as a cause of death by cancer in the USA and has one fo the poorest prognoses among the human neoplasias. Although the etiology and pathophysiology of pancreatic ductal cancer is poorly understood, increasing evidence indicates that alterations in transcription factors (e.g. DPC4/Smad4) are often associated with this disease. Furthermore, transcription factors such as p53 are beginning to be tested as genetic therapeutic tools to treat this disease. The proposal is focused on the biochemical and functional characterization of KS1, a novel zinc finger transcription factor isolated from the pancreas that represses transcription and suppresses neoplastic transformation. Both of these functional properties of KS1 are interrelated since the deletion of a distinct transcriptional repressor domain, R2 abolishes the ability of this protein to suppress neoplastic transformation. Currently, however, the mechanisms that KS1 uses to perform these functions are poorly understood. Moreover, the role of KS1 in the regulation of pancreatic epithelial cell growth is also undefined. In this proposal, the investigator will test the central hypothesis that KS1 is a sequence-specific transcriptional repressor protein that inhibits cell growth and neoplastic transformation by regulating apoptosis and/or cell proliferation. The investigator will use state-of-the-art biochemical and molecular techniques combined with well established assays and cell models for studying neoplastic transformation and pancreatic epithelial cell growth. The proposed aims are to: 1) determine the role of KS1 in the regulation of cell proliferation and apoptosis, 2) determine the DNA binding activity of KS1, and 3) characterize the mechanisms underlying the function of the R2 domain of KS1 as a transcriptional repressor and suppressor of transformation. The investigator expects that successful completion of this proposal will provide novel information on molecular mechanisms used by zinc finger proteins to regulate cell growth and neoplastic transformation. This knowledge will serve as the foundation for future studies aimed at using these proteins as therapeutic tools for controlling abnormal cell growth.
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