KRUPPEL LIKE FACTOR DURING INTESTINAL TUMORIGENESIS

Johns Hopkins University, Baltimore MD

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Abstract

The gut-enriched Kruppel-like factor (GKLF) is a recently identified transcription factor that contains 3 C2H2 Kruppel-type zinc fingers. Several lines of evidence suggest that GKLF is a negative regulator of cellular proliferation. First, expression of GKLF is temporally associated with conditions that promote growth arrest such as serum deprivation and contact inhibition. second, constitutive production of GKLF results in the inhibition of DNA synthesis. Third, GKLF activates the promoter of the cyclin-dependent kinase inhibitor p2l/WAF1/CIP1 gene. Fourth, GKLF is primarily expressed in the post-mitotic epithelial cells of the intestines. Fifth, expression of GKLF is decreased in the intestine of Min mice at the stage when intestinal tumors are formed. The goals of this research proposal are: 1) To examine the expression of GKLF in normal and tumorous intestinal tissues from Min mice and humans using Western blot analysis, ribonuclease protection assay, in situ hybridization and immunohistochemistry and 2) To investigate the mechanisms by which GKLF negatively regulates cell growth using an adenovirus-mediated gene transfer method.