The role of transcription factors in the APC pathway

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DESCRIPTION (provided by applicant) This proposal is for a K08 Award for Dr. Duyen Dang. Dr. Dang graduated from Harvard Medical school in 1994. Thereafter, she trained clinically in Internal Medicine and Gastroenterology. She has dedicated the past two years to scientific training in Dr. Vincent Yang's laboratory at Johns Hopkins University School of Medicine. The focus of her studies has been the role of the gut-enriched Kruppel-like factor (GKLF), a potent inhibitor of epithelial cell growth, in intestinal tumorigenesis. The mammalian gut epithelium is a dynamic system in which cell proliferation is coupled to differentiation. Aberrations in this process lead to disease states such as colon cancer. Mutations of the tumor suppressor gene Adenomatous Polyposis Coli (APC) have been shown to initiate neoplastic transformation in most colorectal cancers. This application proposes to establish two transcription factors, CDX2 and GKLF as downstream mediators of the APC pathway. The hypotheses are: (1) APC regulates CDX2 expression, (2) CDX2 regulates GKLF expression, enterocyte differentiation, and cell growth; while dominant negative mutations of CDX2 inhibit this regulation, and (3) over-expression of GKLF leads to reduced malignancy. Three specific aims are proposed to test these hypotheses: Specific Aim 1: To evaluate whether APC regulates CDX2 expression at the transcriptional or post-transcriptional level; Specific Aim 2: To evaluate a mutant CDX2 for dominant negative effects on the GKLF promoter, enterocyte differentiation, and growth suppression; and Specific Aim 3: To evaluate the impact of GKLF on the pathophysiology of colon cancer by assessing for GKLF mutations and evaluating the effect of GKLF over-expression on malignancy. The proposed research will contribute to the understanding of the mechanisms underlying intestinal development and colorectal tumorigenesis. In addition, the continued mentorship of Dr. Yang and the didactic and methodology curriculum intrinsic to this proposal will provide Dr. Dang with a framework to learn the methods, theories, and concepts recess to embark on an independent research career.