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    Tumor Suppressor APC and Musashi1: Double-Negative Feedback, Wnt Signaling and Colon Cancer

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    Spears_ku_0099D_11698_DATA_1.pdf (1.794Mb)
    Issue Date
    2011-08-31
    Author
    Spears, Erick
    Publisher
    University of Kansas
    Format
    100 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular Biosciences
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Colorectal cancer is the second leading cause of cancer related deaths in the United States. Approximately 80% of all colon cancers are associated with a mutation in the Adenomatous polyposis coli (APC) tumor suppressor gene. We study the intracellular functions of normal APC and how loss of APC function leads to the formation of precancerous polyps in the intestines of mice and humans. The studies presented here are particularly concerned with the role of APC in maintenance of homeostasis in the intestinal epithelium. I have identified a double-negative feedback loop between APC and a sequence specific RNA binding protein, Mushashi-1 (MSI1). I hypothesize that this feedback loop serves to maintain a critical balance and that disruption of this balance leads to loss of homeostasis and ultimately tumorigenesis in the intestinal epithelium. Studies described here and by others have shown that MSI1 is a target of β-catenin transcriptional activation through the canonical Wnt signaling pathway. My work has demonstrated that APC mRNA is a target of MSI1 binding and translational repression. Further study has indicated that MSI1 binding also results in stabilization of the APC mRNA, presumably as a rapid response mechanism to repress Wnt signal transduction once the signal is no longer present. Finally, my studies indicate that MSI1 expression is stimulated by the transcription factor c-MYC, the most commonly deregulated human oncoprotein. Though overexpression of c-MYC stimulates MSI1 expression, c-MYC expression is not stimulated by loss of APC in our cell culture system. The implication is that c-MYC stimulation of MSI1 expression may only occur in tumors with deregulated c-MYC expression. The studies presented here have uncovered novel molecular mechanisms involved in regulation of the canonical Wnt signaling pathway in the intestinal epithelium, thereby expanding the potential methods by which deregulation of this pathway contributes to colorectal carcinogenesis.
    URI
    http://hdl.handle.net/1808/8198
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    • Dissertations [4475]
    • Molecular Biosciences Dissertations and Theses [270]

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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