Colorectal cancer is the one of the most commonly diagnosed forms of cancer and the third leading cause of cancer-related deaths in the United States. Loss of the tumor suppressor adenomatous polyposis coli (APC) gene is the initiating mutation in ~80% of these cancers and the driving mutation behind familial adenomatous polyposis coli (FAP). Loss of the APC gene product (Apc) activates the Canonical Wnt signaling pathway, culminating in cell proliferation, transformation, and tumor formation. Using a variety of APC mutant mouse models, I have found that APC ablation coincides temporally and spatially with drastic upregulation of Kaiso, a nuclear binding partner of the adherens junction protein, p120-catenin (p120). Our previous data further show strong nuclear expression of Kaiso in all instances of Wnt activation, as Kaiso is naturally upregulated in the stem cell compartment of the intestinal crypt and aberrantly upregulated following either APC loss or -catenin activation. Work from our group and others further suggest that this upregulation of Kaiso may play a critical role in the tumor promoting events triggered by APC loss. Based on these observations, my working hypothesis is that Kaiso expression is directly or indirectly regulated by the canonical Wnt pathway. Additionally, I propose that constitutive upregulation of Kaiso may be a critical effector of the tumorigenic consequences of APC loss. The following aims seek to define the mechanism(s) of Kaiso upregulation and the molecular consequences of Kaiso ablation.
In Aim 1, I will optimize an assay I have designed expressly to interrogate immediate physical and molecular consequences of APC ablation in vivo. This "Rapid Epistasis Assay" (hereafter, REA) will permit efficient analysis of the effects of APC ablation in the precise microenvironmental context of tumor formation.
In Aim 2, I will identify the mechanism(s) of Kaiso upregulation following APC ablation. Alterations in Kaiso transcription, translation, and protein stability willbe determined with the goal of identifying means of blocking Kaiso upregulation. Finally, as Kaiso ablation in the ApcMin/+ model markedly delays tumor formation, Aim 3 will utilize the REA in combination with molecular and morphological readouts to clarify the mechanism(s) responsible for the tumor attenuating phenotype (e.g., reduced cell proliferation, rescued cell migration along the villus, reversal of dedifferentiation, etc.). Molecular effectors of the Kaiso ablation phenotype may ultimately provide novel targets for pharmaceutical intervention.

Public Health Relevance

Loss of the tumor suppressor Adenomatous Polyposis Coli (APC) is the initiating event in ~80% of sporadic colorectal cancers (CRC). We show that Kaiso, a nuclear binding partner of p120-catenin (p120), is drastically upregulated by APC mutation and this upregulation plays a positive role in CRC tumorigenesis. Understanding the mechanisms that lead to Kaiso upregulation downstream of APC loss may lead to novel molecular targets for pharmaceutical intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09-D (20))
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Schmidt, Michael K
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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