| The research presented in this dissertation describes the earliest molecular and phenotypic consequences of homozygous loss of apc during zebrafish development and colon adenoma initiation. Additionally, we describe a novel pathway that includes KRAS and RAC1, which results in the nuclear accumulation of beta-catenin and intestinal cell proliferation and may underlie colon adenoma progression. Through juxtaposition of zebrafish and human cell lines, we have uncovered new insights that require the reordering of the canonical model of colon tumorigenesis. A better understanding of early and late events during colon tumorigenesis will aid in diagnosis, prognosis and treatment of colorectal cancer.;Chapter 1 is an introduction to cancer in general and colon cancer specifically. Also, we provide a comprehensive review of the literature that has supported the current model of colon cancer initiation and progression. The majority of the literature focuses on the consequences of APC loss and WNT/beta-catenin activation in human and murine models. However, a review of additional minor pathways, such as the RAS pathway and inflammation, are included.;Chapter 2 describes the consequences of apc loss in the developing zebrafish embryo. Additionally, we describe the somewhat surprising finding that WNT/beta-catenin signaling is not immediately activated following loss of apc. Rather, the activation of KRAS and RAF1, but not MEK1, is required to elicit a full WNT response in zebrafish intestinal cells and in human colon cancer cell lines.;Chapter 3 provides a mechanism for KRAS-mediated nuclear localization of beta-catenin. Specifically, we demonstrate that KRAS activates RAC1 and that this is required for JNK2-mediated phosphorylation of beta-catenin and its subsequent nuclear localization.;Chapter 4 provides evidence that the earliest intestinal cell differentiation defects present in apcmcr embryos are mediated by dysregulation of ctbp1 and are independent of beta-catenin activation. Thus, APC regulates at least two independent pathways and dysregulation of differentiation, which is beta-catenin-independent, represents the earliest consequence of APC loss.;In Chapter 5, the main conclusions of my work are summarized. I have also discussed the implications of our findings on future approaches to colorectal cancer prognosis and treatment. |
