Role of APC and retinoid metabolism in gut development and cancer progression

Update Item Information
Title Role of APC and retinoid metabolism in gut development and cancer progression
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Shelton, Dawne Naomi
Date 2007-05
Description This work explores the dysregulation of retinoid metabolism in early oncogenesis models, and the role of retinoids in early development of the intestine. APC is a tumor suppressor gene mutated or silenced in -85% of all colorectal cancers. Through the canonical pathway, APC negatively regulates protein levels of the transcriptional activator, beta catenin. Under Wnt signaling or mutated APC, beta catenin accumulates, and translocates to the nucleus where it binds to TCF/LEF transcription factors and activates Wnt target genes involved in proliferation. In this dissertation I will provide evidence that in addition to the canonical pathway and excessive proliferation, mutations in APC also lead to defects in retinoid metabolism which contributes to a lack of appropriate differentiation within the intestine, contributing to oncogenic progression. Work in our lab has focused on a role for APC in the regulation of retinoic acid (RA) metabolism; production, catabolism, and transport. Using zebrafish as a model system, I will show that certain retinol dehydrogenases (rdhs) are regulated by APC and mutations in APC lead to their loss. The defects seen in apc[mcr] mutants phenocopy antisense morpholino gene knockdowns of ape and certain rdhs, in addition to having characteristic phenotypes of RA deficiency. These phenotypes include loss of jaw and fin structures and terminal differentiation of the pancreas, intestine, liver, and eye. These phenotypes can be rescued by the addition of exogenous RA or the injection of ape or rdh mRNAs. In addition to this, I will show that through the canonical pathway, catabolism of RA is up regulated in three vertebrate model systems; apc[mcr] zebrafish, Apc[Min] mouse model, and human familial adenomatous polyposis (FAP) syndrome. Inhibition of the enzyme responsible for degradation of RA, Cyp26al, leads to increased levels of rescue of RA deficient phenotypes. Thirdly, I will report on the effects of knocking down retinol binding protein 2a (rbp2a) and retinoid transport in zebrafish and how it affects intestinal and ocular development. In Chapter 5 I will also present data on the consequences of crossing Apc'^' mice with Cyp26al knockout mice, which are embryonic lethal due to RA teratogenicity. These data, together, will support a model wherein APC regulates RA metabolism at several levels and contributes to an alternate model suggesting that loss of differentiation, in addition to increases in proliferation, facilitate the progression of colon cancer. In addition, the elucidation of these alternative pathways provides potential targets for future therapeutic and diagnostic needs.
Type Text
Publisher University of Utah
Subject Colon Cancer; Genetics; Zebra danio; Physiology
Subject MESH Adenomatous Polyposis Coli; Colonic Neoplasms; Zebrafish
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "The role of APC and retinoid metabolism in gut development and cancer progression. Spencer S. Eccles Health Sciences Library. Print version of "The role of APC and retinoid metabolism in gut development and cancer progression. available at J. Willard Marriott Library Special Collection. RC39.5 2007 .S48.
Rights Management © Dawne Naomi Shelton.
Format application/pdf
Format Medium application/pdf
Format Extent 7,161,555 bytes
Identifier undthes,4931
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship National Institutes of Health and the Genetics Training Grant, the American Cancer Societiy and Huntsman Cancer Foundation.
Master File Extent 7,161,612 bytes
ARK ark:/87278/s6w95c21
Setname ir_etd
ID 191614
Reference URL https://collections.lib.utah.edu/ark:/87278/s6w95c21
Back to Search Results