Adenomatous polyposis coli regulation of WNT signaling via retinoic acid and cycloxygenase-2

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Title Adenomatous polyposis coli regulation of WNT signaling via retinoic acid and cycloxygenase-2
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Eisinger, Annie Louise
Date 2006-12
Description Genetic and pharmacological data support the conclusion that cyclooxygenase-2 (COX-2) is negatively regulated by the tumor suppressor adenomatous polyposis coli (APC) and that the loss of APC function and subsequent dysregulation of COX-2 expression promotes turnorigenesis. APC is a negative regulator of ?-catenin and it has been hypothesized that upregulation of COX-2 following loss of APC function is a consequence of dysregulated expression of ?-catenin. These observations are challenged by recent studies suggesting that a product of COX-2, prostaglandin E2 (PGE2), stimulates ?-catenin signaling. These important findings imply that PGE2 and COX-2 are upstream signaling molecules necessary for activation of the ?-catenin/TCF/LEF pathway. In this dissertation I provide evidence supporting the existence of a functional association between APC and COX-2 through a mechanism that involves retinoic acid. The work presented here also demonstrates that PGE2 is a key determinant of ?-catenin stabilization when the function of APC is compromised. Using zebrafish as a model system 1 demonstrate that COX-2 is upregulated in APC mutant zebrafish owing to a deficiency in retinoic acid and that this does not depend on the ability of APC to control ?-catenin. Second, I present data showing that retinoic acid regulates COX-2 by controlling expression of the transcription factor C/EBP-?. Third, I report that retinoic acid is a negative regulator of ?-catenin owing to its ability to suppress COX-2 expression and decrease PGE2 synthesis. My studies demonstrate that in wild-type zebrafish PGE2 stabilizes ?-catenin and that this stabilization is mediated by disassembly of the ?-catenin destruction complex. Conversely, inhibition of PGE2 production in APC mutant zebrafish restores the association between axin and ?-catenin. Interestingly, I found that truncated APC can form functional complexes that result in ?-catenin degradation and that the stability of these entities is regulated by the levels of PGE2. The data I present support a sequence of events in which mutations in APC impair retinoic acid biosynthesis, cause elevated levels of C/EBP-P, upregulation of COX-2, PGE2 accumulation and activation of the ?-catenini/Wnt signaling pathway. The study has important implications for our understanding of the molecular mechanisms that participate in colon cancer progression.
Type Text
Publisher University of Utah
Subject Acid Biosynthesis; Gene Regulaters
Subject MESH Colonic Neoplasms; Gene Expression
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Adenomatous polyposis coli regulation of WNT signaling via retinoic acid and cycloxygenase-2". Spencer S. Eccles Health Sciences Library. Print version of "Adenomatous polyposis coli regulation of WNT signaling via retinoic acid and cycloxygenase-2" available at J. Willard Marriott Library Special Collection. RC39.5 2006 .E38.
Rights Management © Annie Louise Eisinger.
Format application/pdf
Format Medium application/pdf
Format Extent 2,274,680 bytes
Identifier undthes,3807
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available)
Master File Extent 2,274,715 bytes
ARK ark:/87278/s6f47qzt
Setname ir_etd
ID 191424
Reference URL https://collections.lib.utah.edu/ark:/87278/s6f47qzt
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