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Transcriptional Regulation of the c-MYC ( MYC) Proto-Oncogene by Oncogenic Wnt/beta-Catenin Signaling in Colorectal Carcinomas.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Transcriptional Regulation of the c-MYC ( MYC) Proto-Oncogene by Oncogenic Wnt/beta-Catenin Signaling in Colorectal Carcinomas./
Author:	Rennoll, Sherri A.
Description:	1 online resource (209 pages)
Notes:	Source: Dissertation Abstracts International, Volume: 79-07(E), Section: B.
Contained By:	Dissertation Abstracts International79-07B(E).
Subject:	Molecular biology. -
Online resource:	click for full text (PQDT)
ISBN:	9780355652628

Transcriptional Regulation of the c-MYC ( MYC) Proto-Oncogene by Oncogenic Wnt/beta-Catenin Signaling in Colorectal Carcinomas.
Rennoll, Sherri A.

Transcriptional Regulation of the c-MYC ( MYC) Proto-Oncogene by Oncogenic Wnt/beta-Catenin Signaling in Colorectal Carcinomas. - 1 online resource (209 pages)

Source: Dissertation Abstracts International, Volume: 79-07(E), Section: B.

Thesis (Ph.D.)--The Pennsylvania State University, 2015.

Includes bibliographical references

Over 90% of sporadic colorectal cancers (CRCs) are associated with initiating mutations in components of the Wnt/beta-catenin signaling pathway. These mutations result in elevated nuclear levels of the beta-catenin transcriptional co-activator. In the nucleus, beta-catenin associates with the T-cell factor/Lymphoid enhancer factor (TCF/Lef) family of sequence-specific transcription factors at Wnt-responsive DNA elements (WREs) to increase target gene expression. Aberrant expression of these genes by oncogenic Wnt/beta-catenin signaling leads to the formation of small, benign adenomas. The c-MYC (MYC) proto-oncogene is a direct beta-catenin target gene that is required for Wnt/beta-catenin-mediated intestinal tumorigenesis. However, the molecular mechanisms underlying beta-catenin regulation of MYC expression are not fully defined. The work described within this thesis aimed to further define these molecular mechanisms by addressing the involvement of nuclear AXIN2 and the MYC 3' WRE in controlling oncogenic MYC gene expression.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2018

Mode of access: World Wide Web

ISBN: 9780355652628Subjects--Topical Terms:

583443
Molecular biology.
Index Terms--Genre/Form:

554714
Electronic books.

Transcriptional Regulation of the c-MYC ( MYC) Proto-Oncogene by Oncogenic Wnt/beta-Catenin Signaling in Colorectal Carcinomas.
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245 1 0 $a Transcriptional Regulation of the c-MYC ( MYC) Proto-Oncogene by Oncogenic Wnt/beta-Catenin Signaling in Colorectal Carcinomas.
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300 $a 1 online resource (209 pages)
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500 $a Source: Dissertation Abstracts International, Volume: 79-07(E), Section: B.
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502 $a Thesis (Ph.D.)--The Pennsylvania State University, 2015.
504 $a Includes bibliographical references
520 $a Over 90% of sporadic colorectal cancers (CRCs) are associated with initiating mutations in components of the Wnt/beta-catenin signaling pathway. These mutations result in elevated nuclear levels of the beta-catenin transcriptional co-activator. In the nucleus, beta-catenin associates with the T-cell factor/Lymphoid enhancer factor (TCF/Lef) family of sequence-specific transcription factors at Wnt-responsive DNA elements (WREs) to increase target gene expression. Aberrant expression of these genes by oncogenic Wnt/beta-catenin signaling leads to the formation of small, benign adenomas. The c-MYC (MYC) proto-oncogene is a direct beta-catenin target gene that is required for Wnt/beta-catenin-mediated intestinal tumorigenesis. However, the molecular mechanisms underlying beta-catenin regulation of MYC expression are not fully defined. The work described within this thesis aimed to further define these molecular mechanisms by addressing the involvement of nuclear AXIN2 and the MYC 3' WRE in controlling oncogenic MYC gene expression.
520 $a AXIN2, a scaffolding protein and component of the Wnt/beta-catenin signaling pathway, was recently demonstrated to localize to the nucleus. The function of AXIN2 within this subcellular compartment, however, was unknown. By constitutively localizing AXIN2 to the nucleus, we demonstrate that nuclear AXIN2 forms a complex with beta- catenin/TCF and represses MYC gene expression by binding the MYC gene locus. These results indicate that nuclear AXIN2 functions as a molecular rheostat to maintain a "just right" level of MYC necessary for tumorigenesis in CRC. Similar to nuclear AXIN2, we find that the MYC 3' WRE, which maps 1.4-kb downstream from the MYC transcription stop site, drives oncogenic MYC gene expression in CRC cells. Using CRISPR/Cas9 genome editing technology, we generated a knockout CRC cell line in which a single TCF binding element within the MYC 3' WRE was deleted. Deletion of this element decreased beta-catenin/TCF occupancy at the MYC 3' WRE and MYC gene expression. The observed decrease in MYC gene expression corresponded to diminished cellular proliferation and growth of the knockout cells. Together, our studies have uncovered new mechanisms for regulation of MYC gene expression by oncogenic Wnt/beta-catenin signaling, and suggest that approaches to target nuclear AXIN2 or the MYC 3' WRE would be effective strategies for the treatment of individuals suffering from CRC.
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538 $a Mode of access: World Wide Web
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