alexa F-box and WD repeat domain-containing 7 regulates intestinal cell lineage commitment and is a haploinsufficient tumor suppressor.
Medicine

Medicine

Internal Medicine: Open Access

Author(s): Sancho R, Jandke A, Davis H, Diefenbacher ME, Tomlinson I,

Abstract Share this page

Abstract BACKGROUND & AIMS: The E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (Fbw7) degrades several proto-oncogenes including c-Myc, cyclinE, Notch1, and c-Jun. Fbw7 is the fourth most frequently mutated gene in human colorectal carcinomas and has recently been described as a poor prognosis marker in human colorectal carcinoma; however, the molecular mechanism underlying fbw7 mutations in intestinal tumor suppression is unclear. METHODS: To address the role of fbw7 in intestinal homeostasis and tumorigenesis, we generated conditional knock-out mice lacking fbw7 in the intestine and evaluated the effect of fbw7 absence in normal intestinal homeostasis and in adenomatous polyposis coli-mediated tumorigenesis. In parallel, we analyzed a cohort of human tumors bearing mutations in fbw7. RESULTS: Fbw7 was found to be highly expressed in the transit-amplifying progenitor cell compartment, and its deletion resulted in impaired goblet cell differentiation and accumulation of highly proliferating progenitor cells. This function of Fbw7 was mirrored during tumor formation because absence of Fbw7 increased proliferation and decreased differentiation of tumors triggered by aberrant Wnt signalling. Fbw7 exhibited haploinsufficiency for intestinal tumor suppression. Biallelic fbw7 inactivation increased cellular proliferation in physiologic and pathologic conditions in a c-Jun-dependent manner. Increased Notch activity was also observed in human tumors carrying heterozygous fbw7 mutations, suggesting that fbw7 haploinsufficiency for antagonizing Notch activity is conserved between human and murine cancers. CONCLUSIONS: Fbw7 regulates intestinal biology and tumorigenesis by controlling the abundance of different substrates in a dose-dependent fashion, providing a molecular explanation for the heterozygous mutations of fbw7 observed in human colorectal carcinoma. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved. This article was published in Gastroenterology and referenced in Internal Medicine: Open Access

Relevant Expert PPTs

Relevant Speaker PPTs

Recommended Conferences

  • 22nd World Cardiology Conference
    December 11-12, 2017 Rome, Italy

Relevant Topics

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

[email protected]

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

[email protected]

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001 Extn: 9042

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords