Document Detail


Control of beta-catenin signaling in tumor development.
MedLine Citation:
PMID:  10911903     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The wnt signal transduction pathway is involved in various differentiation events during embryonic development and leads to tumor formation when aberrantly activated. The wnt signal is transmitted to the nucleus by the cytoplasmic component beta-catenin: in the absence of wnts, beta-catenin is constitutively degraded in proteasomes, whereas in the presence of wnts beta-catenin is stabilized and can associate with HMG box transcription factors of the LEF/TCF family. The LEF/TCF/beta-catenin complexes activate specific wnt target genes. In tumors, beta-catenin degradation is blocked by mutations of beta-catenin or of the tumor suppressor gene product APC. As a consequence, beta-catenin is stabilized, constitutive complexes with LEF/TCF factors are formed, and oncogenic target genes, such as c-myc, cyclin D1, and c-jun, are activated. Thus, control of beta-catenin is a major regulatory event in normal wnt signaling and during tumor formation. It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes APC, the serine/threonine kinase GSK3 beta, and beta-catenin, which bind to conductin at distinct domains. In colon carcinoma cells, forced expression of conductin downregulates beta-catenin, whereas in normal cells mutants of conductin that are deficient in complex formation stabilize beta-catenin. Fragments of APC that contain a conductin-binding domain also block beta-catenin degradation. In Xenopus embryos, conductin inhibits the wnt pathway. In situ hybridization analysis shows that conductin is expressed in various embryonal tissues known to be regulated by wnts, such as the developing brain, mesenchyme below the epidermis, lung mesenchyme, and kidney. It is suggested that conductin controls wnt signaling by assembling the essential components of the beta-catenin degradation pathway. Alterations of conductin function may lead to tumor formation.
Authors:
J Behrens
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Annals of the New York Academy of Sciences     Volume:  910     ISSN:  0077-8923     ISO Abbreviation:  Ann. N. Y. Acad. Sci.     Publication Date:  2000 Jun 
Date Detail:
Created Date:  2000-08-17     Completed Date:  2000-08-17     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  7506858     Medline TA:  Ann N Y Acad Sci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  21-33; discussion 33-5     Citation Subset:  IM    
Affiliation:
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. jbehren@mdc-berlin.de
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MeSH Terms
Descriptor/Qualifier:
Cell Transformation, Neoplastic*
Cytoskeletal Proteins / physiology*
Gene Expression Regulation, Neoplastic / physiology
Humans
Neoplasms / etiology*,  genetics,  metabolism
Signal Transduction*
Trans-Activators*
beta Catenin
Chemical
Reg. No./Substance:
0/CTNNB1 protein, human; 0/Cytoskeletal Proteins; 0/Trans-Activators; 0/beta Catenin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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