Journal ArticleDOI
Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
Osamu Tetsu,Frank McCormick +1 more
TLDR
It is shown that β-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation.Abstract:
Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.read more
Citations
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Journal ArticleDOI
The Wnt signaling pathway in development and disease.
Catriona Y. Logan,Roel Nusse +1 more
TL;DR: The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels, and that receptor-ligand specificity and feedback loops help to determine WNT signaling outputs.
Journal ArticleDOI
Wnt signalling in stem cells and cancer
Tannishtha Reya,Hans Clevers +1 more
TL;DR: Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.
Journal ArticleDOI
Wnt signaling and cancer
TL;DR: In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.
Journal ArticleDOI
Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor
Noboru Sato,Laurent Meijer,Laurent Meijer,Leandros Skaltsounis,Paul Greengard,Ali H. Brivanlou +5 more
TL;DR: It is shown that activation of the canonical Wnt pathway is sufficient to maintain self-renewal of both HESCs and MESCs, and the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine.
Journal ArticleDOI
The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.
Marc van de Wetering,Elena Sancho,Cornelis Verweij,Wim de Lau,Irma Oving,Adam Hurlstone,Karin van der Horn,Eduard Batlle,Damien Coudreuse,Anna-Pavlina G. Haramis,Menno Tjon-Pon-Fong,Petra Moerer,Maaike van den Born,Gwen Soete,Steven T. Pals,Martin Eilers,René H. Medema,Hans Clevers +17 more
TL;DR: The β-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.
References
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Journal ArticleDOI
Lessons from Hereditary Colorectal Cancer
TL;DR: The authors are grateful to the members of their laboratories for their contributions to the reviewed studies and to F. Giardiello and S. Hamilton for photographs of colorectal lesions.
Journal ArticleDOI
Identification of c-MYC as a Target of the APC Pathway
Tong-Chuan He,Andrew B. Sparks,Carlo Rago,Heiko Hermeking,Leigh Zawel,Luis T. da Costa,Patrice J. Morin,Bert Vogelstein,Kenneth W. Kinzler +8 more
TL;DR: The c-MYC oncogene is identified as a target gene in this signaling pathway and shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c- MYC promoter.
Journal ArticleDOI
Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC
Patrice J. Morin,Andrew B. Sparks,Vladimir Korinek,Nick Barker,Hans Clevers,Bert Vogelstein,Kenneth W. Kinzler +6 more
TL;DR: Results indicate that regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β- catenin.
Journal ArticleDOI
Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma
Vladimir Korinek,Nick Barker,Patrice J. Morin,Dick F. van Wichen,Roel A. de Weger,Kenneth W. Kinzler,Bert Vogelstein,Hans Clevers +7 more
TL;DR: Constitutive transcription of Tcf target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium.
Journal ArticleDOI
Functional interaction of beta-catenin with the transcription factor LEF-1.
Jürgen Behrens,von Kries Jp,Michael Kühl,Bruhn L,Bruhn L,Doris Wedlich,Rudolf Grosschedl,Rudolf Grosschedl,Walter Birchmeier +8 more
TL;DR: β-catenin regulates gene expression by direct interaction with transcription factors such as LEF-1, providing a molecular mechanism for the transmission of signals from cell-adhesion components or wnt protein to the nucleus.