β-Catenin as Oncogene--The Smoking Gun

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Science  21 Mar 1997:
Vol. 275, Issue 5307, pp. 1752
DOI: 10.1126/science.275.5307.1752

Science and detective fiction share many features: a mysterious event, suspects with motive and opportunity, and a collection of evidence. The best cases end with a smoking gun, clinching the guilt of a suspect. This issue of Science contains three such smoking guns (1, 2), on pages 1784, 1787, and 1790, firmly establishing β-catenin as an accomplice in causing colon cancer and as a strong suspect in melanoma. As in many crimes, however, β-catenin did not act alone but with a set of partners.

Suspicion initially fell on β-catenin through association with a known criminal (3). Adenomatous polyposis coli (APC), familial predisposition to colon cancer, is caused by APC mutations. [HN3], [HN4], [HN5] APC encodes a large multidomain protein that binds β-catenin. APC, together with the serine-threonine glycogen synthase kinase (GSK)-3β, regulates the levels of free β-catenin. Normally these levels are quite low, as APC and GSK bind β-catenin, targeting it for destruction. However, in APC mutant colon cells, degradation is disrupted, and levels of free β-catenin rise dramatically. Thus β-catenin is a suspect as the cause of the benign colon polyps resulting from APC mutations.

β-Catenin and its homolog Armadillo in the fruitfly Drosophila are multifunctional proteins (4): Both are key components of cell-cell adhesive junctions and also participate in transduction of Wingless-Wnt cell-cell signals. Wingless-Wnt signals direct many key developmental decisions, regulating anterior-posterior and dorsal-ventral pattern in both flies and vertebrates. [HN6] β-Catenin-Armadillo is a key effector of signal transduction. In the absence of signal, levels of free β-catenin-Armadillo are low; the Wingless-Wnt signal stabilizes β-catenin-Armadillo.

Incriminating β-catenin.

In normal colon cells, GSK-3β and APC target β-catenin for degradation. In both normal embyronic cells and colon or melanoma cells, β-catenin is not degraded and accumulates, binding to Tcf-Lef and triggering gene expression.

Illustration: K. Sutliff

Until recently, the trail ended there. A breakthrough came with the discovery of a new family of protein partners for β-catenin, DNA binding proteins of the T cell factor-lymphoid enhancer factor (Tcf-Lef) family (5). These proteins bind to β-catenin in vivo and when misexpressed in Xenopus eggs alter dorsal-ventral polarity, suggesting a possible role in Wnt signaling. [HN7] Extending this work in Drosophila, three groups using different approaches provided compelling evidence that a fly Tcf family member, dTcf (also called pangolin), plays a key role in transduction of Wingless signal in vivo (6). Loss-of-function mutations in dTcf disrupt normal anterior-posterior patterning, and epistasis analysis places dTcf downstream of armadillo in the Wingless signal transduction pathway. Mutations in dTcf block expression of Wingless-responsive genes, and analysis of a Wingless-response element revealed an essential dTcf binding site. dTcf alone is inactive, even though it binds DNA. The active transcription factor is a bipartite complex, with dTcf contributing the DNA binding domain and Armadillo a potential transactivation domain.

This brings us back to the scene of the crime, suggesting that β-catenin cooperates with Tcf family proteins to alter gene expression in human colon. This thesis was tested and extended in the three reports in this issue. In colon cancer cell lines (1), and surprisingly also in many melanoma cell lines (2), high levels of free β-catenin drive formation of complexes with Tcf-4 or Lef-1, activating gene expression. The genes activated may include those stimulating cell proliferation or inhibiting apoptosis. There are at least two ways to increase levels of free β-catenin. The first is due to the previously described mutations in APC. The second is to mutate β-catenin itself, altering an NH2-terminal domain that down-regulates β-catenin stability in cell lines (7) and up-regulates Wg-Wnt signaling ability in vivo (6, 8). Thus β-catenin itself is an oncogene.

These data firmly establish APC as a negative regulator of β-catenin signaling. However, APC likely has additional abilities. It localizes in vivo to the end of cell processes, clustering at the tips of microtubule bundles (9). This suggests that APC regulates migration by regulation of the cytoskeleton. This model was tested by manipulating APC activity in cultured epithelial cells. APC promotes cell migration and regulates cell adhesion both of individual cells and of cells cooperating to form epithelial tubules (10). This is consistent with the behavior of normal colon epithelial cells, which migrate from crypt to villus, where they die and are sloughed off. These data also suggest that free β-catenin prevents APC from stimulating migration. The APC-β-catenin complex appears to be a binary switch. In the absence of outside input, APC mediates β-catenin degradation and promotes cell migration. In contrast, in the presence of Wg-Wnt signal, β-catenin is stabilized (perhaps by inactivation of GSK kinase). This inactivates APC, down-regulating migration and promoting formation of β-catenin-Tcf complexes, thereby altering gene expression. Mutations in either APC or β-catenin mimic Wg-Wnt signaling, stimulating proliferation or antagonizing apoptosis.

HyperNotes Related Resources on the World Wide Web

FlyBase, a comprehensive database for information on the genetics and biology of Drosophila provides basic information on the armadillo gene.

The Drosophila Virtual Library by Gerard Manning is a component of the World Wide Web Virtual Library Biological Sciences. It includes an introductory page which describes Drosophila and the organism's importance in biological research, links to information about Drosophila genetics and development, and links to Web pages of research groups studying Drosophila and other information on the Web.

The Xenopus Molecular Marker Resource (XMMR) provides a variety of resources related to genetic markers in Xenopus.

The Amphibian Embryology Tutorial is a multimedia tutorial on development in amphibians. It includes illustrations of the early developmental stages of Xenopus.

The stages of Xenopus embryonic development provides illustrations of the embryonic development in Xenopus. The images are reproduced, with permission, from Normal Table of Xenopus laevis (Daudin), edited by P.D. Nieuwkoop and J. Faber (Garland Publishing Inc., 1967).

The World Wide Web Virtual Library: Biosciences points to virtual library pages for Developmental Biology, Biochemistry and Molecular Biology, Genetics, and other topics related to this article. Each of these pages presents a long list of Web resources.

CSUBIOWEB, the California State University Biological Sciences Web server, provides links to other Web sites on developmental biology and related areas.

Bill Wasserman's Developmental Biology Page is a categorized list of Web resources related to developmental biology.

Society for Developmental Biology's Educational Resources is a section of the Society for Developmental Biology Web site with information related to teaching and learning about developmental biology for teachers and students.

1. Mark Peifer's Web page includes a synopsis of his research in developmental genetics of Drosophila.

2. Department of Biology, University of North Carolina at Chapel Hill.

3. Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders authored and edited by Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere, and developed for the World Wide Web by NCBI, the National Center for Biotechnology Information. The chapter on adenomatous polyposis of the colon presents a general description, information on inheritance, cytogenetics, diagnosis of the condition, references to be published, literature, and other information. Links to references in MEDLINE are included.

4. Tumor Suppressors and Cancer by Michael W. King describes familial adenomatosis polyposis and the APC gene.

5. Etiology of Cancer: Carcinogenesis, developed at Cornell Medical College, outlines the causes of cancer and includes a discussion of familial adenomatous polyposis.

6. The Interactive Fly, a guide to Drosophila genes and their roles in development provides an introduction to the armadillo gene. This introduction includes a biological overview and discussions of evolutionary homologs in Xenopus and other species, regulation of the gene, its developmental biology, and effects of mutation. References to recent literature on the armadillo gene are available.

7. The Virtual Embryo provides a link to a description by Randall T. Moon of the role of beta-catenin in Xenopus development. Also included are an introduction to developmental biology, maintained at the University of Calgary, and a developmental biology tutorial.


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