Molecular basis for the tissue specificity of β-catenin oncogenesis.
Wnt-β-catenin-T-cell factor signaling is causally linked to c-myc-dependent tumorigenesis in mouse and human colon epithelial cells. By contrast, β-catenin is not similarly associated with oncogenic transformation of other tissues, including T cells. The molecular basis for tissue specificity of β-catenin-dependent oncogenesis is unknown. Here, we demonstrate that adenomatous polyposis coli mutant APC(Min/+) mice, which have increased expression of β-catenin in all tissues, develop severe intestinal neoplasia, but fail to develop thymic lymphoma. Whereas β-catenin-dependent signals elicit a proliferative response from intestinal cells, thymocytes experience oncogene-induced senescence (OIS), growth arrest and apoptosis. We demonstrate that the differential cellular response of thymocytes and intestinal epithelial cells is a direct consequence of the gene expression elicited by β-catenin expression in each tissue. We find that whereas intestinal cells induce genes that promote proliferation thymocytes induce expression of genes associated with OIS, growth arrest and p53-dependent apoptosis. We correlate gene expression pattern with the role β-catenin plays in the development of each tissue and suggest that susceptibility of transformation by β-catenin is intimately related to its function during development. We propose that when oncogenes are used as signaling molecules, safety nets in the form of OIS, growth arrest and apoptosis prevent accidental transformation.
Lymphocyte Development Unit, Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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Sharma
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Sen
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism*; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D060168:Thymocytes / Q000378:metabolism; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051176:beta Catenin