Molecular basis for the tissue specificity of β-catenin oncogenesis.

Oncogene. 2013 Apr 11;32(15):1901-9.

Sharma A, Sen JM.

Lymphocyte Development Unit, Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

Abstract

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.

PMID: 22689057

 

Supplement

During normal intestinal renewal, intestinal precursor cells induce β-catenin in response to a Wnt gradient to promote proliferation. As the developing cells migrate away from the crypt Wnt gradient diminishes leading to decrease in proliferation, which allows for controlled expression of β-catenin to regulate cellularity. However, in the intestine abnormal induction of β-catenin due to mutations in the genes of the Wnt-β-catenin-TCF4 pathway results in uncontrolled proliferation. By contrast, in thymocytes β-catenin is induced transiently and provides signals for maturation and then thymocytes must turn the protein expression down for further development. Failure to turn down expression of β-catenin during maturation, leads to a developmental block in thymocytes at the pre-DP stage. The developmentally stalled thymocytes experience additional events, become pre-cancerous and experience OIS. We have previously also reported that stalled cells are growth arrested and are then removed from the developmental pool by p53-dependent apoptosis thereby protecting developing T cells from β-catenin dependent oncogenesis. Importantly, this protective response is strictly restricted to the immature thymocytes that utilize β-catenin for maturational signals. In light of these observations we suggest that oncogenic function of β-catenin is orchestrated by the tissue-specific response of the cells and intimately related to the role it plays in the development of the tissue. We propose that when oncogenes are used to provide developmental signals ‘safety nets’ comprising of OIS, growth arrest and apoptosis are put in place to prevent oncogenesis. In conclusion, tissue specificity of oncogenesis is defined by tumors being confined to a few tissues despite expression of oncogenes in multiple tissues. Data provided in this paper provides a novel perspective on the molecular basis for the difference in the response of intestinal epithelial cells and thymocytes to β-catenin expression and the disparate outcomes. Based on the data presented in this paper we propose that the oncogenic function of β-catenin is intimately related to the role it plays in the development of the particular tissue. Finally, as inhibitors of β-catenin pathway and inducers of p53 function have been defined and are available for use in clinical situations these observations provide new opportunities for designing tissue specific therapeutic strategies for treating the human cancers.

Archna Sharma-2

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