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Mol. Cell. Biol. doi:10.1128/MCB.01360-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced-Senescence in Pre-lymphomagenic Thymocytes in-vivo

Lymphocyte Development Unit, Laboratory of Immunology, Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, MD 21224; Section of Cancer Genomics, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

^* To whom correspondence should be addressed. Email: Jyoti-Sen{at}NIH.GOV.

	Abstract

Expression of -Catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising when transgenic expression of oncogenic -catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report we demonstrate that this is because expression of oncogenic -catenin induces DNA damage, growth arrest, oncogene-induced-senescence (OIS) and apoptosis of immature thymocytes. In p53-deficient mice, expression of oncogenic -catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. -Catenin-induced thymic lymphomas are distinct from lymphomas that arise in p53^-/- mice. They are CD4^-CD8^- while p53-dependent lymphomas are largely CD4⁺CD8⁺, they develop at an earlier age and in the absence of c-Myc expression or Notch1 signaling. Thus, we report that oncogenic -catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic -catenin.