β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo

Abstract

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

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank Robert Wersto, Francis J. Chrest, and Cuong Nguyen for expert cell sorting of thymocyte subpopulations; Donna Tignor, Dawn Phillips, Dawn Nines, Heather Breighner, Anna Butler, Crystal Gifford, and Ernest Dabney for maintaining animals; Shengyuan Luo and his group for genotyping animals; Susanne Golech and Dot Bertak for help in immunohistochemistry; and Linda Barenboim-Stapleton for preparation of SKY kits and chromosome-painting probes.

This research was supported by the Intramural Research Programs of the National Institute on Aging and the National Cancer Institute at the National Institutes of Health.