Beta-catenin expression results in p53-independent DNA damage and oncogene-induced senescence in prelymphomagenic thymocytes in vivo.
The expression of beta-catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising that the transgenic expression of oncogenic beta-catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report, we demonstrate that this is because the expression of oncogenic beta-catenin induces DNA damage, growth arrest, oncogene-induced senescence (OIS), and apoptosis of immature thymocytes. In p53-deficient mice, the expression of oncogenic beta-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. beta-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 beta-catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic beta-catenin.
Xu
Mai
M
Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, 5600 Nathan Shock Drive, Room 4B08 GRC, Baltimore, MD 21224, USA.
Yu
Qing
Q
Subrahmanyam
Ramesh
R
Difilippantonio
Michael J
MJ
Ried
Thomas
T
Sen
Jyoti Misra
JM
D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D020732:Cytogenetic Analysis; D004249:DNA Damage; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009857:Oncogenes / Q000502:physiology*; D013223:Statistics as Topic; D013950:Thymus Gland / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D001616:beta-Galactosidase