Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53.
Several proteins encoded by DNA tumor viruses are thought to disrupt cellular growth control by interacting with key cellular proteins, such as p53 and pRB, that normally function to regulate cell growth. However, the biological consequences of intracellular complexing between the viral oncoproteins and cellular proteins have remained unclear. Such complexes could either facilitate functional inactivation of the cellular proteins, leading to a loss-of-function phenotype, or could activate new functions, leading to a gain-of-function phenotype. Here we demonstrate that the simian virus 40 large tumor (T) antigen produces a loss-of-p53-function phenotype when introduced into the thymocytes of transgenic mice. Like thymocytes from the recently characterized p53-null mice, thymocytes from transgenic mice expressing a T-antigen variant capable of binding to p53 are resistant to irradiation-induced apoptosis. Thymocytes from transgenic mice expressing a mutant T antigen that is unable to complex p53, but retains the ability to complex the pRB and p107 proteins, retain sensitivity to irradiation. We further demonstrate that although irradiation-induced apoptosis is impaired by T antigen, clonal deletion of autoreactive thymocytes via p53-independent apoptosis is not perturbed by T antigen. These results provide convincing evidence that T antigen inactivates p53 in thymocytes in vivo and suggest a mechanism by which T antigen predisposes thymocytes to tumorigenesis in T antigen-transgenic mice.
McCarthy
S A
SA
Department of Surgery, University of Pittsburgh, PA 15260.
Symonds
H S
HS
Van Dyke
T
T
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D017637:Clonal Deletion; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D016158:Genes, p53; D016399:Lymphoma, T-Cell / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000737:chemistry*; D013950:Thymus Gland / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000952:Antigens, Polyomavirus Transforming; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53