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Mol Cell Biol, June 1998, p. 3495-3501, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

No Requirement for V(D)J Recombination in p53-Deficient Thymic Lymphoma

Mai-Jing Liao,1 Xiao-Xiang Zhang,2 Rosina Hill,3 Jingjin Gao,1 Mazin B. Qumsiyeh,2 Warren Nichols,3 and Terry Van Dyke1,*

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill Medical School, Chapel Hill, North Carolina 275991; Cytogenetics Laboratory, Duke University Medical Center, Durham, North Carolina 277102; and Genetic and Cellular Toxicology, Merck Research Laboratories, West Point, Pennsylvania 194863

Received 21 January 1998/Returned for modification 20 February 1998/Accepted 2 March 1998

The p53 tumor suppressor is activated in response to a variety of cellular stress signals, although specific in vivo signals that trigger tumor suppression are unknown. In mouse thymocytes, where p53 inactivation leads to tumorigenesis, several observations suggest that V(D)J recombination of T-cell receptor (TCR) loci could provide a DNA damage signal triggering p53-dependent apoptosis and tumor suppression. Inactivation of p53 would allow V(D)J driven mutation of additional cancer genes, facilitating tumorigenesis. Here, we show that mice with a p53 deficiency in thymocytes and unable to carry out V(D)J recombination are not impaired in the development of thymoma. Recombination-activating gene (RAG) deficiencies were introduced into both p53-/- mice and TgTDelta N transgenic mice, a strain in which 100% of the mice develop thymoma due to thymocyte-specific inactivation of p53 by a simian virus 40 T-antigen variant. V(D)J recombination was dispensable for tumorigenesis since thymomas developed with or without the RAG-1 or RAG-2 gene, although some delay was observed. When V(D)J recombination was suppressed by expression of rearranged TCR transgenes, 100% of the TgTDelta N mice developed thymoma, surprisingly with reduced latency. Further introduction of a RAG deficiency into these mice had no impact on the timing or frequency of tumorigenesis. Finally, karyotype and chromosome painting analyses showed no evidence for TCR gene translocations in p53-deficient thymomas, although abundant aneuploidy involving frequent duplication of certain chromosomes was present. Thus, contrary to the current hypothesis, these studies indicate that signals other than V(D)J recombination promote p53 tumor suppression in thymocytes and that the mechanism of tumorigenesis is distinct from TCR translocation oncogene activation.

* Corresponding author. Mailing address: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27599. Phone: (919) 962-2145. Fax: (919) 962-4296. E-mail: tvdlab{at}med.unc.edu.

Mol Cell Biol, June 1998, p. 3495-3501, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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