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No requirement for V(D)J recombination in p53-deficient thymic lymphoma
1Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA.
Abstract:
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 TgTDeltaN 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 TgTDeltaN 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.
Insights
The p53 tumor suppressor pathway is activated by cellular stress, but the exact signals are unknown. This study found that V(D)J recombination does not trigger p53-dependent apoptosis in thymocytes, indicating other signals are involved in tumor suppression.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- The p53 tumor suppressor is crucial for preventing cancer, responding to cellular stress signals.
- In mouse thymocytes, V(D)J recombination of T-cell receptor (TCR) loci was hypothesized to trigger p53-dependent apoptosis and tumor suppression.
- Inactivation of p53 can lead to tumorigenesis, potentially by allowing V(D)J recombination-driven mutations in cancer genes.
Purpose of the Study:
- To investigate whether V(D)J recombination serves as a DNA damage signal triggering p53-dependent tumor suppression in mouse thymocytes.
- To determine the role of V(D)J recombination in thymoma development in mice with p53 deficiency.
- To explore alternative mechanisms of p53-mediated tumor suppression in thymocytes.
Main Methods:
- Utilized mice with p53 deficiency and deficiencies in recombination-activating gene (RAG)-1 or RAG-2 to block V(D)J recombination.
- Employed TgTDeltaN transgenic mice with thymocyte-specific p53 inactivation to study thymoma development.
- Analyzed thymoma development, latency, and frequency in mice with manipulated V(D)J recombination and p53 status.
- Performed karyotype and chromosome painting analyses on p53-deficient thymomas.
Main Results:
- Mice with p53 deficiency and impaired V(D)J recombination did not show impaired thymoma development.
- V(D)J recombination was dispensable for thymoma development, although its suppression caused a slight delay.
- Suppressing V(D)J recombination by expressing rearranged TCR transgenes led to thymoma development with reduced latency in TgTDeltaN mice.
- Karyotype analyses revealed abundant aneuploidy but no TCR gene translocations in p53-deficient thymomas.
Conclusions:
- Contrary to the prevailing hypothesis, V(D)J recombination is not the primary signal for p53-dependent tumor suppression in thymocytes.
- Tumorigenesis in this model occurs through mechanisms distinct from T-cell receptor translocation oncogene activation.
- Alternative, yet unidentified, DNA damage signals likely activate p53-mediated tumor suppression in thymocytes.