Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Apr 26;91(9):3979–3983. doi: 10.1073/pnas.91.9.3979

Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53.

S A McCarthy 1, H S Symonds 1, T Van Dyke 1
PMCID: PMC43706  PMID: 8171023

Abstract

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.

Full text

PDF
3982

Images in this article

3980Image
on p.3980
3981Image
on p.3981
3982Image
on p.3982
3982Image
on p.3982

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acha-Orbea H., Palmer E. Mls--a retrovirus exploits the immune system. Immunol Today. 1991 Oct;12(10):356–361. doi: 10.1016/0167-5699(91)90066-3. [DOI] [PubMed] [Google Scholar]
  2. Bargonetti J., Friedman P. N., Kern S. E., Vogelstein B., Prives C. Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell. 1991 Jun 14;65(6):1083–1091. doi: 10.1016/0092-8674(91)90560-l. [DOI] [PubMed] [Google Scholar]
  3. Cairns J. S., Mainwaring M. S., Cacchione R. N., Walker J. A., McCarthy S. A. Regulation of apoptosis in thymocytes. Thymus. 1993 May;21(3):177–193. [PubMed] [Google Scholar]
  4. Chen J. D., Van Dyke T. Uniform cell-autonomous tumorigenesis of the choroid plexus by papovavirus large T antigens. Mol Cell Biol. 1991 Dec;11(12):5968–5976. doi: 10.1128/mcb.11.12.5968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen J., Tobin G. J., Pipas J. M., Van Dyke T. T-antigen mutant activities in vivo: roles of p53 and pRB binding in tumorigenesis of the choroid plexus. Oncogene. 1992 Jun;7(6):1167–1175. [PubMed] [Google Scholar]
  6. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  7. Cohen J. J., Duke R. C. Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol. 1984 Jan;132(1):38–42. [PubMed] [Google Scholar]
  8. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  9. Farmer G., Bargonetti J., Zhu H., Friedman P., Prywes R., Prives C. Wild-type p53 activates transcription in vitro. Nature. 1992 Jul 2;358(6381):83–86. doi: 10.1038/358083a0. [DOI] [PubMed] [Google Scholar]
  10. Garvin A. M., Abraham K. M., Forbush K. A., Farr A. G., Davison B. L., Perlmutter R. M. Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen. Int Immunol. 1990;2(2):173–180. doi: 10.1093/intimm/2.2.173. [DOI] [PubMed] [Google Scholar]
  11. Hollingsworth R. E., Jr, Hensey C. E., Lee W. H. Retinoblastoma protein and the cell cycle. Curr Opin Genet Dev. 1993 Feb;3(1):55–62. doi: 10.1016/s0959-437x(05)80341-7. [DOI] [PubMed] [Google Scholar]
  12. Kessis T. D., Slebos R. J., Nelson W. G., Kastan M. B., Plunkett B. S., Han S. M., Lorincz A. T., Hedrick L., Cho K. R. Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3988–3992. doi: 10.1073/pnas.90.9.3988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kuerbitz S. J., Plunkett B. S., Walsh W. V., Kastan M. B. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7491–7495. doi: 10.1073/pnas.89.16.7491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  15. Lechner M. S., Mack D. H., Finicle A. B., Crook T., Vousden K. H., Laimins L. A. Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO J. 1992 Aug;11(8):3045–3052. doi: 10.1002/j.1460-2075.1992.tb05375.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  17. Levine A. J. The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses. Virology. 1990 Aug;177(2):419–426. doi: 10.1016/0042-6822(90)90505-l. [DOI] [PubMed] [Google Scholar]
  18. Lin D., Shields M. T., Ullrich S. J., Appella E., Mercer W. E. Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9210–9214. doi: 10.1073/pnas.89.19.9210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. doi: 10.1016/0092-8674(92)90243-6. [DOI] [PubMed] [Google Scholar]
  20. Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  21. Martinez J., Georgoff I., Martinez J., Levine A. J. Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein. Genes Dev. 1991 Feb;5(2):151–159. doi: 10.1101/gad.5.2.151. [DOI] [PubMed] [Google Scholar]
  22. McCarthy S. A., Cacchione R. N., Mainwaring M. S., Cairns J. S. The effects of immunosuppressive drugs on the regulation of activation-induced apoptotic cell death in thymocytes. Transplantation. 1992 Sep;54(3):543–547. doi: 10.1097/00007890-199209000-00029. [DOI] [PubMed] [Google Scholar]
  23. Michalovitz D., Halevy O., Oren M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell. 1990 Aug 24;62(4):671–680. doi: 10.1016/0092-8674(90)90113-s. [DOI] [PubMed] [Google Scholar]
  24. Mietz J. A., Unger T., Huibregtse J. M., Howley P. M. The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein. EMBO J. 1992 Dec;11(13):5013–5020. doi: 10.1002/j.1460-2075.1992.tb05608.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nikolić-Zugić J. Phenotypic and functional stages in the intrathymic development of alpha beta T cells. Immunol Today. 1991 Feb;12(2):65–70. doi: 10.1016/0167-5699(91)90160-u. [DOI] [PubMed] [Google Scholar]
  26. Oren M., Maltzman W., Levine A. J. Post-translational regulation of the 54K cellular tumor antigen in normal and transformed cells. Mol Cell Biol. 1981 Feb;1(2):101–110. doi: 10.1128/mcb.1.2.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Oren M. p53: the ultimate tumor suppressor gene? FASEB J. 1992 Oct;6(13):3169–3176. doi: 10.1096/fasebj.6.13.1397838. [DOI] [PubMed] [Google Scholar]
  28. Owens G. P., Hahn W. E., Cohen J. J. Identification of mRNAs associated with programmed cell death in immature thymocytes. Mol Cell Biol. 1991 Aug;11(8):4177–4188. doi: 10.1128/mcb.11.8.4177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pipas J. M., Peden K. W., Nathans D. Mutational analysis of simian virus 40 T antigen: isolation and characterization of mutants with deletions in the T-antigen gene. Mol Cell Biol. 1983 Feb;3(2):203–213. doi: 10.1128/mcb.3.2.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sarnow P., Ho Y. S., Williams J., Levine A. J. Adenovirus E1b-58kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells. Cell. 1982 Feb;28(2):387–394. doi: 10.1016/0092-8674(82)90356-7. [DOI] [PubMed] [Google Scholar]
  31. Scheffner M., Werness B. A., Huibregtse J. M., Levine A. J., Howley P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990 Dec 21;63(6):1129–1136. doi: 10.1016/0092-8674(90)90409-8. [DOI] [PubMed] [Google Scholar]
  32. Shaw P., Bovey R., Tardy S., Sahli R., Sordat B., Costa J. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4495–4499. doi: 10.1073/pnas.89.10.4495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Suda Y., Aizawa S., Hirai S., Inoue T., Furuta Y., Suzuki M., Hirohashi S., Ikawa Y. Driven by the same Ig enhancer and SV40 T promoter ras induced lung adenomatous tumors, myc induced pre-B cell lymphomas and SV40 large T gene a variety of tumors in transgenic mice. EMBO J. 1987 Dec 20;6(13):4055–4065. doi: 10.1002/j.1460-2075.1987.tb02751.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Symonds H. S., McCarthy S. A., Chen J., Pipas J. M., Van Dyke T. Use of transgenic mice reveals cell-specific transformation by a simian virus 40 T-antigen amino-terminal mutant. Mol Cell Biol. 1993 Jun;13(6):3255–3265. doi: 10.1128/mcb.13.6.3255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sáenz Robles M. T., Symonds H., Chen J., Van Dyke T. Induction versus progression of brain tumor development: differential functions for the pRB- and p53-targeting domains of simian virus 40 T antigen. Mol Cell Biol. 1994 Apr;14(4):2686–2698. doi: 10.1128/mcb.14.4.2686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wyllie A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]
  37. Yew P. R., Berk A. J. Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. Nature. 1992 May 7;357(6373):82–85. doi: 10.1038/357082a0. [DOI] [PubMed] [Google Scholar]
  38. Yin Y., Tainsky M. A., Bischoff F. Z., Strong L. C., Wahl G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell. 1992 Sep 18;70(6):937–948. doi: 10.1016/0092-8674(92)90244-7. [DOI] [PubMed] [Google Scholar]
  39. Yonish-Rouach E., Resnitzky D., Lotem J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991 Jul 25;352(6333):345–347. doi: 10.1038/352345a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES