1887

Abstract

The p51/p63/KET proteins were identified based on their strong homology to the tumour suppressor p53 and a related set of proteins termed p73. All these protein species were shown to activate transcription from at least some p53-responsive promoters. To evaluate a possible role of the transcriptionally active splicing variant p51A/p63γ in tumour suppression, we determined whether viral oncoproteins that inactivate p53 might also target p51A. Neither the large T-antigen of simian vacuolating virus 40 (SV40) nor the E6 protein from human papillomavirus type 18 were found to inhibit p51A-mediated transcription, whereas they strongly suppress the activity of p53. Further, SV40 T-antigen directly interacts with p53 but not detectably with p51A. Finally, a cytoplasmic mutant (K128A) of SV40 T-antigen relocalizes p53 from the nucleus to the cytoplasm, but p51A remains in the nucleus when coexpressed with cytoplasmic T-antigen. These results strongly suggest that the inhibitory effect of these viral oncoproteins is specific for p53 and does not measurably affect p51A. Thus, unlike p53, p51A does not appear to be a necessary target in virus-induced cell transformation and may not exert a role comparable to p53 in tumour suppression.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-80-12-3251
1999-12-01
2019-12-12
Loading full text...

Full text loading...

/deliver/fulltext/jgv/80/12/0803251.html?itemId=/content/journal/jgv/10.1099/0022-1317-80-12-3251&mimeType=html&fmt=ahah

References

  1. Bian, J. & Sun, Y. ( 1997; ). p53CP, a putative p53 competing protein that specifically binds to the consensus p53 DNA binding sites: a third member of the p53 family? Proceedings of the National Academy of Sciences, USA 94, 14753-14758.[CrossRef]
    [Google Scholar]
  2. De Laurenzi, V., Costanzo, A., Barcaroli, D., Terrinoni, A., Falco, M., Annicchiarico-Petruzzelli, M., Levrero, M. & Melino, G. ( 1998; ). Two new p73 splice variants, gamma and delta, with different transcriptional activity. Journal of Experimental Medicine 188, 1763-1768.[CrossRef]
    [Google Scholar]
  3. Dobbelstein, M. & Roth, J. ( 1998; ). The large T antigen of simian virus 40 binds and inactivates p53 but not p73. Journal of General Virology 79, 3079-3083.
    [Google Scholar]
  4. Dobbelstein, M., Wienzek, S., König, C. & Roth, J. ( 1999; ). Inactivation of the p53-homologue p73 by the mdm2-oncoprotein. Oncogene 18, 2101-2106.[CrossRef]
    [Google Scholar]
  5. Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A.Jr, Butel, J. S. & Bradley, A. ( 1992; ). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215-221.[CrossRef]
    [Google Scholar]
  6. Freedman, D. A., Epstein, C. B., Roth, J. C. & Levine, A. J. ( 1997; ). A genetic approach to mapping the p53 binding site in the MDM2 protein. Molecular Medicine 3, 248-259.
    [Google Scholar]
  7. Henning, W., Rohaly, G., Kolzau, T., Knippschild, U., Maacke, H. & Deppert, W. ( 1997; ). MDM2 is a target of simian virus 40 in cellular transformation and during lytic infection. Journal of Virology 71, 7609-7618.
    [Google Scholar]
  8. Higashino, F., Pipas, J. M. & Shenk, T. ( 1998; ). Adenovirus e4orf6 oncoprotein modulates the function of the p53-related protein, p73. Proceedings of the National Academy of Sciences, USA 95, 15683-15687.[CrossRef]
    [Google Scholar]
  9. Huibregtse, J. M., Scheffner, M. & Howley, P. M. ( 1991; ). A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO Journal 10, 4129-4135.
    [Google Scholar]
  10. Jost, C. A., Marin, M. C. & Kaelin, W. G.Jr ( 1997; ). p73 is a human p53-related protein that can induce apoptosis. Nature 389, 191-194.[CrossRef]
    [Google Scholar]
  11. Kaelin, W. G.Jr ( 1998; ). Another p53 Doppelganger? Science 281, 57-58.[CrossRef]
    [Google Scholar]
  12. Kaghad, M., Bonnet, H., Yang, A., Creancier, L., Biscan, J. C., Valent, A., Minty, A., Chalon, P., Lelias, J. M., Dumont, X., Ferrara, P., McKeon, F. & Caput, D. ( 1997; ). Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809-819.[CrossRef]
    [Google Scholar]
  13. Kalderon, D., Richardson, W. D., Markham, A. F. & Smith, A. E. ( 1984a; ). Sequence requirements for nuclear location of simian virus 40 large-T antigen. Nature 311, 33-38.[CrossRef]
    [Google Scholar]
  14. Kalderon, D., Roberts, B. L., Richardson, W. D. & Smith, A. E. ( 1984b; ). A short amino acid sequence able to specify nuclear location. Cell 39, 499-509.[CrossRef]
    [Google Scholar]
  15. Levine, A. J. ( 1997; ). p53, the cellular gatekeeper for growth and division. Cell 88, 323-331.[CrossRef]
    [Google Scholar]
  16. Lin, J., Chen, J., Elenbaas, B. & Levine, A. J. ( 1994; ). Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes & Development 8, 1235-1246.[CrossRef]
    [Google Scholar]
  17. Mai, M., Yokomizo, A., Qian, C., Yang, P., Tindall, D. J., Smith, D. I. & Liu, W. ( 1998; ). Activation of p73 silent allele in lung cancer. Cancer Research 58, 2347-2349.
    [Google Scholar]
  18. Marin, M. C., Jost, C. A., Irwin, M. S., DeCaprio, J. A., Caput, D. & Kaelin, W. G.Jr ( 1998; ). Viral oncoproteins discriminate between p53 and the p53 homolog p73. Molecular and Cellular Biology 18, 6316-6324.
    [Google Scholar]
  19. Mills, A. A., Zheng, B., Wang, X. J., Vogel, H., Roop, D. R. & Bradley, A. ( 1999; ). p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708-713.[CrossRef]
    [Google Scholar]
  20. Nomoto, S., Haruki, N., Kondo, M., Konishi, H. & Takahashi, T. ( 1998; ). Search for mutations and examination of allelic expression imbalance of the p73 gene at 1p36.33 in human lung cancers. Cancer Research 58, 1380-1383.
    [Google Scholar]
  21. Osada, M., Ohba, M., Kawahara, C., Ishioka, C., Kanamaru, R., Katoh, I., Ikawa, Y., Nimura, Y., Nakagawara, A., Obinata, M. & Ikawa, S. ( 1998; ). Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nature Medicine 4, 839-843.[CrossRef]
    [Google Scholar]
  22. Prabhu, N. S., Somasundaram, K., Satyamoorthy, K., Herlyn, M. & El-Deiry, W. S. ( 1998; ). p73, unlike p53, suppresses growth and induces apoptosis of human papillomavirus E6-expressing cancer cells. International Journal of Oncology 13, 5-9.
    [Google Scholar]
  23. Reichelt, M., Zang, K. D., Seifert, M., Welter, C. & Ruffing, T. ( 1999; ). The yeast two-hybrid system reveals no interaction between p73 alpha and SV40 large T-antigen. Archives of Virology 144, 621-626.[CrossRef]
    [Google Scholar]
  24. Roth, J., König, C., Wienzek, S., Weigel, S., Ristea, S. & Dobbelstein, M. ( 1998; ). Inactivation of p53 but not p73 by adenovirus type 5 E1B 55-kilodalton and E4 34-kilodalton oncoproteins. Journal of Virology 72, 8510-8516.
    [Google Scholar]
  25. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. ( 1990; ). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129-1136.[CrossRef]
    [Google Scholar]
  26. Scheffner, M., Huibregtse, J. M., Vierstra, R. D. & Howley, P. M. ( 1993; ). The HPV-16 E6 and E6–AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75, 495-505.[CrossRef]
    [Google Scholar]
  27. Schmale, H. & Bamberger, C. ( 1997; ). A novel protein with strong homology to the tumor suppressor p53. Oncogene 15, 1363-1367.[CrossRef]
    [Google Scholar]
  28. Senoo, M., Seki, N., Ohira, M., Sugano, S., Watanabe, M., Tachibana, M., Tanaka, T., Shinkai, Y. & Kato, H. ( 1998; ). A second p53-related protein, p73L, with high homology to p73. Biochemical and Biophysical Research Communications 248, 603-607.[CrossRef]
    [Google Scholar]
  29. Steegenga, W. T., Shvarts, A., Riteco, N., Bos, J. L. & Jochemsen, A. G. ( 1999; ). Distinct regulation of p53 and p73 activity by adenovirus E1A, E1B, and e4orf6 proteins. Molecular and Cellular Biology 19, 3885-3894.
    [Google Scholar]
  30. Sunahara, M., Ichimiya, S., Nimura, Y., Takada, N., Sakiyama, S., Sato, Y., Todo, S., Adachi, W., Amano, J. & Nakagawara, A. ( 1998; ). Mutational analysis of the p73 gene localized at chromosome 1p36.3 in colorectal carcinomas. International Journal of Oncology 13, 319-323.
    [Google Scholar]
  31. Takahashi, H., Ichimiya, S., Nimura, Y., Watanabe, M., Furusato, M., Wakui, S., Yatani, R., Aizawa, S. & Nakagawara, A. ( 1998; ). Mutation, allelotyping, and transcription analyses of the p73 gene in prostatic carcinoma. Cancer Research 58, 2076-2077.
    [Google Scholar]
  32. Trink, B., Okami, K., Wu, L., Sriuranpong, V., Jen, J. & Sidransky, D. ( 1998; ). A new human p53 homologue. Nature Medicine 4, 747-748.[CrossRef]
    [Google Scholar]
  33. Werness, B. A., Levine, A. J. & Howley, P. M. ( 1990; ). Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76-79.[CrossRef]
    [Google Scholar]
  34. Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D. & McKeon, F. ( 1998; ). p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Molecular Cell 2, 305-316.[CrossRef]
    [Google Scholar]
  35. Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C., Sharpe, A., Caput, D., Crum, C. & McKeon, F. ( 1999; ). p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714-718.[CrossRef]
    [Google Scholar]
  36. Zeng, X., Levine, A. J. & Lu, H. ( 1998; ). Non-p53 p53RE binding protein, a human transcription factor functionally analogous to P53. Proceedings of the National Academy of Sciences, USA 95, 6681-6686.[CrossRef]
    [Google Scholar]
  37. Zeng, X., Chen, L., Jost, C. A., Maya, R., Keller, D., Wang, X., Kaelin, W. G.Jr, Oren, M., Chen, J. & Lu, H. ( 1999; ). MDM2 suppresses p73 function without promoting p73 degradation. Molecular and Cellular Biology 19, 3257-3266.
    [Google Scholar]
  38. Zhu, J., Jiang, J., Zhou, W. & Chen, X. ( 1998; ). The potential tumor suppressor p73 differentially regulates cellular p53 target genes. Cancer Research 58, 5061-5065.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-80-12-3251
Loading
/content/journal/jgv/10.1099/0022-1317-80-12-3251
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error