Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Gain of function mutations in p53

Nature Genetics volume 4, pages 42–46 (1993)Cite this article

Abstract

We report that the expression of murine or human mutant p53 proteins in cells with no endogenous p53 proteins confers new or additional phenotypes upon these cells. Mutant p53 proteins expressed in cell lines lacking p53 resulted in either enhanced tumorigenic potential in nude mice ((10)3 cells) or enhanced plating efficiency in agar cell culture (human SAOS–2 cells). Also, mutant human p53 alleles, unlike the wild–type p53 protein, could also enhance the expression of a test gene regulated by the multi–drug resistance enhancer–promoter element. These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Johnson, P. & Benchimol, S. Friend virus induced murine erythroleukaemia: The p53 locus, in Cancer Surveys 12, (ed. A.J. Levine) 137–151 (Cold Spring Harbor Press, New York, 1992).

    Google Scholar 

  2. Baker, S.J. et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinoma. Science 244, 217–221 (1989).

    Article  CAS  Google Scholar 

  3. Baker, S.J., Markowitz, S., Fearon, E.R., Willson, J.K.U. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912–915 (1990).

    Article  CAS  Google Scholar 

  4. Finlay, C.A., Hinds, P.W. & Levine, A.J. The p53 proto-oncogene can act as a suppressor of transformation. Cell 57, 1083–1093 (1989).

    Article  CAS  Google Scholar 

  5. Chen, P.-L., Chen, Y., Bookstein, R. & Lee, W.-H. Genetic mechanisms of tumour suppression by the human p53 gene. Science 250, 1576–1579 (1990).

    Article  CAS  Google Scholar 

  6. Farmer, G.E. et al. Wild-type p53 activates transcription in vitro. Nature 358, 83–86 (1992).

    Article  CAS  Google Scholar 

  7. Kern, S. et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827–32 (1992).

    Article  CAS  Google Scholar 

  8. Zambetti, G.P., Bargonetti, J., Walker, K., Prives, C. & Levine, A.J. Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element. Genes Dev. 6, 1143–1152 (1992).

    Article  CAS  Google Scholar 

  9. 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 65, 1083–1091 (1991).

    Article  CAS  Google Scholar 

  10. El-Deiry, W.S., Kern, S.E., Pietenpol, J.A., Kinzler, K.W. & Vogelstein, B. Definition of a consensus binding site for p53. Nature Genet. 1, 45–49 (1992).

    Article  CAS  Google Scholar 

  11. Funk, W.D. et al. A transcriptionally active DNA-binding site for human p53 protein complexes. Molec. cell. Biol. 12, 2866–2871 (1992).

    Article  CAS  Google Scholar 

  12. Kern, S.E. et al. Identification of p53 as a sequence-specific DNA-binding protein. Science 252, 1708–1711 (1991).

    Article  CAS  Google Scholar 

  13. Barnonetti, J. et al. Site-specific binding of wild-type p53 to cellular DMA is inhibited by SV40 T antigen and mutant p53. Genes Dev. 6, 1886–1898 (1992).

    Article  Google Scholar 

  14. Levine, A.J., Momand, J. & Finlay, C.A. The p53 tumour suppressor gene. Nature 351, 453–456 (1991).

    Article  CAS  Google Scholar 

  15. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C.C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  CAS  Google Scholar 

  16. Kern, S.E. et al. Mutant p53 proteins bind DNA abnormally in vitro. Oncogene 6, 131–136 (1991).

    CAS  Google Scholar 

  17. 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. 11, 5013–5020 (1992).

    Article  CAS  Google Scholar 

  18. Yew, P.R. & Berk, A.J. Inhibition of p53 transactivat ion required for transformation by adenovirus E1B 55 Kd protein. Nature 357, 82–85 (1992).

    Article  CAS  Google Scholar 

  19. Momand, J., Zambetti, G.P., Olson, D.C., George, D. & Levine, A.J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53 mediated transactivation. Cell 69, 1237–1245 (1992).

    Article  CAS  Google Scholar 

  20. Zambetti, G.P., Olson, D., Labow, M. & Levine, A.J. A mutant p53 protein is required for the maintenance of the transformed cell phenotype in p53 plus ras transformed cells. Proc. natn. Acad. Sci. U.S.A. 89, 3952–3956 (1992).

    Article  CAS  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. 5, 151–159 (1991).

    Article  CAS  Google Scholar 

  22. Eliyahu, D., Raz, A., Gruss, P., Givol, D. & Oren, M. Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature 312, 646–649 (1984).

    Article  CAS  Google Scholar 

  23. Parada, L.F., Land, H., Weinberg, R.A., Wolf, D. & Rotter, V. Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature 312, 649–651 (1984).

    Article  CAS  Google Scholar 

  24. Jenkins, J.R., Rudge, K. & Currie, G.A. Cellular immortalization by a cDNA clone encoding the transformation–associated phosphoprotein p53. Nature 312, 651–654 (1984).

    Article  CAS  Google Scholar 

  25. Wolf, D., Admon, S., Oren, M. & Rotter, V. Abelson murine leukemia virus-transformed cells that lack p53 protein synthesis express aberrant p53 mRNA species. Molec. cell. Biol. 4, 552–558 (1984).

    Article  CAS  Google Scholar 

  26. Shaulsky, G., Goldfinger, N. & Rotter, V. Alterations in tumour development in vivo mediated by expression of wild-type or mutant p53 proteins. Cancer Res. 51, 5232–5237 (1991).

    CAS  PubMed  Google Scholar 

  27. Harvey, D. & Levine, A.J. p53 alteration is a common event in the spontaneous immortalization of primary BALB/C murine embryo fibroblasts. Genes Dev. 5, 2375–2385 (1991).

    Article  CAS  Google Scholar 

  28. Masuda, H., Miller, C., Koeffler, H.P., Battifora, H. & Cline, M.J. Rearrangement of the p53 gene in human osteogenic sarcomas. Proc. natn. Acad. Sci. U.S.A. 84, 7716–7719 (1987).

    Article  CAS  Google Scholar 

  29. Hinds, P.W. et al. Mutant p53 cDNAs from human colorectal carcinomas can cooperate with ras in transformation of primary rat cells: A comparison of the “hot spot” mutant phenotypes. Cell Growth Diff. 1, 571–580 (1990).

    CAS  Google Scholar 

  30. Baker, S.J., Markowitz, S., Fearon, E.R., Willson, J.K.U. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912–915 (1990).

    Article  CAS  Google Scholar 

  31. Diller, L. et al. p53 functions as a cell cycle control protein in osteosarcomas. Molec. cell. Biol. 10, 5772–5781 (1990).

    Article  CAS  Google Scholar 

  32. Johnson, P., Gray, D., Mowat, M. & Benchimol, S. Expression of wild-type p53 is not compatible with continued growth of p53-negative tumour cells. Molec. cell. Biol. 11, 1–11 (1991).

    Article  CAS  Google Scholar 

  33. Mercer, W.E. et al. Negative growth regulation in a glioblastoma tumour cell line that conditionally expresses human wild-type p53. Proc. natn. Acad. Sci. U.S.A. 87, 6166–6170 (1990).

    Article  CAS  Google Scholar 

  34. Eliyahu, D., Michalovitz, D. & Oren, M. Overproduction of p53 antigen makes established cells highly tumorigenic. Nature 316, 158–160 (1985).

    Article  CAS  Google Scholar 

  35. Chin, K.V., Ueda, K., Pastan, I. & Gottesman, M.M. Modulation of activity of the promoter of the human MDR1 gene by ras and p53. Science, 255, 459–462 (1992).

    Article  CAS  Google Scholar 

  36. Werness, B.A., Levine, A.J. & Howley, P.M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76–79 (1990).

    Article  CAS  Google Scholar 

  37. Scheffner, M., Werness, B.A., Huibregtse, J.M., Levine, A.J. & Howley, P.M. The E6 oncoprotein encoded by human papillomavirus 16 or 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).

    Article  CAS  Google Scholar 

  38. Riou, G. et al. Association between poor prognosis in early stage invasive cervical carcinomas and nondetection of HPV DNA. Lancet 335, 1171–1174 (1990).

    Article  CAS  Google Scholar 

  39. Tan, T.-H., Wallis, J. & Levine, A.J. Identification of the p53 protein domain involved in formation of the simian virus 40 large T antigen-p53 protein complex. J. Virol. 59, 574–583 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Reich, N.C. & Levine, A.J. Growth regulation of a cellular tumour antigen, p53, in nontransformed cells. Nature 308, 199–201 (1984).

    Article  CAS  Google Scholar 

  41. Thor, A.D. et al. Accumulation of p53 tumour suppressor gene protein: an independent marker of prognosis in breast cancer. J. natn. Cancer Inst. 84, 845–855 (1992).

    Article  CAS  Google Scholar 

  42. Martin, H.M., Filipe, M.I., Morris, R.W., Lane, D.P. & Silvestre, F. p53 expression and prognosis in gastric carcinoma. Int. J. Cancer 50, 859–862 (1992).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, New Jersey, 08544–1014, USA

    Dirk Dittmer, Sibani Pati, Gerard Zambetti, Shelley Chu, Angelika K. Teresky, Mary Moore, Cathy Finlay & Arnold J. Levine

Authors
  1. Dirk Dittmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sibani Pati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerard Zambetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shelley Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angelika K. Teresky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mary Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cathy Finlay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arnold J. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dittmer, D., Pati, S., Zambetti, G. et al. Gain of function mutations in p53. Nat Genet 4, 42–46 (1993). https://doi.org/10.1038/ng0593-42

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0593-42

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing