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
. 1996 Apr 30;93(9):4091–4095. doi: 10.1073/pnas.93.9.4091

Dominant-negative p53 mutations selected in yeast hit cancer hot spots.

R K Brachmann 1, M Vidal 1, J D Boeke 1
PMCID: PMC39492  PMID: 8633021

Abstract

Clinically important mutant p53 proteins may be tumorigenic through a dominant-negative mechanism or due to a gain-of-function. Examples for both hypotheses have been described; however, it remains unclear to what extent they apply to TP53 mutations in general. Here it is shown that the mutational spectrum of dominant-negative p53 mutants selected in a novel yeast assay correlates tightly with p53 mutations in cancer. Two classes of dominant-negative mutations are described; the more dominant one affects codons that are essential for the stabilization of the DNA-binding surface of the p53 core domain and for the direct interaction of p53 with its DNA binding sites. These results predict that the vast majority of TP53 mutations leading to cancer do so in a dominant-negative fashion.

Full text

PDF
4091

Images in this article

4092Fig. 1
on p.4092
4092Fig. 2
on p.4092
4094Fig. 3
on p.4094

Selected References

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

  1. Baker S. J., Preisinger A. C., Jessup J. M., Paraskeva C., Markowitz S., Willson J. K., Hamilton S., Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990 Dec 1;50(23):7717–7722. [PubMed] [Google Scholar]
  2. Banks L., Matlashewski G., Crawford L. Isolation of human-p53-specific monoclonal antibodies and their use in the studies of human p53 expression. Eur J Biochem. 1986 Sep 15;159(3):529–534. doi: 10.1111/j.1432-1033.1986.tb09919.x. [DOI] [PubMed] [Google Scholar]
  3. Boeke J. D., LaCroute F., Fink G. R. A positive selection for mutants lacking orotidine-5'-phosphate decarboxylase activity in yeast: 5-fluoro-orotic acid resistance. Mol Gen Genet. 1984;197(2):345–346. doi: 10.1007/BF00330984. [DOI] [PubMed] [Google Scholar]
  4. Cariello N. F., Beroud C., Soussi T. Database and software for the analysis of mutations at the human p53 gene. Nucleic Acids Res. 1994 Sep;22(17):3549–3550. [PMC free article] [PubMed] [Google Scholar]
  5. Caron de Fromentel C., Soussi T. TP53 tumor suppressor gene: a model for investigating human mutagenesis. Genes Chromosomes Cancer. 1992 Jan;4(1):1–15. doi: 10.1002/gcc.2870040102. [DOI] [PubMed] [Google Scholar]
  6. Cho Y., Gorina S., Jeffrey P. D., Pavletich N. P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994 Jul 15;265(5170):346–355. doi: 10.1126/science.8023157. [DOI] [PubMed] [Google Scholar]
  7. Devine S. E., Boeke J. D. Efficient integration of artificial transposons into plasmid targets in vitro: a useful tool for DNA mapping, sequencing and genetic analysis. Nucleic Acids Res. 1994 Sep 11;22(18):3765–3772. doi: 10.1093/nar/22.18.3765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Donehower L. A., Bradley A. The tumor suppressor p53. Biochim Biophys Acta. 1993 Aug 23;1155(2):181–205. doi: 10.1016/0304-419x(93)90004-v. [DOI] [PubMed] [Google Scholar]
  9. Durfee T., Becherer K., Chen P. L., Yeh S. H., Yang Y., Kilburn A. E., Lee W. H., Elledge S. J. The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev. 1993 Apr;7(4):555–569. doi: 10.1101/gad.7.4.555. [DOI] [PubMed] [Google Scholar]
  10. Fields S., Jang S. K. Presence of a potent transcription activating sequence in the p53 protein. Science. 1990 Aug 31;249(4972):1046–1049. doi: 10.1126/science.2144363. [DOI] [PubMed] [Google Scholar]
  11. Fields S., Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. doi: 10.1038/340245a0. [DOI] [PubMed] [Google Scholar]
  12. Frebourg T., Friend S. H. Cancer risks from germline p53 mutations. J Clin Invest. 1992 Nov;90(5):1637–1641. doi: 10.1172/JCI116034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Friend S. p53: a glimpse at the puppet behind the shadow play. Science. 1994 Jul 15;265(5170):334–335. doi: 10.1126/science.8023155. [DOI] [PubMed] [Google Scholar]
  14. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  15. Gutiérrez M. I., Bhatia K. G., Barreiro C., Spangler G., Schvartzmann E., Muriel F. S., Magrath I. T. A de novo p53 germline mutation affecting codon 151 in a six year old child with multiple tumors. Hum Mol Genet. 1994 Dec;3(12):2247–2248. doi: 10.1093/hmg/3.12.2247. [DOI] [PubMed] [Google Scholar]
  16. Gyuris J., Golemis E., Chertkov H., Brent R. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell. 1993 Nov 19;75(4):791–803. doi: 10.1016/0092-8674(93)90498-f. [DOI] [PubMed] [Google Scholar]
  17. Hann B. C., Lane D. P. The dominating effect of mutant p53. Nat Genet. 1995 Mar;9(3):221–222. doi: 10.1038/ng0395-221. [DOI] [PubMed] [Google Scholar]
  18. Harris C. C., Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med. 1993 Oct 28;329(18):1318–1327. doi: 10.1056/NEJM199310283291807. [DOI] [PubMed] [Google Scholar]
  19. Herskowitz I. Functional inactivation of genes by dominant negative mutations. Nature. 1987 Sep 17;329(6136):219–222. doi: 10.1038/329219a0. [DOI] [PubMed] [Google Scholar]
  20. Hollstein M., Rice K., Greenblatt M. S., Soussi T., Fuchs R., Sørlie T., Hovig E., Smith-Sørensen B., Montesano R., Harris C. C. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1994 Sep;22(17):3551–3555. [PMC free article] [PubMed] [Google Scholar]
  21. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  22. Ishioka C., Frebourg T., Yan Y. X., Vidal M., Friend S. H., Schmidt S., Iggo R. Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nat Genet. 1993 Oct;5(2):124–129. doi: 10.1038/ng1093-124. [DOI] [PubMed] [Google Scholar]
  23. Malkin D. Germline p53 mutations and heritable cancer. Annu Rev Genet. 1994;28:443–465. doi: 10.1146/annurev.ge.28.120194.002303. [DOI] [PubMed] [Google Scholar]
  24. Mazoyer S., Lalle P., Moyret-Lalle C., Marçais C., Schraub S., Frappaz D., Sobol H., Ozturk M. Two germ-line mutations affecting the same nucleotide at codon 257 of p53 gene, a rare site for mutations. Oncogene. 1994 Apr;9(4):1237–1239. [PubMed] [Google Scholar]
  25. Michalovitz D., Halevy O., Oren M. p53 mutations: gains or losses? J Cell Biochem. 1991 Jan;45(1):22–29. doi: 10.1002/jcb.240450108. [DOI] [PubMed] [Google Scholar]
  26. Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. doi: 10.1038/342705a0. [DOI] [PubMed] [Google Scholar]
  27. Prives C. How loops, beta sheets, and alpha helices help us to understand p53. Cell. 1994 Aug 26;78(4):543–546. doi: 10.1016/0092-8674(94)90519-3. [DOI] [PubMed] [Google Scholar]
  28. Sikorski R. S., Hieter P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics. 1989 May;122(1):19–27. doi: 10.1093/genetics/122.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  30. Wang M. M., Reed R. R. Molecular cloning of the olfactory neuronal transcription factor Olf-1 by genetic selection in yeast. Nature. 1993 Jul 8;364(6433):121–126. doi: 10.1038/364121a0. [DOI] [PubMed] [Google Scholar]
  31. Zambetti G. P., Levine A. J. A comparison of the biological activities of wild-type and mutant p53. FASEB J. 1993 Jul;7(10):855–865. doi: 10.1096/fasebj.7.10.8344485. [DOI] [PubMed] [Google Scholar]
  32. el-Deiry W. S., Kern S. E., Pietenpol J. A., Kinzler K. W., Vogelstein B. Definition of a consensus binding site for p53. Nat Genet. 1992 Apr;1(1):45–49. doi: 10.1038/ng0492-45. [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