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Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Nature Medicine volume 8, pages 282–288 (2002)Cite this article

Abstract

The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.

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Figure 1: Identification and properties of PRIMA-1.
Figure 2: PRIMA-1 induces cell death by apoptosis.
Figure 3: Effect of PRIMA-1 on the conformation of mutant p53 proteins.
Figure 4: Effect of PRIMA-1 on the DNA binding of mutant p53 proteins.
Figure 5: Restoration of transcriptional transactivation activity to mutant p53 by PRIMA-1.
Figure 6: Tumor suppression by PRIMA-1.

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References

  1. Ko, L.J. & Prives, C. p53: puzzle and paradigm. Genes Dev. 10, 1054–1072 (1996).

    Article  CAS  Google Scholar 

  2. Sherr, C.J. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 12, 2984–2991 (1998).

    Article  CAS  Google Scholar 

  3. Giaccia, A.J. & Kastan, M.B. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 12, 2973–2983 (1998).

    Article  CAS  Google Scholar 

  4. Asker, C., Wiman, K.G. & Selivanova, G. p53-induced apoptosis as a safeguard against cancer. Biochem. Biophys. Res. Commun. 265, 1–6 (1999).

    Article  CAS  Google Scholar 

  5. Béroud, C. & Soussi, T. p53 gene mutation: software and database. Nucl. Acids Res. 26, 200–204 (1998).

    Article  Google Scholar 

  6. Lowe, S.W. et al. p53 status and the efficacy of cancer therapy in vivo. Science 266, 807–810 (1994).

    Article  CAS  Google Scholar 

  7. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–31 (1997).

    Article  CAS  Google Scholar 

  8. Evan, G. & Littlewood, T. A matter of life and cell death. Science. 281, 1317–1322 (1998).

    Article  CAS  Google Scholar 

  9. Selivanova, G., Kawasaki, T., Ryabchenko, L. & Wiman, K.G. Reactivation of mutant p53: a new strategy for cancer therapy. Semin. Cancer Biol. 8, 369–378 (1998).

    Article  CAS  Google Scholar 

  10. Wieczorek, A.M., Waterman, J.L.F., Waterman, M.J.F. & Halazonetis, T.D. Structure-based rescue of common tumor-derived p53 mutants. Nature Med. 2, 1143–1146 (1996).

    Article  CAS  Google Scholar 

  11. Brachmann, R.K., Yu, K., Eby, Y., Pavletich, N.P & Boeke, J.D. Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. EMBO J. 17, 1847–1859 (1998).

    Article  CAS  Google Scholar 

  12. Nikolova, P.V., Wong, K-B., DeDecker, B., Henckel, J. & Fersht. A.R. Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations. EMBO J. 19, 370–378 (2000).

    Article  CAS  Google Scholar 

  13. Selivanova, G. et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nature Med. 3, 632–638 (1997).

    Article  CAS  Google Scholar 

  14. Kim, A.L. et al. Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells. J. Biol. Chem. 274, 34924–34931 (1999).

    Article  CAS  Google Scholar 

  15. Selivanova, G., Ryabchenko, L., Jansson, E., Iotsova, V. & Wiman, K.G. Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol. Cell Biol. 19, 3395–3402 (1999).

    Article  CAS  Google Scholar 

  16. Wiman, K.G., Magnusson, K.P., Ramqvist, T. & Klein, G. Mutant p53 detected in a majority of Burkitt lymphoma cell lines by monoclonal antibody PAb240. Oncogene 6, 1633–1639 (1991).

    CAS  PubMed  Google Scholar 

  17. Lindström, M.S. et al. Immunolocalization of human p14ARF to the granular component of the interphase nucleolus. Exp. Cell Res. 256, 400–410 (2000).

    Article  Google Scholar 

  18. Bunz, F. et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents J. Clin. Invest. 104, 263–269 (1999).

    Article  CAS  Google Scholar 

  19. Cho, Y., Gorina, S., Jeffrey, P.D. & Pavletich, N.P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265, 346–355 (1994).

    Article  CAS  Google Scholar 

  20. Lin, J., Chen, J., Elenbaas, B. & Levine, A.J. 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 Dev. 8, 1235–1246 (1994).

    Article  CAS  Google Scholar 

  21. Bullock, A.N., Henckel, J. & Fersht, A.R. Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy. Oncogene 19, 1245–1256 (2000).

    Article  CAS  Google Scholar 

  22. Selivanova, G. & Wiman, K.G. Functional rescue of mutant p53 as a strategy to combat cancer. in Tumor Supressing Viruses, Genes, and Drugs (ed. Maruta, H.) 397–415 (Academic Press, San Diego, California, 2001).

    Google Scholar 

  23. Abarzúa, P., LoSardo, J.E., Gubler, M.L. & Neri, A. Microinjection of monoclonal antibody PAb421 into human SW480 colorectal carcinoma cells restores the transcription activation function to mutant p53. Cancer Res. 55, 3490–3494 (1995).

    PubMed  Google Scholar 

  24. Friedlander, P., Legros, Y., Soussi, T. & Prives, C. Regulation of mutant p53 temperature-sensitive DNA binding. J. Biol. Chem. 271, 25468–25478 (1996).

    Article  CAS  Google Scholar 

  25. Hansen, S., Hupp, T.R. & Lane, D.P. Allosteric regulation of the thermostability and DNA binding activity of human p53 by specific interacting proteins. J. Biol. Chem. 271, 3917–3924 (1996).

    Article  CAS  Google Scholar 

  26. Hupp, T.R., Meek, D.W., Midgley, C.A. & Lane, D.P. Regulation of the specific DNA binding function of p53. Cell 71, 875–886 (1992).

    Article  CAS  Google Scholar 

  27. Hupp, T.R., Meek, D.W., Midgley, C.A. & Lane, D.P. Activation of the cryptic DNA binding function of mutant forms of p53. Nucleic Acids Res. 21, 3167–3174 (1993).

    Article  CAS  Google Scholar 

  28. Müller-Tiemann, B.F., Halazonetis, T.D. & Elting, J.J. Identification of an additional negative regulatory region for p53 sequence-specific DNA binding. Proc. Natl. Acad. Sci. USA 95, 6079–6084 (1998).

    Article  Google Scholar 

  29. Foster, B.A., Coffey, H.A., Morin, M.J. & Rastinejad, F. Pharmacological rescue of mutant p53 conformation and function. Science, 286, 2507–2510 (1999).

    Article  CAS  Google Scholar 

  30. Cohen, P.A., Hupp, T.R., Lane, D.P. & Daniels, D.A. Biochemical characterization of different conformational states of the Sf9 cell-purified p53His175 mutant protein. FEBS Lett. 463, 179–184 (1999).

    Article  CAS  Google Scholar 

  31. Selivanova, G. et al. The single-stranded DNA end binding site of p53 coincides with the C-terminal regulatory region. Nucl. Acids Res. 24, 3560–3567 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Fritsche for Saos-2-His-273 cells; B. Vogelstein for HCT-116 cells; E. Lukanidin for the p53-pfLUC plasmid; M. Rodensjö for the preparation of histological sections; and the Drug Synthesis & Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, for the library of low-molecular-weight compounds. This study was supported by project grants from the Swedish Cancer Society (Cancerfonden), the Swedish Medical Research Council, the Swedish Royal Academy of Sciences and the European Union 5th Framework Program. V.J.N.B. was supported by a postdoctoral fellowship from the Swedish Cancer Society.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden

    Vladimir J.N. Bykov, Natalia Issaeva, Alexandre Shilov, Monica Hultcrantz, Klas G. Wiman & Galina Selivanova

  2. Institute of Cytology and Genetics, RAN, Novosibirsk, Russia

    Alexandre Shilov

  3. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

    Elena Pugacheva & Peter Chumakov

  4. Department of Biosciences at Novum, Karolinska Institutet, Novum, Huddinge, Sweden

    Jan Bergman

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  1. Vladimir J.N. Bykov
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Correspondence to Klas G. Wiman.

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Bykov, V., Issaeva, N., Shilov, A. et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8, 282–288 (2002). https://doi.org/10.1038/nm0302-282

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