Structure–based rescue of common tumor–derived p53 mutants (original) (raw)
- Article
- Published: 01 October 1996
- Jennifer L.F. Waterman1 na1,
- Matthew J.F. Waterman1,2 &
- …
- Thanos D. Halazonetis1,3
Nature Medicine volume 2, pages 1143–1146 (1996)Cite this article
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Abstract
The p53 tumor suppressor protein induces cell–cycle arrest or cell death in response to DNA–damaging agents, such as radiation and many of the chemotherapeutics used in cancer therapy1,2. The function of p53 is dependent on its ability to bind DNA in a sequence–specific manner3, but in one–half of all human tumors, its sequence–specific DNA binding domain is compromised by single–amino acid substitutions4. The nature of these substitutions, which target residues that directly contact DNA or that stabilize the structure of the DNA binding domain5, has raised concerns as to whether the function of p53 mutants could ever be rescued6. Nevertheless, pharmaceuticals that restore function to p53 mutants could specifically suppress proliferation of cancer cells in patients. To determine whether tumor–derived p53 mutants are irreversibly inactivated, we introduced basic residues in their DNA binding domains, aiming to establish novel contacts between p53 and the DNA phosphate backbone. In three of the seven most common p53 mutants, replacement of Thr284 with Arg significantly enhanced DNA binding affinity, without affecting DNA binding specificity, and rescued their transactivation and tumor suppressor functions. Thus, many tumor–derived p53 mutants retain their sequence–specific DNA binding determinants and can be activated to suppress tumor growth.
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Author notes
- Ania M. Wieczorek and Jennifer L.F. Waterman: The first two authors contributed equally to this work.
Authors and Affiliations
- Department of Molecular Oncology, the Wistar Institute, Philadelphia, Pennsylvania, 19104-4268, USA
Ania M. Wieczorek, Jennifer L.F. Waterman, Matthew J.F. Waterman & Thanos D. Halazonetis - Program in Molecular Biology and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA
Matthew J.F. Waterman - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA
Thanos D. Halazonetis
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- Ania M. Wieczorek
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Wieczorek, A., Waterman, J., Waterman, M. et al. Structure–based rescue of common tumor–derived p53 mutants.Nat Med 2, 1143–1146 (1996). https://doi.org/10.1038/nm1096-1143
- Received: 14 June 1996
- Accepted: 05 August 1996
- Issue Date: 01 October 1996
- DOI: https://doi.org/10.1038/nm1096-1143