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Reactivation of mutant p53: molecular mechanisms and therapeutic potential

Oncogene volume 26, pages 2243–2254 (2007)Cite this article

Abstract

The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Most p53 mutations are missense point mutations that cluster in the DNA-binding core domain. This results in distortion of core domain folding and disruption of DNA binding and transcriptional transactivation of p53 target genes. Structural studies have demonstrated that mutant p53 core domain unfolding is not irreversible. Mutant p53 is expressed at high levels in many tumors. Therefore, mutant p53 is a promising target for novel cancer therapy. Mutant p53 reactivation will restore p53-dependent apoptosis, resulting in efficient removal of tumor cells. A number of strategies for targeting mutant p53 have been designed, including peptides and small molecules that restore the active conformation and DNA binding to mutant p53 and induce p53-dependent suppression of tumor cell growth in vitro and in vivo. This opens possibilities for the clinical application of mutant p53 reactivation in the treatment of cancer.

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Acknowledgements

We thank the Swedish Cancer Society, EU FP6, the Cancer Society of Stockholm, the Swedish Research Council and the Karolinska Institutet for generous support, and Andrej Okorokov for help with Figure 2. We apologize to all our colleagues whose work could not be cited because of space limitations.

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  1. G Selivanova, Galina.Selivanova@ki.se

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  1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    G Selivanova

  2. Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden

    K G Wiman

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Selivanova, G., Wiman, K. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene 26, 2243–2254 (2007). https://doi.org/10.1038/sj.onc.1210295

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