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A novel approach to cancer treatment using structural hybrids of the p53 gene family

Cancer Gene Therapy volume 19, pages 749–756 (2012)Cite this article

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Abstract

The p53 tumor suppressor belongs to a gene family that includes two other structurally and functionally related members: p73 and p63. The regulation of p53 activity differs significantly from that of p73 and p63. To enhance the tumor suppressive activity of p53, we constructed six recombinant adenoviruses that encode hybrid proteins with three functional domains derived from either p53 or TAp63γ. The potency of these hybrid molecules in suppressing tumorigenesis was evaluated using in vitro and in vivo models. Of the hybrid molecules tested, one hybrid named p63–53O was the most potent activator of apoptosis in human cancer cells. The p63–53O hybrid is composed of the transcriptional activation domain and DNA-binding domain of TAp63γ and the oligomerization domain of p53. The p63–53O hybrid efficiently transactivated p53AIP1. Moreover, silencing of p53AIP1 partially abolished the apoptotic response to p63–53O in human cancer cells. The p53–p63 hybrid molecule is a novel potent anti-proliferative agent for the treatment of cancer.

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Acknowledgements

This research was supported in part by grants-in-aid for cancer research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Setsuko Ishida for excellent technical support.

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Authors and Affiliations

  1. Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

    Y Sasaki, Y Oshima, R Koyama, M Tamura, L Kashima, M Idogawa & T Tokino

  2. First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan

    Y Sasaki, M Idogawa & Y Shinomura

  3. Department of Dermatology, Sapporo Medical University, Sapporo, Japan

    T Yamashita

  4. Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan

    M Toyota

  5. Division of Novel Therapy for Cancer, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    K Imai

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  1. Y Sasaki
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Correspondence to T Tokino.

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Sasaki, Y., Oshima, Y., Koyama, R. et al. A novel approach to cancer treatment using structural hybrids of the p53 gene family. Cancer Gene Ther 19, 749–756 (2012). https://doi.org/10.1038/cgt.2012.51

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