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Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes

Oncogene volume 23, pages 4430–4443 (2004)Cite this article

Abstract

We have studied the mechanism of mutant p53-mediated oncogenesis using several tumor-derived mutants. Using a colony formation assay, we found that the majority of the mutants increased the number of colonies formed compared to the vector. Expression of tumor-derived p53 mutants increases the rate of cell growth, suggesting that the p53 mutants have ‘gain of function’ properties. We have studied the gene expression profile of cells expressing tumor-derived p53-D281G to identify genes transactivated by mutant p53. We report the transactivation of two genes, asparagine synthetase and human telomerase reverse transcriptase. Quantitative real-time PCR confirms this upregulation. Transient transfection promoter assays verify that tumor-derived p53 mutants transactivate these promoters significantly. An electrophoretic mobility shift assay shows that tumor-derived p53-mutants cannot bind to the wild-type p53 consensus sequence. The results presented here provide some evidence of a possible mechanism for mutant p53-mediated transactivation.

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Acknowledgements

This work was supported by grants from NIH to Sumitra Deb (CA70712) and to Swati Palit Deb (CA74172) and a dissertation award for Katherine ER Stagliano from the Susan G Komen Breast Cancer Foundation (DISS0201749). Mariano Scian is supported by a pre-doctoral fellowship from NCI (1 F31 CA97520). Part of the work for this manuscript was done in the Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. We thank Arnold Levine, Bert Vogelstein, Glenn Merlino, Jennifer Pietenpol, Michael S Kilberg, Ione P Barbossa-Tessman, Riccardo Dalla-Favera, Julie Bronder and Richard Moran for providing us with plasmids, cells and technical advice.

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  1. Department of Biochemistry and the Massey Cancer Center, Virginia Commonwealth University, PO Box 980614, Richmond, 23298, VA, USA

    Mariano J Scian, Katherine E R Stagliano, Debabrita Deb, Michelle A Ellis, Evie H Carchman, Anindita Das, Swati Palit Deb & Sumitra Deb

  2. Department of Radiation Oncology, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Kristopher Valerie

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Scian, M., Stagliano, K., Deb, D. et al. Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes. Oncogene 23, 4430–4443 (2004). https://doi.org/10.1038/sj.onc.1207553

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