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Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by tumor-associated p53 mutants

Oncogene volume 22, pages 5667–5676 (2003)Cite this article

Abstract

Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which probably confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the CD95 (Fas/APO-1) gene, encoding a death receptor implicated in a variety of apoptotic responses. Moderate (40–50%) downregulation of CD95 mRNA and surface protein expression by mutant p53 correlates with partial protection against CD95-dependent cell death. Excess mutant p53 represses the transcriptional activity of the CD95 promoter, with the extent of repression varying among different tumor-associated p53 mutants. Furthermore, mutant p53 protein binds the CD95 promoter in vitro, in a region distinct from the one implicated in tight interactions of the CD95 gene with wild-type p53. Hence, the CD95 promoter is likely to be a direct target for downregulation by mutant p53. This activity of mutant p53 may contribute to its gain of function effects in oncogenesis.

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Acknowledgements

We thank B Vogelstein and W Kaelin for p53 expression plasmids and S Benchimol for the ecotropic receptor expression plasmid. This work was supported in part by Grants QLG1-1999-00273 and QLK6-2000-00159 from the European Commission, and by grants from the Cooperation Program in Cancer Research of the DKFZ and Israel's Ministry of Science (MOS), the German-Israel Project Cooperation (DIP), the Kadoorie Charitable Foundations, and the Yad Abraham Center for Cancer Diagnosis and Therapy.

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 76100, Israel

    Amir Zalcenstein, Perry Stambolsky, Lilach Weisz, Varda Rotter & Moshe Oren

  2. Department of Internal Medicine IV, University Hospital, Heidelberg, 69115, Germany

    Martina Müller

  3. Department of Biological Chemistry, Weizmann Institute of Science, PO Box 26, Rehovot, 76100, Israel

    David Wallach & Tanya M Goncharov

  4. Tumor Immunology Program, German Cancer Research Center, Heidelberg, 69120, Germany

    Peter H Krammer

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  1. Amir Zalcenstein
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Correspondence to Moshe Oren.

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Zalcenstein, A., Stambolsky, P., Weisz, L. et al. Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by tumor-associated p53 mutants. Oncogene 22, 5667–5676 (2003). https://doi.org/10.1038/sj.onc.1206724

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