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A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis

Oncogene volume 21, pages 3872–3878 (2002)Cite this article

Abstract

Correlative evidence links stress, accumulation of oxidative cellular damage and ageing in lower organisms and in mammals. We investigated their mechanistic connections in p66Shc knockout mice, which are characterized by increased resistance to oxidative stress and extended life span. We report that p66Shc acts as a downstream target of the tumour suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. Other functions of p53 are not influenced by p66Shc expression. In basal conditions, p66Shc−/− and p53−/− cells have reduced amounts of intracellular oxidants and oxidation-damaged DNA. We propose that steady-state levels of intracellular oxidants and oxidative damage are genetically determined and regulated by a stress-induced signal transduction pathway involving p53 and p66Shc.

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Acknowledgements

We thank L Luzi, L Pozzi, K Helin, R Carbone, M Capogrossi, A Cocito and R Cortese for many helpful discussions; G Giardina, G Pelliccia, M Bono, MT Sciurpi, S Ronzoni and M Faretta for technical help; A Ariesi for secretarial work. M Trinei, A Ventura and E Milia are recipient of fellowships from FIRC, VAR from M Curie. Supported by grants from EC, AIRC and CNR.

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Author notes

  1. M Trinei and M Giorgio contributed equally to this paper

Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology, Milan, 20141, Italy

    Mirella Trinei, Marco Giorgio, Angelo Cicalese, Sara Barozzi, Andrea Ventura, Enrica Migliaccio, Elisabetta Milia, Ines Martin Padura, Veronica A Raker, Marco Maccarana, Saverio Minucci, Luisa Lanfrancone & Pier Giuseppe Pelicci

  2. FIRC Institute for Molecular Oncology, Milan, 20139, Italy

    Mirella Trinei, Marco Giorgio, Sara Barozzi, Enrica Migliaccio, Ines Martin Padura, Marco Maccarana & Pier Giuseppe Pelicci

  3. CNR Unit for the Study of Biomembranes, Padova, 35100, Italy

    Valeria Petronilli & Paolo Bernardi

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  1. Mirella Trinei
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  2. Marco Giorgio
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Corresponding authors

Correspondence to Luisa Lanfrancone or Pier Giuseppe Pelicci.

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Trinei, M., Giorgio, M., Cicalese, A. et al. A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene 21, 3872–3878 (2002). https://doi.org/10.1038/sj.onc.1205513

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