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

• Published in: Oncogene Vol. 21; no. 24; pp. 3872 - 3878
• Main Authors: TRINEI, Mirella, GIORGIO, Marco, PETRONILLI, Valeria, MINUCCI, Saverio, BERNARDI, Paolo, LANFRANCONE, Luisa, PELICCI, Pier Giuseppe, CICALESE, Angelo, BAROZZI, Sara, VENTURA, Andrea, MIGLIACCIO, Enrica, MILIA, Elisabetta, PADURA, Ines Martin, RAKER, Veronica A, MACCARANA, Marco
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 30-05-2002; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Ageing, cell death; Aging; Animals; Antioxidants - pharmacology; Apoptosis; Biological and medical sciences; Cell cycle; Cell physiology; Cells, Cultured; Cytochrome c; Cytochrome c Group - metabolism; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - pharmacology; Deoxyribonucleic acid; DNA; DNA Damage; Fundamental and applied biological sciences. Psychology; Gene Deletion; Intracellular; Intracellular signalling; Invertebrates; Kinases; Life span; Luciferases - metabolism; Mice; Mice, Knockout; Molecular and cellular biology; Oncology; Oxidants; Oxidation; Oxidation-Reduction; Oxidative Stress; Oxygen - metabolism; p53 Protein; Polymerase Chain Reaction; Protein Binding; Proteins; Proteins - metabolism; Reactive Oxygen Species; Shc Signaling Adaptor Proteins; Signal Transduction; Src Homology 2 Domain-Containing, Transforming Protein 1; Transcriptional Activation; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Tumors; Up-Regulation; Italy; Redox state; Oxidative stress; TP53 Gene; DNA; Oxidation; Intracellular; Signalling; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205513

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.