A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis.
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.
Trinei
Mirella
M
Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.
Giorgio
Marco
M
Cicalese
Angelo
A
Barozzi
Sara
S
Ventura
Andrea
A
Migliaccio
Enrica
E
Milia
Elisabetta
E
Padura
Ines Martin
IM
Raker
Veronica A
VA
Maccarana
Marco
M
Petronilli
Valeria
V
Minucci
Saverio
S
Bernardi
Paolo
P
Lanfrancone
Luisa
L
Pelicci
Pier Giuseppe
PG
D000080242:8-Hydroxy-2'-Deoxyguanosine; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D017353:Gene Deletion; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000975:Antioxidants; D003574:Cytochrome c Group; D011506:Proteins; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016159:Tumor Suppressor Protein p53; D000080242:8-Hydroxy-2'-Deoxyguanosine; D008156:Luciferases; D003849:Deoxyguanosine; D010100:Oxygen