title: The p53-p66Shc apoptotic pathway is dispensable for tumor suppression whereas the p66Shc-generated oxidative stress initiates tumorigenesis.
abstract: Reactive oxygen species (ROS) are regarded as hazardous by-products of mitochondrial respiration. In addition to the respiratory chain, specific ROS-generating systems have evolved. In particular, p66Shc is a mitochondrial redox protein that oxidizes cytochrome c to generate H2O2. Consistently, the deletion of p66Shc in cells and tissue results in reduced levels of ROS and oxidative stress. Taking advantage of the p66Shc knock out (p66KO) mouse model of decreased ROS production, we assessed the role of endogenously-produced ROS in tumorigenesis. Spontaneous tumor incidence was investigated and found unaltered in two different strains, 129Sv and C57Bl/6J, p66KO mice. In addition, papilloma formation upon exposure to ultraviolet radiation (UV) or 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol- 13-acetate (DMBA/TPA) was found to be slightly lower in the absence of p66Shc. The role of p66Shc in tumorigenesis was also investigated in the absence of the tumor suppressor gene p53 (p53KO) by generating p53-p66Shc double knock out (DKO) mice. Notably, DKO mice displayed a significantly increased lifespan compared to p53KO mice. In addition, 2-deoxy-2-(18F)fluoro-D-glucose Positron Emission Tomography ([18F]FDG PET) analysis allowed to determine that disease onset occurred later in life in DKO mice compared to p53KO and that a low percentage of these mice did not develop tumors. Overall, these results indicate that although tumor incidence is not decreased in p66KO mice, p66Shc contributes to tumor initiation, in particular upon activation by carcinogens as well as when p53- mediated tumor suppression mechanisms defect.
authors.affiliation: European Institute of Oncology, Experimental Oncology Department, Via Adamello 16, 20139 Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Beltrami
authors.forename: Silvia
authors.initials: S
authors.lastname: Valtorta
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Moresco
authors.forename: Raluca
authors.initials: R
authors.lastname: Marcu
authors.forename: Sara
authors.initials: S
authors.lastname: Belloli
authors.forename: Ambrogio
authors.initials: A
authors.lastname: Fassina
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Fazio
authors.forename: Piergiuseppe
authors.initials: P
authors.lastname: Pelicci
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D002273:Carcinogens; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate