Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri
Priami Chiara1,3, De Michele Giulia1, Cotelli Franco3, Cellerino Alessandro4, Giorgio Marco1, Pelicci Pier Giuseppe1,2,*(), Migliaccio Enrica1,*()
1European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. 2Dipartimento di Medicina, Chirurgia e Odontoiatria, University of Milan, Italy 3Dipartimento di Bioscienze, University of Milan, Italy. 4Scuola Normale Superiore, Pisa, Italy
Oxidative stress induced by reactive oxygen species (ROS) increases during lifespan and is involved in aging processes. The p66Shc adaptor protein is a master regulator of oxidative stress response in mammals. Ablation of p66Shc enhances oxidative stress resistance both in vitro and in vivo. Most importantly, it has been demonstrated that its deletion retards aging in mice. Recently, new insights in the molecular mechanisms involving p66Shc and the p53 tumor suppressor genes were given: a specific p66Shc/p53 transcriptional regulation pathway was uncovered as determinant in oxidative stress response and, likely, in aging. p53, in a p66Shc-dependent manner, negatively downregulates the expression of 200 genes which are involved in the G2/M transition of mitotic cell cycle and are downregulated during physiological aging. p66Shc modulates the response of p53 by activating a p53 isoform (p44/p53, also named Delta40p53). Based on these latest results, several developments are expected in the future, as the generation of animal models to study aging and the evaluation of the use of the p53/p66Shc target genes as biomarkers in aging related diseases. The aim of this review is to investigate the conservation of the p66Shc and p53 role in oxidative stress between fish and mammals. We propose to approach this study trough a new model organism, the annual fish Nothobranchius furzeri, that has been demonstrated to develop typical signs of aging, like in mammals, including senescence, neurodegeneration, metabolic disorders and cancer.
Figure 1. Multiple sequence alignment of p53 of different species. Predicted p53 orthologs were searched using online resources (UCSC Genome Browser, Ensembl Genome Browser and Nothobranchius furzeri transcriptome browser found at https://gen100.imb-jena.de/EST2UNI/nfintb/) and aligned using the online Praline program. Post-translational modified amino acid residues conserved in 7 or more out of 9 species are boxed in black and highlighted with a black spot: note that S15, the phosphorylation site of ATM, is conserved in all the species with the exception of N. furzeri; post-translational modified amino acid residues conserved in 6 or 5 out of 9 species are boxed in red; post-translational modified amino acid residues conserved in 3 or 4 out of 9 are boxed in orange or blue; post-translational modified amino acid residues conserved in 2 out of 9 species are boxed in yellow; post-translational modified amino acid residues present only in human sequence are not indicated. Starting site of Transactivating Domain (TAD), Proline rich Domain (PRD), DNA Binding Domain (DBD), Tetramerization Domain (TD) and C-terminal Regulating Domain (CRD) are indicated. Hsa: Homo sapiens, Mmu: Mus musculus, Xtr: Xenopus tropicalis, Ola: Oryzias latipes (medaka), Tru: Takifugu rubripes (fugu), Dre: Danio rerio (zebrafish), Nfu: Nothobranchius furzeri, Dme: Drosophila melanogaster, Cel: Caenorhabditis elegans.
Figure 2. Modular organization of p53 orthologs of different vertebrate and invertebrate species. TAD, violet: Transactivation Domain; PRD, green: Proline Rich Domain; DBD, yellow: DNA Binding Domain, TD, dark blue: Tetramerization domain; CRD, fuchsia: C-terminal Regulatory Domain. Post-translational modified amino acid residues are indicated: serines with a pink spot, threonines with a blue spot, and lysines with a green spot and cysteines with an orange spot. For Homo sapiens, it is also indicated the position in the sequence and the type of post-translational modification (P=phosphorylation, A=acetylation, R=changing of the redox status, G=glycosylation, N=neddylation, S=sumoylation, M=methylation and U=ubiquitination). Amino acids of the human sequence are also numbered from 1 to 43: in other sequences than human, conserved amino acid residues are indicated only with the corresponding number and not with the position in their sequence. Amino acids are considered conserved even if they are substituted with a functionally similar one: for example, T18 is not found in N. furzeri, but this amino acid is here substituted with a serine, thus the number (4) is the same, but the color of the spot changes from blue to pink. S15 is indicated with a pink spot surrounded by a black circle: we want to focus the attention on this residue because it is the best known target site of ATM (Ataxia-Telangiectasia Mutated) kinase and it is one of the few amino acids conserved among all the considered species, with the interesting exception of N. furzeri.
Figure 3. Multiple sequence alignment of p66Shc CH2 domain of different species. Predicted p66Shc orthologs were searched using online resources (UCSC Genome Browser, Ensembl Genome Browser and Nothobranchius furzeri transcriptome browser found at https://gen100.imb-jena.de/EST2UNI/nfintb/) and aligned using the online Praline program. High homology regions within the CH2 domains are boxed in blue. Post-translational modified amino acid residues conserved in 8 or more out of 10 sequences are boxed in black and highlighted with a black spot: S54 is conserved among vertebrates and C. elegans T27F7.2; S139 is conserved among vertebrates and Drosophila. Post-translational modified amino acid residues conserved in 7 out of 10 sequences are boxed in red and highlighted with a red spot: S36 is conserved in vertebrates (with the exception of D. rerio) and C. elegans T27F7.2; amino acids constituting the Cytochrome c binding domain (E125, E132, E133, W134 and W148) of p66Shc are conserved in vertebrates. Starting methionine of the predicted p66Shc is boxed in orange. Starting methionine of the predicted p52Shc is boxed in black: it is strictly conserved among vertebrates. Starting methionine of the predicted p46Shc is boxed in blue: it is conserved in mammals, X. tropicalis, D. melanogaster and C. elegans T27F7.2. Starting site of Phosphotyrosine Binding Domain (PTB) is indicated. Hsa: Homo sapiens, Mmu: Mus musculus, Xtr: Xenopus tropicalis, Ola: Oryzias latipes (medaka), Tru: Takifugu rubripes (fugu), Dre: Danio rerio (zebrafish), Nfu: Nothobranchius furzeri, Dme: Drosophila melanogaster, Cel: Caenorhabditis elegans T27F7.2 and F54A5.3a.
Figure 4. Modular organization of p66Shc orthologs of different vertebrate species. CH2, light green: Collagen Homology 2 domain; PTB, red: Phosphotyrosine Binding Domain; CH1, light blue: Collagen Homology 1 domain; SH2, yellow: Src homology 2 domain. Note that a CH2 region is present in all the vertebrate species, whereas it is absent or not recognizable in invertebrates. Post-translational modified amino acid residues are indicated: serines with a pink spot, threonines with a blue spot and tyrosines with a light green spot. For Homo sapiens, it is also indicated the position in the sequence and the type of post-translational modification (P=phosphorylation). Amino acids of the human sequence are also numbered from 1 to 7: in other sequences than human, conserved amino acid residues are indicated only with the corresponding number and not with the position in their sequence. Amino acids are considered conserved even if they are substituted with a functionally similar one: T386 is not found in X. tropicalis, but this amino acid is here substituted with a serine, thus the number (6) is the same, but the color of the spot changes from blue to pink. The Cytochrome c Binding (CB) domain is indicated with a yellow pentagon with the amino acids of the core: EEW in H. sapiens and M. musculus, DEW in X. tropicalis, N. furzeri and D. rerio. Starting site of the p52Shc isoform is also indicated with an arrow.
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