title: Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging.
abstract: Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress. We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence. They are selectively down-regulated in cultured fibroblasts after oxidative stress, and, in vivo, in proliferating tissues and during physiological aging. Selectivity is imposed by p66 expression and activation of p44/p53 (also named Delta40p53), a p53 isoform that accelerates aging and prevents mitosis after protein damage. p66 deletion retards aging and increases longevity of p44/p53 transgenic mice. Thus, oxidative stress activates a specific p53 transcriptional response, mediated by p44/p53 and p66, which regulates cellular senescence and aging.
authors: European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.
authors: Valentina
authors: V
authors: Gambino
authors: Giulia
authors: G
authors: De Michele
authors: Oriella
authors: O
authors: Venezia
authors: Pierluigi
authors: P
authors: Migliaccio
authors: Valentina
authors: V
authors: Dall'Olio
authors: Loris
authors: L
authors: Bernard
authors: Simone Paolo
authors: SP
authors: Minardi
authors: Maria Agnese
authors: MA
authors: Della Fazia
authors: Daniela
authors: D
authors: Bartoli
authors: Giuseppe
authors: G
authors: Servillo
authors: Myriam
authors: M
authors: Alcalay
authors: Lucilla
authors: L
authors: Luzi
authors: Marco
authors: M
authors: Giorgio
authors: Heidi
authors: H
authors: Scrable
authors: Pier Giuseppe
authors: PG
authors: Pelicci
authors: Enrica
authors: E
authors: Migliaccio
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D008136:Longevity; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D020033:Protein Isoforms; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C503486:WDR77 protein, mouse