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

Abstract

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 in¯uenced by p66Shc expression. In basal conditions, p66Shc7/7 and p537/7 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.

The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death

“…Indeed, this mouse strain is characterised by a 30% extension of lifespan, 8 a decrease in the levels of in vivo systemic and tissue oxidative stress and vascular apoptosis, 9 and by an abrogation of oxidative stress-induced, p53-dependent apoptosis. [8][9][10] Together with other literature data, these results suggest that p53-dependent mechanisms are candidates to play a crucial role in the pathogenesis of agerelated diseases, such as atherosclerosis and myocardial dysfunction, that is, the major causes of morbidity and mortality among elderly people. [11][12][13][14] In humans, the age of the donor affects the in vitro susceptibility to oxidative stress-induced apoptosis, but a wide interstudy and interindividual variability has been reported.…”

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

“…Oxidative stress shortens telomeres (von Zglinicki, 2002), and the deletion of p66SHC reduces oxidative stress (Trinei et al ., 2002 and Fig. 3A and B).…”

“…Eight‐hydroxy‐2‐deoxy guanosine (8‐OH‐dG) and isoprostanes are recurrent oxidized DNA base and fatty acids products, respectively, that marks oxidative stress to DNA and lipids and were found reduced in p66SHC −/− mice (Trinei et al ., 2002; Napoli et al ., 2003; Lunghi et al ., 2015). We have measured the content of 8‐OH‐dG in the genomic DNA extracted from liver, spleen, lung, and testis of G0 and G3; and liver and spleen of G5 TERC −/− p66SHC +/+ or TERC −/− p66SHC −/− 6‐month‐old mice using a competitive ELISA assay with specific anti‐8‐OH‐dG antibody and of 8‐iso‐PGF2α (8‐isoprostane) by immunohistochemistry analysis of tissue sections from testis, lung, and liver of G0 and G3, TERC −/− p66SHC +/+ , and TERC −/− p66SHC −/− mice.…”

“…At mechanistic level, substantial evidence indicates that p66SHC regulates redox balance and mitochondrial apoptosis by suppressing ROS scavenging and increasing ROS production from plasma membrane oxidases and mitochondria where, in particular, p66SHC favors H 2 O 2 production by ETC (Gertz & Steegborn, 2010; Trinei et al ., 2013). Accordingly, p66SHC −/− tissues showed a reduced level of oxidative damage to nuclear and mitochondrial DNA (Trinei et al ., 2002), lipids (Napoli et al ., 2003), carbohydrates (Menini et al ., 2007), and proteins (Carpi et al ., 2009), which can be either unspecifically or specifically (e.g., redox‐regulated phosphatases; Frijhoff et al ., 2014) damaged by oxidative stress.…”

Characterization of skeletal alterations in a model of prematurely aging mice

“…In bone cells, one important effect of FoxO activation is that this transcription factor binds β-catenin to promote the expression of antioxidant gene program but avoiding that β-catenin might drive the transcription of several genes implicated in osteoblastic function (Almeida et al 2007a;Hoogeboom et al 2008). Other consequences of ROS increase include lipid peroxidation and phosphorylation of p66 Shc leading to an increase in osteoblast and osteocyte apoptosis (Trinei et al 2002;Almeida et al 2007a).…”