P66Shc signals to age

Trinei, Mirella; Berniakovich, Ina; Beltrami, Elena; Migliaccio, Enrica; Fassina, Ambrogio; Pelicci, PierGiuseppe

doi:10.18632/aging.100057

Cited by 83 publications

(63 citation statements)

References 35 publications

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“…Furthermore, inactivation of p66Shc by mutating the NH 2 -terminal CH domain unique to p66Shc (with no effect on p46 and p52 isoform transcription) greatly reduces atherosclerosis in mice (see TABLE 2). Indeed, p66Shc seems to signal cells to age generally (1809) and even promotes insulin resistance (1457). Interestingly, p66Shc expression is specifically inhibited by SIRT1 (2106).…”

Section: Ros Effects On Nf-b Signalingmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

390

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Ros Effects On Nf-b Signalingmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

390

344

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“…P66SHC protein is the largest isoform encoded by the ShcA locus, typical of vertebrates, and it sustains intracellular levels of ROS (Giorgio et al ., 2005 Gertz & Steegborn, 2010) and regulates redox signaling pathways (Frijhoff et al ., 2014), mitochondrial apoptosis (Migliaccio et al ., 2006), and aging (Trinei et al ., 2009). P66SHC null mice (p66SHC −/− ) develop normally and resulted to be protected from aging‐associated diseases, such as atherosclerosis (Martin‐Padura et al ., 2008), diabetes compliances (Menini et al ., 2007), onset (Tomilov et al ., 2011), cognitive decline (Berry et al ., 2007), and neurodegeneration (Savino et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

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

2016

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SummaryOxidative stress and telomere attrition are considered the driving factors of aging. As oxidative damage to telomeric DNA favors the erosion of chromosome ends and, in turn, telomere shortening increases the sensitivity to pro‐oxidants, these two factors may trigger a detrimental vicious cycle. To check whether limiting oxidative stress slows down telomere shortening and related progeria, we have investigated the effect of p66SHC deletion, which has been shown to reduce oxidative stress and mitochondrial apoptosis, on late‐generation TERC (telomerase RNA component)‐deficient mice having short telomeres and reduced lifespan. Double mutant (TERC −/− p66SHC −/−) mice were generated, and their telomere length, fertility, and lifespan investigated in different generations. Results revealed that p66SHC deletion partially rescues sterility and weight loss, as well as organ atrophy, of TERC‐deficient mice, but not their short lifespan and telomere erosion.Therefore, our data suggest that p66SHC‐mediated oxidative stress and telomere shortening synergize in some tissues (including testes) to accelerate aging; however, early mortality of late‐generation mice seems to be independent of any link between p66SHC‐mediated oxidative stress and telomere attrition.

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“…p66 Shc differs from the smaller isoforms by the presence of an additional N-terminal region, which is required for its redox activity (10). The distinct nature of this structural feature is reflected by the diverse functions of the Shc isoforms; the p46 Shc and p52 Shc isoforms have been linked to the transmission of mitogenic signals from tyrosine kinases to RAS proteins, whereas the larger p66 Shc isoform is primarily associated with mitochondrial ROS generation and apoptosis (11). p66 Shc is partially localized within the mitochondrial fraction, where it reduces equivalents of the mitochondrial electron transfer chain through the oxidation of cytochrome c (12,13).…”

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confidence: 99%

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

Bock

Shahzad

Wang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

131

178

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The coagulation protease activated protein C (aPC) confers cytoprotective effects in various in vitro and in vivo disease models, including diabetic nephropathy. The nephroprotective effect may be related to antioxidant effects of aPC. However, the mechanism through which aPC may convey these antioxidant effects and the functional relevance of these properties remain unknown. Here, we show that endogenous and exogenous aPC prevents glomerular accumulation of oxidative stress markers and of the redox-regulating protein p66 Shc in experimental diabetic nephropathy. These effects were predominately observed in podocytes. In vitro, aPC inhibited glucose-induced expression of p66 Shc mRNA and protein in podocytes (via PAR-1 and PAR-3) and various endothelial cell lines, but not in glomerular endothelial cells. Treatment with aPC reversed glucose-induced hypomethylation and hyperacetylation of the p66 Shc promoter in podocytes. The hyperacetylating agent sodium butyrate abolished the suppressive effect of aPC on p66 Shc expression both in vitro and in vivo. Moreover, sodium butyrate abolished the beneficial effects of aPC in experimental diabetic nephropathy. Inhibition of p66 Shc expression and mitochondrial translocation by aPC normalized mitochondrial ROS production and the mitochondrial membrane potential in glucose-treated podocytes. Genetic ablation of p66 Shc compensated for the loss of protein C activation in vivo, normalizing markers of diabetic nephropathy and oxidative stress. These studies identify a unique mechanism underlying the cytoprotective effect of aPC. Activated PC epigenetically controls expression of the redox-regulating protein p66 Shc , thus linking the extracellular protease aPC to mitochondrial function in diabetic nephropathy.

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P66Shc signals to age

Cited by 83 publications

References 35 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

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

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

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P66Shc signals to age

Cited by 83 publications

References 35 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

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

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

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Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc