Endothelin-1 Induces Serine Phosphorylation of the Adaptor Protein p66Shc and Its Association with 14-3-3 Protein in Glomerular Mesangial Cells

Foschi, Marco; Franchi, F; Han, Jiahuai; Villa, Giorgio La; Sorokin, Andrey

doi:10.1074/jbc.m102008200

Cited by 43 publications

(39 citation statements)

References 45 publications

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“…Accordingly, in this study, overexpression of a phosphorylation-defective p66 Shc mutant protein in INS-1E cells did not affect basal and reduced palmitate-induced apoptosis, respectively. Depending on the cellular context and stimulus, Ser 36 phosphorylation of p66 Shc was found to be promoted by either the MAP kinases ERK-1/2 or the stressactivated kinases JNK and p38 MAPK [14,15,35,[38][39][40][41][42]. In specific cells, it was shown to be mediated by PKCβ activation [43][44][45].…”

Section: Discussionmentioning

confidence: 96%

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

et al. 2015

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Aims/hypothesis The role of the redox adaptor protein p66 Shc as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. Methods The effects of the FA palmitate on p66 Shc expression were evaluated in human and murine islets and in rat insulinsecreting INS-1E cells. p66 Shc expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66 Shc was investigated using pancreatic islets from p66 Shc−/− mice and in INS-1E cells with knockdown of p66 Shc or overexpression of wildtype and phosphorylation-defective p66 Shc . Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. Results Palmitate induced a selective increase in p66 Shc protein expression and phosphorylation on Ser 36 and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66 Shc expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 Shc−/− mice and following p66 Shc knockdown in INS-1E cells; by contrast, overexpression of p66 Shc , but not that of the phosphorylation-defective p66 Shc mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66 Shc were dependent upon its c-Jun N-terminal kinasemediated phosphorylation on Ser 36 and associated with generation of ROS. p66 Shc protein expression and function were also elevated in islets from HFD-fed mice and from obese/ overweight cadaveric human donors. Conclusions/interpretation p53-dependent augmentation of p66 Shc expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.

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Section: Discussionmentioning

confidence: 96%

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

et al. 2015

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“…Recently, several groups, including ours, have reported serine phosphorylation of the p66 Shc isoform induced by various extracellular stimuli such as growth factors and TPA (19), hydrogen peroxide and UV irradiation (20), Taxol (21), and endothelin-1 (22). In this work, we identified three serine/threonine phosphorylation sites in p66 Shc (20) and appears to be the main phosphorylation site in this isoform.…”

Section: Discussionmentioning

confidence: 67%

“…In addition to tyrosine phosphorylation, p66 Shc can also be phosphorylated at serine/threonine residues in response to epidermal growth factor (EGF) (18), 12-O-tetradecanoylphorbol-13-acetate (TPA) (19), UV stress (20), Taxol (21), and endothelin-1 (22). EGF-induced serine/threonine phosphorylation of p66…”

mentioning

confidence: 99%

Serine/Threonine Phosphorylation of ShcA

Faisal¹,

El-Shemerly²,

Heß

et al. 2002

Journal of Biological Chemistry

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“…In fact, when this amino acid is substituted with an alanine residue, p66Shc-mediated cell death is abrogated [4]. Moreover, it has been demonstrated that Endothelin-1 (ET-1), a vasoconstrictor peptide known to be a potent mitogen for glomerular mesangial cells (GMC), can trigger the phosphorylation of p66Shc on S36: p66Shc serine phosphorylation results in its association with the sequestering protein 14-3-3 [78]. Human and mouse S36 are found within the minimal S/TP (serine/threonine followed by proline) target motif that is recognized by MAPK (Mitogen Activated Protein Kinases), comprising ERKs (Extracellular signal Regulated Kinases), p38MAPK and JNKs (c-Jun N-terminal Kinases) [79,80].…”

Section: P66shc Is a Vertebrate Protein Conserved In Fishmentioning

confidence: 99%

Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

Priami¹,

Michele²,

Cotelli³

et al. 2015

Aging and disease

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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.

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Endothelin-1 Induces Serine Phosphorylation of the Adaptor Protein p66Shc and Its Association with 14-3-3 Protein in Glomerular Mesangial Cells

Cited by 43 publications

References 45 publications

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

Serine/Threonine Phosphorylation of ShcA

Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

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