p66SHC: The apoptotic side of Shc proteins

Pellegrini, Michela; Pacini, Sonia; Baldari, Cosima T.

doi:10.1007/s10495-005-6057-8

Cited by 71 publications

(58 citation statements)

References 33 publications

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“…14 Although the expression of ShcB and ShcC seems to be restricted to neuronal cells, ShcA is ubiquitously expressed except for in the brain and in neurons. 14,15 ShcA (hereafter referred to simply as 'Shc') was identified in 1992 as an adaptor molecule coupling the activated epidermal growth factor receptor to Ras and the mitogen-activated protein kinase (MAPK) cascade. 15 Shc proteins have been studied mainly regarding the mechanisms of their mitogenic properties.…”

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“…14,15 ShcA (hereafter referred to simply as 'Shc') was identified in 1992 as an adaptor molecule coupling the activated epidermal growth factor receptor to Ras and the mitogen-activated protein kinase (MAPK) cascade. 15 Shc proteins have been studied mainly regarding the mechanisms of their mitogenic properties. However, p66 Shc inhibits activation of the Ras/MAP kinase pathway by competing with p46 Shc and p52 Shc for binding to Grb2.…”

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“…However, p66 Shc inhibits activation of the Ras/MAP kinase pathway by competing with p46 Shc and p52 Shc for binding to Grb2. [14][15][16][17][18] Recent studies have reported that p66 Shc contributes to the regulation of cellular OS and apoptosis. [19][20][21] Fibroblasts and hepatocytes without p66 Shc have increased resistance to OS and apoptosis with increased levels of Mn-superoxide dismutase (SOD), redox factor-1 (Ref-1), and Bcl-xL.…”

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p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism

Haga

Morita

Irani

et al. 2010

Laboratory Investigation

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Liver regeneration involves complicated processes and is affected by various patho-physiological conditions. This study was designed to examine the molecular mechanisms underlying the aging-associated impairment of liver regeneration. Male C57BL/6J mice were used as young and aged mice (o10 weeks and 420 months old, respectively). These mice were subjected to 70% partial hepatectomy (PH). Liver regeneration and liver injury/stresses were evaluated chronologically after PH. Post-hepatectomy liver regeneration was markedly impaired in aged mice. Though the extent of hepatocyte proliferation in the regenerating liver was similar in aged and young mice, cell growth was absent in aged mice. Oxidative stress (OS) was observed immediately after hepatectomy, followed by marked apoptosis in aged mice. Signaling molecules regarding cell proliferation (mitogen-activated protein kinase, STAT3, p46/52 Shc ) and anti-oxidation (catalase, superoxide dismutase, Ref-1, glutathione peroxidase) were expressed/activated after hepatectomy in livers of both aged and young mice. Akt was not activated in aged-mouse liver, but its expression was similar to that in young mice. p66 Shc , known as an age-/oxidantassociated protein, was strongly phosphorylated. By knocking down p66 Shc , the impairment of liver regeneration was normalized. OS immediately after hepatectomy induced subsequent liver injury (apoptosis), and deletion of p66 Shc suppressed both OS and hepatocyte apoptosis in the regenerating liver of aged mice. Though we need additional data in other animal models to fully understand the mechanism, p66 Shc may have a pivotal function in the impairment of liver regeneration in aged mice by triggering OS and subsequent apoptosis. This data may provide a clue to understanding the mechanism underlying the association between aging and the impairment of liver regeneration.

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p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism

Haga

Morita

Irani

et al. 2010

Laboratory Investigation

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“…[2][3][4] Furthermore, p66Shc is implicated in signaling pathways linking oxidative stress to apoptosis. 5 This property maps to a unique N-terminal domain containing a critical serine residue at position 36, which is phosphorylated in response to stress. 4,[6][7][8] Inactivation of the gene encoding p66Shc in the mouse results in prolonged life span, 6 which has been ascribed to a decreased production of reactive oxygen species (ROS).…”

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p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

et al. 2006

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p66Shc, a redox enzyme that enhances reactive oxygen species (ROS) production by mitochondria, promotes T cell apoptosis. We have addressed the mechanisms regulating p66Shc-dependent apoptosis in T cells exposed to supraphysiological increases in [Ca 2 þ ] c . p66Shc expression resulted in profound mitochondrial dysfunction in response to the Ca 2 þ ionophore A23187, as revealed by dissipation of mitochondrial transmembrane potential, cytochrome c release and decreased ATP levels. p66Shc expression also caused a dramatic alteration in the cells' Ca 2 þ -handling ability, which resulted in Ca 2 þ overload after A23187 treatment. The impairment in Ca 2 þ homeostasis was ROS dependent and caused by defective Ca 2 þ extrusion due at least in part to decreased plasma membrane ATPase (PMCA) expression. Both effects of p66Shc required Ca 2 þ -dependent serine-36 phosphorylation. The mitochondrial effects of p66Shc were potentiated by but not strictly dependent on the rise in [Ca 2 þ ] c . Thus, Ca 2 þ -dependent p66Shc phosphorylation causes both mitochondrial dysfunction and impaired Ca 2 þ homeostasis, which synergize in promoting T cell apoptosis.

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“…Shc is expressed as three isoforms that are encoded by a single gene locus (2,3). p46Shc and p52Shc are ubiquitous isoforms that arise through the use of alternative translation initiation sites within the same transcript.…”

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Distinct Signaling Functions for Shc Isoforms in the Heart

Obreztchikova

Elouardighi

et al. 2006

Journal of Biological Chemistry

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Thrombin activates protease-activated receptor-1 (PAR-1) and engages signaling pathways that influence the growth and survival of cardiomyocytes as well as extracellular matrix remodeling by cardiac fibroblasts. This study examines the role of Shc proteins in PAR-1-dependent signaling pathways that influence ventricular remodeling. We show that thrombin increases p46Shc/p52Shc phosphorylation at and/or Tyr 317 phosphorylation). Importantly, p66Shc protein expression is detected in neonatal, but not adult, cardiomyocytes; p66Shc expression is induced (via a mechanism that requires protein kinase C and MEK activity) by Pasteurella multocida toxin, a G␣ q agonist that promotes cardiomyocyte hypertrophy. These results identify novel regulation of individual Shc isoforms in receptor-dependent pathways leading to cardiac hypertrophy and the transition to heart failure. The observations that p66Shc expression is induced by a G␣ q agonist and that PAR-1 activation leads to p66Shc-Ser 36 phosphorylation identifies p66Shc as a novel candidate hypertrophy-induced mediator of cardiomyocyte apoptosis and heart failure.Cardiac hypertrophy and the progression to heart failure is the result of a complex array of signaling events that lead to structural remodeling of the ventricle. The literature has focused primarily on signaling mechanisms that regulate cardiomyocyte growth and survival. However, cardiac fibroblasts (activated by fibrogenic growth factors and pro-inflammatory cytokines) also play an important role in influencing the architecture and mechanical behavior of the heart by regulating collagen matrix remodeling and by elaborating growth factors that promote cardiomyocyte hypertrophy. Extensive cardiac fibroblast-induced structural remodeling disrupts the normal transmission of electrical impulses, impairs contractile performance, and critically influences clinical heart failure syndromes.Protease-activated receptor-1 (PAR-1) 2 is a G protein-coupled receptor that is proteolytically activated by thrombin and other pro-inflammatory proteases. We previously demonstrated that chronic/persistent PAR-1 activation leads to cardiomyocyte hypertrophy and cardiac fibroblast proliferation (1). PAR-1-dependent growth responses are mediated by distinct signaling mechanisms in cardiomyocytes and cardiac fibroblasts. PAR-1 evokes a robust increase in ERK, p38-MAPK, and AKT and increases DNA synthesis via an epidermal growth factor receptor (EGFR) transactivation pathway in cardiac fibroblasts, whereas PAR-1 activates ERK (and induces only a relatively minor increase in AKT) via a mechanism that does not require EGFR kinase activity in cardiomyocytes. The contextual nature of PAR-1 signaling emphasizes the need to directly examine PAR-1 actions in physiologically relevant cardiac preparations.Shc proteins are molecular adapters that link surface receptors to mitogenic responses. Shc is expressed as three isoforms that are encoded by a single gene locus (2, 3). p46Shc and p52Shc are ubiquitous isoforms that arise through the use of ...

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p66SHC: The apoptotic side of Shc proteins

Cited by 71 publications

References 33 publications

p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism

p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

Distinct Signaling Functions for Shc Isoforms in the Heart

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