The Shc locus regulates insulin signaling and adiposity in mammals
Open accessAbstract
Summary: Longevity of a p66Shc knockout strain (ShcP) was previously attributed to increased stress resistance and altered mitochondria. Microarrays of ShcP tissues indicated alterations in insulin signaling. Consistent with this observation, ShcP mice were more insulin sensitive and glucose tolerant at organismal and tissue levels, as was a novel p66Shc knockout (ShcL). Increasing and decreasing Shc expression in cell lines decreased and increased insulin sensitivity, respectively – consistent with p66Shc’s function as a repressor of insulin signaling. However, differences between the two p66Shc knockout strains were also observed. ShcL mice were fatter and susceptible to fatty diets, and their fat was more insulin sensitive than controls. On the other hand, ShcP mice were leaner and resisted fatty diets, and their adipose was less insulin sensitive than controls. ShcL and ShcP strains are both highly inbred on the C57Bl/6 background, so we investigated gene expression at the Shc locus, which encodes three isoforms, p66, p52, and p46. Isoform p66 is absent in both strains; thus, the remaining difference to which to attribute the ‘lean’ phenotype is expression of the other two isoforms. ShcL mice have a precise deletion of p66Shc and normal expression of p52 and p46Shc isoforms in all tissues; thus, a simple deletion of p66Shc results in a ‘fat’ phenotype. However, ShcP mice in addition to p66Shc deletion have a fourfold increase in p46Shc expression in white fat. Thus, p46Shc overexpression in fat, rather than p66Shc deletion, is the likely cause of decreased adiposity and reduced insulin sensitivity in the fat of ShcP mice, which has implications for the longevity of the strain.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
(1985) · International Journal of Biochemistry · doi:10.1016/0020-711x(85)90098-9 · Cited by 3,497 · see citing works
IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice
Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Géloën, A., Even, P. C., Cervera, P., & Le Bouc, Y. (2003) · Nature · doi:10.1038/nature01298 · Cited by 2,109 · cited 2× · see citing works
“Lifespan extension occurs in multiple small mice including in Igf1r ⁄ ) mice (Holzenberger et al. 2003), GH-deficient ‘Little’ and ‘Midi’, and mice with reduced local (tissue) availability of IGF-1 – PAPP-A ⁄ .”
BackgroundSuppression of Aging in Mice by the Hormone Klotho
Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., McGuinness, O. P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., et al. (2005) · Science · doi:10.1126/science.1112766 · Cited by 1,935 · see citing works
Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., et al. (2001) · Nature · doi:10.1038/35093050 · Cited by 1,821 · cited 1× · see citing works
“Insulin-inhibitable glucose release was assayed similarly as described (Yoon et al., 2001; Li et al., 2007).”
MethodThe p66shc adaptor protein controls oxidative stress response and life span in mammals
Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Pandolfi, P. P., Lanfrancone, L., & Pelicci, P. G. (1999) · Nature · doi:10.1038/46311 · Cited by 1,712 · cited 5× · see citing works
“It was reported that cells from long-lived ShcP knockout mice resist oxidative stress (Migliaccio et al., 1999) and that the longevity of ShcP mice has been attributed to oxidative stress resistance and changes in mitochondrial biogenesis (Trinei et al., 2009) and the role of p66Shc in…”
BackgroundMethodInfluentialSelf-citationExtended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue
Blüher, M., Kahn, B. B., & Kahn, C. R. (2003) · Science · doi:10.1126/science.1078223 · Cited by 1,348 · cited 6× · see citing works
“pose as a determinant of longevity and are consistent with the FIRKO mice in which insulin receptor deletion in fat decreased fat mass and caused increased longevity (Bluher et al., 2003; Kloting & Bluher, 2005).”
BackgroundResultInfluentialA novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction
Pelicci, G., Lanfrancone, L., Grignani, F., McGlade, J. C., Cavallo, F., Forni, G., Nicoletti, I., Grignani, F., Pawson, T. J., & Pelicci, P. G. (1992) · Cell · doi:10.1016/0092-8674(92)90536-l · Cited by 1,326 · cited 6× · see citing works
“However, asShc proteins arealso implicated in insulin ⁄ IGF-1 and other receptor tyrosine kinases signaling (Pelicci et al., 1992; Saucier et al., 2004; Laviola et al., 2007; Neumann-Haefelin et al., 2008), mutations at Shc locus could influence the insulin ⁄ IGF-1 pathway that has been demonstrated to be critical in…”
BackgroundInfluentialSelf-citationA systems biology approach for pathway level analysisPreprint
Drăghici, S., Khatri, P., Tarca, A. L., Amin, K., Done, A., Voichiţa, C., Georgescu, C., & Romero, R. J. (2007) · Genome Research · doi:10.1101/gr.6202607 · Cited by 1,250 · cited 4× · see citing works
“upregulated and 500 downregulated through genes of different tissues were analyzed using Onto-Tool: Pathway Express (Draghici et al., 2007).”
MethodInfluentialGiorgio, M., Migliaccio, E., Orsini, F., Paolucci, D., Moroni, M., Contursi, C., Pelliccia, G., Luzi, L., Minucci, S., Marcaccio, M., et al. (2005) · Cell · doi:10.1016/j.cell.2005.05.011 · Cited by 1,176 · cited 2× · see citing works
“…ShcP knockout mice resist oxidative stress (Migliaccio et al., 1999) and that the longevity of ShcP mice has been attributed to oxidative stress resistance and changes in mitochondrial biogenesis (Trinei et al., 2009) and the role of p66Shc in mitochondrial apoptosis process (Giorgio et al., 2005).”
BackgroundSelf-citationFlurkey, K., Papaconstantinou, J., Miller, R. A., & Harrison, D. E. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111158898 · Cited by 826 · cited 1× · see citing works
“Thus, mutations in long-lived prop-1 and pit-1 mice (Flurkey et al., 2001; Hsieh et al., 2002a) cause defects in the development of hypophysis, leading to defects in the production of GH, prolactin, and TSH in mice, which is responded to by somatotrophs.”
BackgroundLife without white fat: a transgenic mousePreprint
Moitra, J., Mason, M. M., Olive, M., Krylov, D. Y., Gavrilova, O., Marcus‐Samuels, B., Feigenbaum, L., Lee, E., Aoyama, T., Eckhaus, M., et al. (1998) · Genes & Development · doi:10.1101/gad.12.20.3168 · Cited by 776 · cited 1× · see citing works
“Mice with the complete deletion of fat are diabetic and short-lived (Moitra et al., 1998).”
BackgroundSelman, C., Lingard, S., Choudhury, A. I., Batterham, R. L., Claret, M., Clements, M., Ramadani, F., Okkenhaug, K., Schuster, E., Blanc, E., et al. (2008) · The FASEB Journal · doi:10.1096/fj.07-9261com · Cited by 532 · see citing works
Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis
Taguchi, A., Wartschow, L. M., & White, M. F. (2007) · Science · doi:10.1126/science.1142179 · Cited by 523 · see citing works
Coschigano, K. T., Holland, A. N., Riders, M. E., List, E. O., Flyvbjerg, A., & Kopchick, J. J. (2003) · Endocrinology · doi:10.1210/en.2003-0374 · Cited by 510 · cited 1× · see citing works
“…in growth hormone receptor extends lifespan, increases body insulin sensitivity, increases food intake, and decreases adiposity in GHR) ⁄ ) mice (Coschigano et al., 2003), and tissue insulin sensitivity is also improved in Aims and Snell dwarfs, GHRKO, FIRKO, and calorie-restricted mice…”
BackgroundAkt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator
Li, X., Monks, B., Ge, Q., & Birnbaum, M. J. (2007) · Nature · doi:10.1038/nature05861 · Cited by 487 · cited 1× · see citing works
“Insulin-inhibitable glucose release was assayed similarly as described (Yoon et al., 2001; Li et al., 2007).”
MethodBarbieri, M., Bonafè, M., Franceschi, C., & Paolisso, G. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00296.2003 · Cited by 456 · cited 2× · see citing works
“…of lifespan across several species have identified mutations in the insulin ⁄ IGF-1 pathway as a common cause of longevity in Mus. musculus, Drosophila melanogaster, and Caenorhabditis elegans (Barbieri et al., 2003; Bluher et al., 2003; Ayyadevara et al., 2008; Bartke, 2008b; Selman et al., 2008).”
BackgroundEvidence That Glucose Metabolism Regulates Leptin Secretion from Cultured Rat Adipocytes
Mueller, W. M., Gregoire, F. M., Stanhope, K. L., Mobbs, C. V., Mizuno, T. M., Warden, C. H., Stern, J. S., & Havel, P. J. (1998) · Endocrinology · doi:10.1210/endo.139.2.5716 · Cited by 427 · see citing works
Migliaccio, E., Mele, S., Salcini, A. E., Pelicci, G., Lai, K. V., Superti‐Furga, G., Pawson, T. J., Fiore, P. P. D., Lanfrancone, L., & Pelicci, P. G. (1997) · The EMBO Journal · doi:10.1093/emboj/16.4.706 · Cited by 395 · cited 6× · see citing works
“The Shc locus and longevity: oxidative stress, mitochondria, and apoptosis The mammalian Shc locus encodes three adaptor proteins – p66Shc, p46Shc, and p52Shc (Pelicci et al., 1992) – which transmit hormonal signals in cells (Migliaccio et al., 1997).”
BackgroundInfluentialSelf-citationLife Extension in the Dwarf Mouse
Bartke, A., & Brown‐Borg, H. M. (2004) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(04)63006-7 · Cited by 354 · cited 3× · see citing works
“Also, some long-lived rodents, such as Ames, Snell and little mice, and GHRKO mice (Hsieh et al., 2002b; Amador-Noguez et al., 2004; Bartke & Brown-Borg, 2004), have more fat than controls at the end of life.”
BackgroundLaviola, L., Natalicchio, A., & Giorgino, F. (2007) · Current Pharmaceutical Design · doi:10.2174/138161207780249146 · Cited by 296 · cited 4× · see citing works
“…Shc proteins are adaptors, which directly interact with receptor tyrosine kinases (RTK), activating Shc ⁄ Ras ⁄ ERK pathway, such as IGF-1 receptor (Laviola et al., 2007), insulin receptor (IR), and EGF receptor (Pelicci et al., 1992; Lotti et al., 1996; Migliaccio et al., 1997; Laviola et…”
BackgroundInfluentialSchadt, E. E., Cheng, L., Ellis, B., & Wong, W. H. (2001) · Journal of Cellular Biochemistry · doi:10.1002/jcb.10073 · Cited by 288 · see citing works
Visceral adipose tissue modulates mammalian longevity
Muzumdar, R. H., Allison, D. B., Huffman, D. M., Ma, X., Atzmon, G., Einstein, F. H., Fishman, S., Poduval, A., McVei, T., Keith, S. W., et al. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00391.x · Cited by 213 · cited 3× · see citing works
“The results of our study are also consistent with the observation that surgical deletion or transplantation of visceral fat is an important determinant of longevity in rodents (Muzumdar et al., 2008).”
BackgroundResultRemarkable longevity and stress resistance of nematode PI3K‐null mutants
Ayyadevara, S., Alla, R., Thaden, J. J., & Reis, R. J. S. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00348.x · Cited by 205 · cited 2× · see citing works
“…of lifespan across several species have identified mutations in the insulin ⁄ IGF-1 pathway as a common cause of longevity in Mus. musculus, Drosophila melanogaster, and Caenorhabditis elegans (Barbieri et al., 2003; Bluher et al., 2003; Ayyadevara et al., 2008; Bartke, 2008b; Selman et al., 2008).”
Backgroundp66Shc-generated Oxidative Signal Promotes Fat Accumulation
Berniakovich, I., Trinei, M., Stendardo, M., Migliaccio, E., Minucci, S., Bernardi, P., Pelicci, P. G., & Giorgio, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804362200 · Cited by 161 · cited 3× · see citing works
“These results are consistent with the view that Shc antagonizes insulin signaling through the PI3Kinase pathway, as has recently been reported for IGF-1 signaling (Xi et al., 2008) and for insulin signaling (Berniakovich et al., 2008).”
BackgroundResultSelf-citationAdiponectin Levels and Genotype: A Potential Regulator of Life Span in Humans
Atzmon, G., Pollin, T. I., Crandall, J. P., Tanner, K., Schechter, C. B., Scherer, P. E., Rincón, M., Siegel, G., Katz, M., Lipton, R. B., et al. (2008) · The Journals of Gerontology Series A · doi:10.1093/gerona/63.5.447 · Cited by 145 · cited 1× · see citing works
“Obesity in rodents and humans is a very important contributor to ‘unhealthy aging’ conditions, including diabetes and inflammatory diseases, which shorten lifespan (Barzilai & Gabriely, 2001; Gabriely & Barzilai, 2001; Atzmon et al., 2008).”
BackgroundImpact of reduced insulin‐like growth factor‐1/insulin signaling on aging in mammals: novel findings
Bartke, A. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00387.x · Cited by 142 · see citing works
Gene expression profile of long‐lived Ames dwarf mice and Little mice
Amador‐Noguez, D., Yagi, K., Venable, S., & Darlington, G. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00125.x · Cited by 132 · cited 1× · see citing works
“Also, some long-lived rodents, such as Ames, Snell and little mice, and GHRKO mice (Hsieh et al., 2002b; Amador-Noguez et al., 2004; Bartke & Brown-Borg, 2004), have more fat than controls at the end of life.”
BackgroundLow Body Temperature in Long-Lived Ames Dwarf Mice at Rest and During Stress
Hunter, W. S., Croson, W., Bartke, A., Gentry, M. V., & Meliska, C. J. (1999) · Physiology & Behavior · doi:10.1016/s0031-9384(99)00098-0 · Cited by 106 · cited 2× · see citing works
“However, these mice also appear to have functional trade-offs for their longevity, including reduced reproductive capacity, reduced body temperature, obesity, and dwarfism (Hunter et al., 1999; Van Voorhies et al., 2006).”
BackgroundMammalian life-span determinant p66 shcA mediates obesity-induced insulin resistance
Ranieri, S. C., Fusco, S., Panieri, E., Labate, V., Mele, M., Tesori, V., Ferrara, A. M., Maulucci, G., Spirito, M. D., Martorana, G. E., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008647107 · Cited by 101 · cited 3× · see citing works
“Increased insulin sensitivity and glucose tolerance of ShcP mice were also demonstrated recently when ShcP mice were put on the Ob ⁄ Ob background (Ranieri et al., 2010).”
BackgroundIsoform-specific knockdown and expression of adaptor protein ShcA using small interfering RNA
Kisielow, M., Kleiner, S., Nagasawa, M., Faisal, A., & Nagamine, Y. (2002) · Biochemical Journal · doi:10.1042/0264-6021:3630001 · Cited by 96 · cited 1× · see citing works
“The si-RNA for the specific knockdown of p66Shc was described by Kisielow et al. (2002).”
BackgroundInsulin Signaling in Human Visceral and Subcutaneous Adipose Tissue In Vivo
Laviola, L., Perrini, S., Cignarelli, A., Natalicchio, A., Leonardini, A., Stefano, F. D., Cuscito, M., Fazio, M. D., Memeo, V., Neri, V., et al. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-1414 · Cited by 95 · cited 2× · see citing works
“…proteins are adaptors, which directly interact with receptor tyrosine kinases (RTK), activating Shc ⁄ Ras ⁄ ERK pathway, such as IGF-1 receptor (Laviola et al., 2007), insulin receptor (IR), and EGF receptor (Pelicci et al., 1992; Lotti et al., 1996; Migliaccio et al., 1997; Laviola et al., 2006).”
BackgroundHsieh, C.-C., DeFord, J. H., Flurkey, K., Harrison, D. E., & Papaconstantinou, J. (2002) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(02)00037-4 · Cited by 93 · cited 2× · see citing works
“Thus, mutations in long-lived prop-1 and pit-1 mice (Flurkey et al., 2001; Hsieh et al., 2002a) cause defects in the development of hypophysis, leading to defects in the production of GH, prolactin, and TSH in mice, which is responded to by somatotrophs.”
BackgroundLong-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging
Bartke, A. (2006) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.01.002 · Cited by 89 · cited 1× · see citing works
“…receptor extends lifespan, increases body insulin sensitivity, increases food intake, and decreases adiposity in GHR) ⁄ ) mice (Coschigano et al., 2003), and tissue insulin sensitivity is also improved in Aims and Snell dwarfs, GHRKO, FIRKO, and calorie-restricted mice (Bartke, 2006, 2008a).”
BackgroundTrinei, M., Berniakovich, I., Beltrami, E., Migliaccio, E., Fassina, A., Pelicci, P. G., & Giorgio, M. (2009) · Aging · doi:10.18632/aging.100057 · Cited by 88 · cited 1× · see citing works
“…ShcP knockout mice resist oxidative stress (Migliaccio et al., 1999) and that the longevity of ShcP mice has been attributed to oxidative stress resistance and changes in mitochondrial biogenesis (Trinei et al., 2009) and the role of p66Shc in mitochondrial apoptosis process (Giorgio et al., 2005).”
BackgroundSelf-citationThe Role of Fat Depletion in the Biological Benefits of Caloric Restriction
Barzilai, N., & Gabriely, I. (2001) · Journal of Nutrition · doi:10.1093/jn/131.3.903s · Cited by 84 · cited 1× · see citing works
“Obesity in rodents and humans is a very important contributor to ‘unhealthy aging’ conditions, including diabetes and inflammatory diseases, which shorten lifespan (Barzilai & Gabriely, 2001; Gabriely & Barzilai, 2001; Atzmon et al., 2008).”
BackgroundPérez‐Matute, P., Martí, A., Martínez, J. A., Fernández-Otero, M. P., Stanhope, K. L., Havel, P. J., & Moreno-Aliaga, M. J. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00727.2004 · Cited by 84 · cited 2× · see citing works
“Assays were performed similarly as described (Mueller et al., 1998; Perez-Matute et al., 2005).”
MethodExtended longevity and insulin signaling in adipose tissue
Klöting, N., & Blüher, M. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.07.004 · Cited by 77 · cited 1× · see citing works
“These results highlight the importance of insulin signaling in adipose as a determinant of longevity and are consistent with the FIRKO mice in which insulin receptor deletion in fat decreased fat mass and caused increased longevity (Bluher et al., 2003; Kloting & Bluher, 2005).”
ResultHsieh, C.-C., DeFord, J. H., Flurkey, K., Harrison, D. E., & Papaconstantinou, J. (2002) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(02)00036-2 · Cited by 76 · see citing works
Saucier, C., Khoury, H., Lai, K. V., Peschard, P., Dankort, D. L., Naujokas, M. A., Holash, J. A., Yancopoulos, G. D., Muller, W. J., Pawson, T. J., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308065101 · Cited by 73 · see citing works
Lotti, L. V., Lanfrancone, L., Migliaccio, E., Zompetta, C., Pelicci, G., Salcini, A. E., Falini, B., Pelicci, P. G., & Torrisi, M. R. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.1946 · Cited by 73 · cited 2× · see citing works
“…proteins are adaptors, which directly interact with receptor tyrosine kinases (RTK), activating Shc ⁄ Ras ⁄ ERK pathway, such as IGF-1 receptor (Laviola et al., 2007), insulin receptor (IR), and EGF receptor (Pelicci et al., 1992; Lotti et al., 1996; Migliaccio et al., 1997; Laviola et al., 2006).”
BackgroundSelf-citationIsoform-specific knockdown and expression of adaptor protein ShcA using small interfering RNA
Kisielow, M., Kleiner, S., Nagasawa, M., et al. (2002) · Biochemical Journal · doi:10.1042/bj3630001 · Cited by 65 · see citing works
The role of insulin and insulin-like growth factor-I in mammalian ageing
Richardson, A., Liu, F., Adamo, M. L., Remmen, H. V., & Nelson, J. F. (2004) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2004.02.002 · Cited by 64 · cited 1× · see citing works
“A growing body of literature supports the claim that reductions in the insulin ⁄ IGF axis extend rodent lifespan (Richardson et al., 2004; Selman et al., 2008).”
BackgroundNeumann‐Haefelin, E., Qi, W., Finkbeiner, E., Walz, G., Baumeister, R., & Hertweck, M. (2008) · Genes & Development · doi:10.1101/gad.478408 · Cited by 62 · see citing works
A Cryptic Targeting Signal Induces Isoform-specific Localization of p46Shc to Mitochondria
Ventura, A., Maccarana, M., Raker, V. A., & Pelicci, P. G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m307655200 · Cited by 60 · cited 1× · see citing works
“…that this part of the phenotype is the result of p46Shc overexpression in fat, and we showed by ex vivo experiments that insulin-dependent glucose uptake is decreased in ShcP fat, but increased in ShcL fat. p46Shc has been previously reported to reside in mitochondria (Ventura et al., 2004).”
BackgroundSelf-citationDecreased Superoxide Production in Macrophages of Long-lived p66Shc Knock-out Mice
Tomilov, A. A., Bicocca, V. T., Schoenfeld, R. A., Giorgio, M., Migliaccio, E., Ramsey, J. J., Hagopian, K., Pelicci, P. G., & Cortopassi, G. A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.017491 · Cited by 60 · see citing works
Self-citationXi, G., Shen, X., & Clemmons, D. R. (2008) · Molecular Endocrinology · doi:10.1210/me.2008-0079 · Cited by 47 · cited 3× · see citing works
“These results are consistent with the view that Shc antagonizes insulin signaling through the PI3Kinase pathway, as has recently been reported for IGF-1 signaling (Xi et al., 2008) and for insulin signaling (Berniakovich et al., 2008).”
BackgroundResulther, M. B. U. (2008) · Obesity Facts · doi:10.1159/000145930 · Cited by 43 · cited 1× · see citing works
“Fat-specific disruption of the insulin receptor gene is sufficient to increase lifespan in FIRKO mice, suggesting that reduced adiposity, even in the presence of normal or increased food intake, can extend lifespan (Bluher et al., 2003; Bluher, 2008).”
BackgroundDo longevity mutants always show trade-offs?
Voorhies, W. A. V., Curtsinger, J. W., & Rose, M. R. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.05.006 · Cited by 43 · see citing works
Involvement of the p66Shcprotein in glucose transport regulation in skeletal muscle myoblasts
Natalicchio, A., Stefano, F. D., Perrini, S., Laviola, L., Cignarelli, A., Caccioppoli, C., Quagliara, A., Melchiorre, M., Leonardini, A., Conserva, A., et al. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90347.2008 · Cited by 31 · cited 4× · see citing works
“An inhibitory effect of p66Shc on glucose uptake and activation of ERK by insulin was recently shown in vitro for L6 myoblasts (Natalicchio et al., 2009) and smooth muscle cells (Xi et al.”
BackgroundInfluentialThe role of fat cell derived peptides in age-related metabolic alterations
Gabriely, I., & Barzilai, N. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(01)00287-1 · Cited by 24 · cited 1× · see citing works
“Obesity in rodents and humans is a very important contributor to ‘unhealthy aging’ conditions, including diabetes and inflammatory diseases, which shorten lifespan (Barzilai & Gabriely, 2001; Gabriely & Barzilai, 2001; Atzmon et al., 2008).”
BackgroundNew findings in gene knockout, mutant and transgenic mice☆
Bartke, A. (2007) · Experimental Gerontology · doi:10.1016/j.exger.2007.10.009 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution
Niemann, B., Rohrbach, S., Miller, M. R., Newby, D. E., Fuster, V., & Kovacic, J. C. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.05.043 · Cited by 354 · see citing works
Oxidative Stress in Cardiovascular Diseases and Obesity: Role of p66Shc and Protein Kinase C
Marchi, E. D., Baldassari, F., Bononi, A., Wieckowski, M. R., & Pinton, P. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/564961 · Cited by 132 · see citing works
“rmed the role of p66Shc in insulin signalling; they have demonstrated that it is also the overexpression of fat of another isoform of Shc locus, p46, that is the likely cause of decreased adiposity and reduced insulin sensitivity [104].”
BackgroundNutrient-sensing mTORC1: Integration of metabolic and autophagic signals
Tan, V. P., & Miyamoto, S. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.01.005 · Cited by 110 · see citing works
“and p66Shc upregulation is also suggested to be associated with type 2 diabetes and obesity [98-101].”
Mitochondrial dysfunction and neurodegeneration in multiple sclerosis
Su, K., BOURDETTE, D. N., & Forte, M. A. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00169 · Cited by 93 · see citing works
“Recent studies have shown however that in response to the elimination of p66 in this KO line, another Shc isoform, p46 has a fourfold increased expression in white fat (Tamilov et al., 2011).”
BackgroundNew aspects of p66Shc in ischaemia reperfusion injury and other cardiovascular diseases
Lisa, F. D., Giorgio, M., Ferdinándy, P., & Schulz, R. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13478 · Cited by 66 · see citing works
“In contrast, cold exposure or obesogenic high fat diet increase p66Shc protein levels in mouse fat and muscle (Berniakovich et al., 2008; Tomilov et al., 2011; Giorgio et al., 2012).”
BackgroundInfluentialSelf-citationStructure-functional implications of longevity protein p66Shc in health and disease
Mir, H. A., Ali, R., Mushtaq, U., & Khanday, F. A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101139 · Cited by 60 · see citing works
Gómez‐Serrano, M., Camafeita, E., García‐Santos, E., López, J. A., Rubio, M. Á., Sánchez-Pernaute, A., Torres, A., Vázquez, J., & Peral, B. (2016) · Scientific Reports · doi:10.1038/srep25756 · Cited by 58 · see citing works
P66shc and its role in ischemic cardiovascular diseases
Boengler, K., Bornbaum, J., Schlüter, K., & Schulz, R. (2019) · Basic Research in Cardiology · doi:10.1007/s00395-019-0738-x · Cited by 55 · see citing works
Safari‐Alighiarloo, N., Taghizadeh, M. T., Tabatabaei, S. M., Shahsavari, S., Namaki, S., Khodakarim, S., & Rezaei–Tavirani, M. (2016) · Journal of Diabetes · doi:10.1111/1753-0407.12483 · Cited by 54 · see citing works
“in a p66Shc-knockout strain of mice (ShcP).(59) All five markers were incorporated in ErbB signaling pathway.”
Backgroundp66Shc, Mitochondria, and the Generation of Reactive Oxygen Species
Trinei, M., Migliaccio, E., Bernardi, P., Paolucci, F., Pelicci, P. G., & Giorgio, M. (2013) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-405881-1.00006-9 · Cited by 51 · see citing works
Self-citationAndreadou, I., Daiber, A., Baxter, G. F., Brizzi, M. F., Lisa, F. D., Kaludercic, N., Lazou, A., Varga, Z. V., Zuurbier, C. J., Schulz, R., et al. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.012 · Cited by 52 · see citing works
Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation
Pesaresi, M. G., Amori, I., Giorgi, C., Ferri, A., Fiorenzo, P., Gabanella, F., Salvatore, A. M., Giorgio, M., Pelicci, P. G., Pinton, P., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr347 · Cited by 49 · see citing works
Self-citationTargeting SHCBP1 Inhibits Cell Proliferation in Human Hepatocellular Carcinoma Cells
Tao, H., Wang, H.-X., Dai, M., Gu, C., Wang, Q., Han, Z., & Cai, B. (2013) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2013.14.10.5645 · Cited by 44 · see citing works
“Shc proteins can activate tyrosine kinases receptor via tyrosine phosphorylated (Tomilov et al., 2011; Tomilov et al., 2011; Sweet et al., 2012).”
BackgroundThe Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism
Lamming, D. W., Soliman, M. A., Rahman, A. M. A., Birsoy, K., Pawling, J., Frigolet, M. E., Lu, H., Fantus, I. G., Pasculescu, A., Zheng, Y., et al. (2013) · DSpace@MIT (Massachusetts Institute of Technology) · Cited by 44 · see citing works
The p66Shc gene paves the way for healthspan: Evolutionary and mechanistic perspectives
Berry, A., & Cirulli, F. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.03.005 · Cited by 43 · see citing works
The Influence of Shc Proteins on Life Span in Mice
Ramsey, J. J., Tran, D., Giorgio, M., Griffey, S. M., Koehne, A. L., Laing, S. T., Taylor, S. L., Kim, K., Cortopassi, G. A., Lloyd, K. C. K., et al. (2013) · The Journals of Gerontology Series A · doi:10.1093/gerona/glt198 · Cited by 43 · see citing works
“There is also evidence that ShcKO decreases adiposity (6,22,25) and increases capacity for fatty acid oxidation (8) and these changes may influence life span under certain conditions, such as diet-induced obesity.”
BackgroundInfluentialSelf-citationBellisario, V., Berry, A., Capoccia, S., Raggi, C., Panetta, P., Branchi, I., Piccaro, G., Giorgio, M., Pelicci, P. G., & Cirulli, F. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00285 · Cited by 41 · see citing works
Self-citationp66Shc-induced redox changes drive endothelial insulin resistance
Paneni, F., Costantino, S., & Cosentino, F. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.07.027 · Cited by 38 · see citing works
“On the other hand, previous work has demonstrated that other Shc isoforms, namely p46Shc, mediate insulin signalling in adipocytes [18].”
Backgroundp66Shc in Cardiovascular Pathology
Haslem, L., Hays, J. M., & Hays, F. A. (2022) · Cells · doi:10.3390/cells11111855 · Cited by 37 · see citing works
Role of adaptor protein p66Shc in renal pathologies
Wright, K. D., Staruschenko, A., & Sorokin, A. (2017) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00414.2017 · Cited by 33 · see citing works
“Potentially confounding the role of p66Shc in longevity in this initial p66Shc-knockout mouse strain, however, is the fact that p46Shc expression is more than fourfold upregulated compared with control mice, accompanied by a decrease in p52Shc expression (101).”
BackgroundInfluentialp66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans
Ciciliot, S., Albiero, M., Menegazzo, L., Poncina, N., Scattolini, V., Danesi, A., Pagnin, E., Marabita, M., Blaauw, B., Giorgio, M., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3667-8 · Cited by 32 · see citing works
“This difference has been attributed to upregulation of p46Shc in the adipose tissue of p66Shc mice [12].”
BackgroundResultInfluentialSelf-citationIdebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition
Tomilov, A. A., Allen, S. A., Hui, C. K., Bettaieb, A., & Cortopassi, G. A. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.09.024 · Cited by 30 · see citing works
Self-citationThe Endothelium Abridges Insulin Resistance to Premature Aging
Avogaro, A., de Kreutzenberg, S. V., Federici, M., & Fadini, G. P. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000262 · Cited by 30 · see citing works
“improve insulin sensitivity in obese diabetic mice on a SV/129 or mixed background, although this effect is controversial.(76) As deletion of p66Shc prevents insulin-resistance, delays aging, and protects from aging-associated diseases, one wonders why p66Shc has been selected and what its physiological role is.”
Transcriptome Analysis of Potential miRNA Involved in Adipogenic Differentiation of C2C12 Myoblasts
Hou, Y., Fu, L., Li, J., Li, J., Zhao, Y., Luan, Y., Liu, A., Liu, H., Li, X., Zhao, S., et al. (2018) · Lipids · doi:10.1002/lipd.12032 · Cited by 27 · see citing works
Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66Shc
Ciciliot, S., & Fadini, G. P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20040985 · Cited by 26 · see citing works
“The authors showed that ShcL mice did not have perturbations in the expression pattern of p52Shc and p46Shc, compared with the original p66Shc−/− mice (called ShcP), while p46Shc was increased in the adipose tissue of the ShcP; they reasoned that this might be the reason for the discrepancy in obesity.”
BackgroundResultInfluentialShah, M. A., Tariq, S., Abuzar, S. M., Ilyas, K., Qadees, I., Alsharif, I., Anam, K., Almutairi, R. T., Al-Regaiey, K., Babalghith, A. O., et al. (2024) · Current Research in Biotechnology · doi:10.1016/j.crbiot.2024.100204 · Cited by 25 · see citing works
The p66Shc Redox Protein and the Emerging Complications of Diabetes
Biondi, G., Marrano, N., Borrelli, A., Rella, M., D’Oria, R., Genchi, V. A., Caccioppoli, C., Cignarelli, A., Perrini, S., Laviola, L., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010108 · Cited by 25 · see citing works
“Conversely, a study performed on a different p66 Shc-/- mouse model, named ShcL, demonstrated that reduced p66 Shc levels improved insulin sensitivity in adipocytes, muscles, and the liver without preventing diet-induced obesity [47].”
BackgroundResultJiang, J. X., Fish, S. R., Tomilov, A. A., Li, Y., Fan, W., Dehnad, A., Gae, D. D., Das, S., Mozes, G. D., Charville, G. W., et al. (2020) · Hepatology · doi:10.1002/hep.31118 · Cited by 24 · see citing works
“P52Shc also modulates insulin signaling(6); thus, it is tempting to speculate that it is a central adaptor linking redox burst to dysregulated insulin responses through redoxosomal compartmentalization.”
BackgroundInfluentialSelf-citationp66Shc aging protein in control of fibroblasts cell fate
Suski, J. M., Karkucinska-Wieckowska, A., Lebiedzinska, M., Giorgi, C., Szczepanowska, J., Szabadkai, G., Duszynski, J., Pronicki, M., Pinton, P., & Wieckowski, M. R. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12085373 · Cited by 22 · see citing works
“Thus, p46Shc overexpression in fat, rather than p66Shc deletion, could be the likely cause of decreased adiposity and reduced insulin sensitivity in the fat of p66Shc mice [47].”
BackgroundThe Role of p66Shc in Diabetes: A Comprehensive Review from Bench to Bedside
Mousavi, S., Tabari, M. A. K., Bagheri, A., Samieefar, N., Shaterian, N., & Kelishadi, R. (2022) · Journal of Diabetes Research · doi:10.1155/2022/7703520 · Cited by 22 · see citing works
“Therefore, the role of p66Shc mechanism in regulation of body weight is far from being fully understood [18, 65].”
BackgroundResultRanieri, S. C., Fusco, S., & Pani, G. (2013) · Vitamins and hormones · doi:10.1016/b978-0-12-407766-9.00009-2 · Cited by 22 · see citing works
p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria
Tomilov, A. A., Tomilova, N. B., Shan, Y., Hagopian, K., Bettaieb, A., Kim, K., Pelicci, P. G., Haj, F. G., Ramsey, J. J., & Cortopassi, G. A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.695577 · Cited by 21 · see citing works
“This is consistent with previous findings that lipid oxidation is increased in livers of ShcP ShcKO mice (2), where Shc expression is significantly decreased, and p46Shc is decreased to 20% of wildtype level (3, 4).”
BackgroundResultInfluentialSelf-citationShc depletion stimulates brown fat activity in vivo and in vitro
Tomilov, A. A., Bettaieb, A., Kim, K., Sahdeo, S., Tomilova, N. B., Lam, A., Hagopian, K., Connell, M. C., Fong, J., Rowland, D. J., et al. (2014) · Aging Cell · doi:10.1111/acel.12267 · Cited by 19 · see citing works
“While ShcKO mice have deletion of p66Shc, they also exhibit a significant reduction of p52/46Shc isoforms in insulin-responsive tissues (Tomilov et al., 2011).”
InfluentialSelf-citationA New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation
Azzalin, A., Brambilla, F., Arbustini, E., Basello, K., Speciani, A. F., Mauri, P., Bezzi, P., & Magrassi, L. (2020) · Cells · doi:10.3390/cells9051249 · Cited by 18 · see citing works
“Mice lacking p66Shc1 have low levels of all other Shc1 isoforms and display increased insulin sensitivity and glucose tolerance [24] with reduced glycolysis and increased gluconeogenesis in muscle and liver [23,25].”
BackgroundProtein kinase C-beta: An emerging connection between nutrient excess and obesity
Mehta, N., & Mehta, K. D. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.07.011 · Cited by 17 · see citing works
Hagopian, K., Tomilov, A. A., Kim, K., Cortopassi, G. A., & Ramsey, J. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124204 · Cited by 17 · see citing works
“The levels of the Shc proteins were lower in skeletal muscle in the KO versus WT mice, as previously reported [8,10], and the mechanism through which Shc proteins influence the activities of glycolytic enzymes is not known.”
BackgroundMethodResultInfluentialSelf-citationShc and the mechanotransduction of cellular anchorage and metastasis
Terada, L. S. (2017) · Small GTPases · doi:10.1080/21541248.2016.1273172 · Cited by 15 · see citing works
“with increased rather than decreased susceptibility to fatty diets and no apparent health benefits.(25,26) While the reasons for the discrepant p66 phenotypes are not clear, a conserved role for the SHC1 locus overall in”
BackgroundShc proteins influence the activities of enzymes involved in fatty acid oxidation and ketogenesis
Hagopian, K., Tomilov, A. A., Tomilova, N. B., Kim, K., Taylor, S. L., Lam, A., Cortopassi, G. A., McDonald, R. B., & Ramsey, J. J. (2012) · Metabolism · doi:10.1016/j.metabol.2012.05.007 · Cited by 14 · see citing works
“Previous studies have shown that ShcKO mice are resistant to weight gain on a high fat diet [11,12].”
BackgroundMethodSelf-citationInterplay between gut microbiota and p66Shc affects obesity‐associated insulin resistance
Ciciliot, S., Albiero, M., Campanaro, S., Poncina, N., Tedesco, S., Scattolini, V., Costa, F. D., Cignarella, A., Vettore, M., Gangi, I. M. D., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201701409r · Cited by 14 · see citing works
Role of p66shc in skeletal muscle function
Granatiero, V., Gherardi, G., Vianello, M., Salerno, E., Zecchini, E., Toniolo, L., Pallafacchina, G., Murgia, M., Blaauw, B., Rizzuto, R., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-06363-0 · Cited by 13 · see citing works
Giorgio, M., Stendardo, M., Migliaccio, E., & Pelicci, P. G. (2016) · Aging Cell · doi:10.1111/acel.12448 · Cited by 11 · see citing works
“, 2007), onset (Tomilov et al., 2011), cognitive decline (Berry et al.”
BackgroundSelf-citationNovel idebenone analogs block Shc’s access to insulin receptor to improve insulin sensitivity
Hui, C. K., Tomilov, A. A., Garcia, C., Jiang, J. X., Fash, D. M., Khdour, O. M., Rosso, C., Filippini, G., Prato, M., Graham, J. L., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110823 · Cited by 11 · see citing works
Self-citationHuman SHC‐transforming protein 1 and its isoforms p66shc: A novel marker for prediabetes
Jelinek, H. F., Helf, C., & Khalaf, K. A. (2021) · Journal of Diabetes Investigation · doi:10.1111/jdi.13551 · Cited by 11 · see citing works
Stern, J. H., Kim, K., & Ramsey, J. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048790 · Cited by 8 · see citing works
“Only male mice were used for the present study and this reflects the fact that our initial studies investigating the influence of ShcKO on energy metabolism have been completed in male mice [20,21].”
MethodSelf-citationSelective upregulation of p66-Shc gene expression in the liver and brain of aged rats
Sone, K., Mori, M., & Mori, N. (2012) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2011.11.001 · Cited by 8 · see citing works
“, 2009), adiposity (Tomilov et al., 2011), and many other signaling routes including the main signal pathway of the so-called Ras-MAPK pathway via direct interaction with Grb2 (for reviews see Bonfini et al.”
BackgroundCardiovascular Disease in Aging and the Role of Oxidative Stress
Alzaïd, F., Patel, V. B., & Preedy, V. R. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-405933-7.00003-2 · Cited by 7 · see citing works
Comparative proteomic analysis of insulin receptor isoform A and B signaling
Malaguarnera, R., Gabriele, C., Santamaria, G., Giuliano, M., Vella, V., Massimino, M., Vigneri, P. G., Cuda, G., Gaspari, M., & Belfiore, A. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111739 · Cited by 7 · see citing works
Shc Is Implicated in Calreticulin-Mediated Sterile Inflammation in Alcoholic Hepatitis
Li, Y., Jiang, J. X., Fan, W., Fish, S. R., Das, S., Gupta, P., Mozes, G. D., Váncza, L., Sarkar, S., Kunimoto, K., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.09.005 · Cited by 6 · see citing works
“10 attributed to p66Shc, however the knockout mice used in these experiments in reality were hypomorphs having reduced levels of all three isoforms; therefore, the other isoforms deserve attention[3].”
BackgroundSelf-citationStern, J. H., Kim, K., & Ramsey, J. J. (2012) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2012.05.001 · Cited by 6 · see citing works
“It has been previously demonstrated that body weight is reduced in ad libitum fed young (2– 5 month old) p66Shc(−/−) mice compared to WT controls, and this decrease in body weight is primarily due to lower fat pad weights in the p66Shc(−/−) animals (Berniakovich et al., 2008; Tomilov et al., 2011).”
BackgroundInfluentialSelf-citationPinaffi‐Langley, A. C. D. C., Melia, E., & Hays, F. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073656 · Cited by 5 · see citing works
Temporal Analysis of Gene Expression and Isoform Switching in Brown Bears (Ursus arctos)
Perry, B. W., Armstrong, E. E., Robbins, C. T., Jansen, H. T., & Kelley, J. L. (2022) · Integrative and Comparative Biology · doi:10.1093/icb/icac093 · Cited by 5 · see citing works
Hagopian, K., Kim, K., Lopez-Dominguez, J. A., Tomilov, A. A., Cortopassi, G. A., & Ramsey, J. J. (2016) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2016.06.021 · Cited by 5 · see citing works
“However, while these mice lack p66Shc, it has been recently shown that they also have decreased levels of p52Shc in all tissues and decreased levels of p46Shc in liver, skeletal muscle and heart [7].”
Self-citationAcetylation in Cardiac Aging: Molecular Mechanism and Therapeutic Approaches
Hase, A. D., & Banerjee, S. (2025) · Results and problems in cell differentiation · doi:10.1007/978-3-031-91459-1_9 · Cited by 3 · see citing works
Li, Y., Fan, W., Lo, T.-H., Jiang, J. X., Fish, S. R., Tomilov, A. A., Chronopoulos, A., Bansal, V., Mozes, G. D., Váncza, L., et al. (2024) · American Journal Of Pathology · doi:10.1016/j.ajpath.2024.10.022 · Cited by 2 · see citing works
Self-citationStern, J. H., Kim, K., & Ramsey, J. J. (2014) · ISRN Nutrition · doi:10.1155/2014/562075 · Cited by 2 · see citing works
Self-citationCardiovascular disease in aging and the role of oxidative stress
Orliaguet, L., Patel, V. B., Preedy, V. R., & Alzaïd, F. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818698-5.00003-1 · Cited by 2 · see citing works
The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism
Soliman, M. A., Rahman, A. M. A., Lamming, D. W., Birsoy, K., Pawling, J., Frigolet, M. E., Lu, H., Fantus, I. G., Pasculescu, A., Zheng, Y., et al. (2014) · Science Signaling · doi:10.1126/scisignal.2004785 · Cited by 1 · see citing works
“Furthermore, p66Shc deficiency in mice improves glucose tolerance and insulin sensitivity (13, 14).”
BackgroundThe influence of Shc proteins and high‐fat diet on energy metabolism of mice
Baldassini, W. A., Ramsey, J. J., Hagopian, K., & Lanna, D. P. D. (2017) · Cell Biochemistry and Function · doi:10.1002/cbf.3310 · Cited by 1 · see citing works
“This decrease in BW was due to the fact that the weights of all fat pads were lower in ShcKO compared to WT mice.(5,6) Similarly, it has been reported that ShcKO mice show less weight gain on a high‐fat diet (HFD) than WT animals,(5) and p66Shc knockout in leptin‐deficient ob/ob mice decreased weight gain in these obe…”
Self-citationShc and the Control of Small GTPase Dynamics in Cellular Anchorage
Terada, L. S. (2021) · Springer eBooks · doi:10.1007/978-3-030-73856-3_4
Role of Reactive Oxygen Species in Cellular Signalling
Bondhopadhyay, B., Gupta, S., & Shamsi, Y. H. (2025) · Advances in medical diagnosis, treatment, and care (AMDTC) book series · doi:10.4018/979-8-3693-7919-6.ch005
Lee, C. Y. (2026) · Medicinal Chemistry Research · doi:10.1007/s00044-026-03577-8
“Protein molecules that interact with the insulin receptor, blocking its activation and downstream effect such as Shc and Grb14 have been implicated in insulin resistance [ 119, 120].”
Kaur, K., & Singh, G. (2026) · HORMONES · doi:10.1007/s42000-026-00819-7
- Authors
- Tomilov, A. A., Ramsey, J. J., Hagopian, K., Giorgio, M., Kim, K. M., Lam, A., Migliaccio, E., Lloyd, K. C., Berniakovich, I., Prolla, T. A., Pelicci, P., & Cortopassi, G. A.
- Affiliations
- University of California, Davis (US)
- IFOM (IT)
- University of Wisconsin–Madison (US)
- Corresponding author
- Cortopassi, Gino A.
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2010-11-15
- Volume
- 10
- Issue
- 1
- Pages
- 55-65
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC4157392
- OpenAlex
- W1756960484
- Cited by
- 64
- References
- 51
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 2 · 2014: 7 · 2013: 9 · 2012: 4
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- U.S. Public Health Service
- National Institute on Aging (AG16719, AG025532, P01AG025532, R01AG016719)
- National Eye Institute (R01EY012245, EY 12245)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- p66Shc, insulin signaling, insulin sensitivity, adiposity, white adipose tissue, glucose tolerance, longevity, fatty diet, stress tolerance, mitochondria
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Animals, Cells, Cultured, Dietary Fats, Female, Glucose, Insulin, Insulin Resistance, Longevity, Male, Mice, Inbred C57BL, Thinness, Signal Transduction, Mice, Knockout, Oxidative Stress, Protein Isoforms, Oligonucleotide Array Sequence Analysis, Adiposity, Mice, Shc Signaling Adaptor Proteins, Genetic Loci
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
