{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:28:39Z","timestamp":1788326919679,"version":"build-2803163510"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"21","license":[{"start":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T00:00:00Z","timestamp":1478476800000},"content-version":"vor","delay-in-days":835,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation : A large number of experimental studies on ageing focus on the effects of genetic perturbations of the insulin\/insulin-like growth factor signalling pathway (IIS) on lifespan. Short-lived invertebrate laboratory model organisms are extensively used to quickly identify ageing-related genes and pathways. It is important to extrapolate this knowledge to longer lived mammalian organisms, such as mouse and eventually human, where such analyses are difficult or impossible to perform. Computational tools are needed to integrate and manipulate pathway knowledge in different species.<\/jats:p>\n               <jats:p>Results: We performed a literature review and curation of the IIS and target of rapamycin signalling pathways in Mus Musculus . We compare this pathway model to the equivalent models in Drosophila melanogaster and Caenorhabtitis elegans . Although generally well-conserved, they exhibit important differences. In general, the worm and mouse pathways include a larger number of feedback loops and interactions than the fly. We identify \u2018functional orthologues\u2019 that share similar molecular interactions, but have moderate sequence similarity. Finally, we incorporate the mouse model into the web-service NetEffects and perform in silico gene perturbations of IIS components and analyses of experimental results. We identify sub-paths that, given a mutation in an IIS component, could potentially antagonize the primary effects on ageing via FOXO in mouse and via SKN-1 in worm. Finally, we explore the effects of FOXO knockouts in three different mouse tissues.<\/jats:p>\n               <jats:p>Availability and implementation: \u00a0http:\/\/www.ebi.ac.uk\/thornton-srv\/software\/NetEffects<\/jats:p>\n               <jats:p>Contact: \u00a0ip8@sanger.ac.uk or thornton@ebi.ac.uk<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btu493","type":"journal-article","created":{"date-parts":[[2014,7,27]],"date-time":"2014-07-27T00:29:24Z","timestamp":1406420964000},"page":"2999-3003","source":"Crossref","is-referenced-by-count":14,"title":["Comparison of the mammalian insulin signalling pathway to invertebrates in the context of FOXO-mediated ageing"],"prefix":"10.1093","volume":"30","author":[{"given":"Irene","family":"Papatheodorou","sequence":"first","affiliation":[{"name":"1 EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK, 2 Institute of Healthy Ageing and Department of Genetics Evolution and Environment, University College London, London WC1E 6BT, UK"},{"name":"1 EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK, 2 Institute of Healthy Ageing and Department of Genetics Evolution and Environment, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolfs","family":"Petrovs","sequence":"additional","affiliation":[{"name":"1 EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK, 2 Institute of Healthy Ageing and Department of Genetics Evolution and Environment, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet M.","family":"Thornton","sequence":"additional","affiliation":[{"name":"1 EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK, 2 Institute of Healthy Ageing and Department of Genetics Evolution and Environment, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,7,26]]},"reference":[{"key":"2023012711562986700_btu493-B1","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/msb.2011.36","article-title":"Genome-wide dfoxo targets and topology of the transcriptomic response to stress and insulin signalling","volume":"7","author":"Alic","year":"2011","journal-title":"Mol. 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Biol."},{"key":"2023012711562986700_btu493-B2","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.cmet.2009.12.009","article-title":"Foxo-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice","volume":"11","author":"Ambrogini","year":"2010","journal-title":"Cell Metab."},{"key":"2023012711562986700_btu493-B3","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.1078223","article-title":"Extended longevity in mice lacking the insulin receptor in adipose tissue","volume":"299","author":"Bl\u00fcher","year":"2003","journal-title":"Science"},{"key":"2023012711562986700_btu493-B4","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/j.1474-9726.2010.00580.x","article-title":"drr-2 encodes an eiF4H that acts downstream of TOR in diet-restriction-induced longevity of \n              C. elegans","volume":"9","author":"Ching","year":"2010","journal-title":"Aging Cell"},{"key":"2023012711562986700_btu493-B5","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1126\/science.1057991","article-title":"Extension of life-span by loss of chico, a \n              drosophila\n               insulin receptor substrate protein","volume":"292","author":"Clancy","year":"2001","journal-title":"Science"},{"key":"2023012711562986700_btu493-B6","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/msb.2011.79","article-title":"Modularity and hormone sensitivity of the \n              Drosophila melanogaster\n               insulin receptor\/target of rapamycin interaction proteome","volume":"7","author":"Glatter","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"2023012711562986700_btu493-B7","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1039\/c3mb25485b","article-title":"Transcriptional feedback in the insulin signalling pathway modulates ageing in both \n              Caenorhabditis elegans\n               and Drosophila melanogaster","volume":"9","author":"Ivanov","year":"2013","journal-title":"Mol. BioSyst."},{"key":"2023012711562986700_btu493-B8","doi-asserted-by":"crossref","first-page":"D109","DOI":"10.1093\/nar\/gkr988","article-title":"KEGG for integration and interpretation of large-scale molecular data sets","volume":"40","author":"Kanehisa","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023012711562986700_btu493-B9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1098\/rstb.2010.0276","article-title":"The first long-lived mutants: discovery of the insulin\/igf-1 pathway for ageing","volume":"366","author":"Kenyon","year":"2011","journal-title":"Philos. Trans. R. Soc. B"},{"key":"2023012711562986700_btu493-B10","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/366461a0","article-title":"A \n              C. elegans\n               mutant that lives twice as long as wild type","volume":"366","author":"Kenyon","year":"1993","journal-title":"Nature"},{"key":"2023012711562986700_btu493-B11","doi-asserted-by":"crossref","first-page":"7624","DOI":"10.1074\/jbc.M412889200","article-title":"Rack1-mediated integration of adhesion and insulin-like growth factor i (igf-i) signaling and cell migration are defective in cells expressing an igf-i receptor mutated at tyrosines 1250 and 1251","volume":"280","author":"Kiely","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2023012711562986700_btu493-B12","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.cell.2006.12.029","article-title":"Foxos are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis","volume":"128","author":"Paik","year":"2007","journal-title":"Cell"},{"key":"2023012711562986700_btu493-B13","doi-asserted-by":"crossref","first-page":"e50881","DOI":"10.1371\/journal.pone.0050881","article-title":"Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing","volume":"7","author":"Papatheodorou","year":"2012","journal-title":"PLoS One"},{"key":"2023012711562986700_btu493-B14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.18632\/aging.100638","article-title":"MDL-1, a growth- and tumor-suppressor, slows aging and prevents germline hyperplasia and hypertrophy in \n              C. elegans","volume":"6","author":"Riesen","year":"2014","journal-title":"Aging"},{"key":"2023012711562986700_btu493-B15","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1096\/fj.07-9261com","article-title":"Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice","volume":"22","author":"Selman","year":"2008","journal-title":"FASEB J."},{"key":"2023012711562986700_btu493-B16","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1126\/science.1177221","article-title":"Ribosomal protein s6 kinase 1 signaling regulates mammalian life span","volume":"326","author":"Selman","year":"2009","journal-title":"Science"},{"key":"2023012711562986700_btu493-B17","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/0-387-29362-0_23","article-title":"Limma: linear models for microarray data","volume-title":"Bioinformatics and Computational Biology Solutions using R and Bioconductor","author":"Smyth","year":"2005"},{"key":"2023012711562986700_btu493-B18","doi-asserted-by":"crossref","first-page":"e1000452","DOI":"10.1371\/journal.pgen.1000452","article-title":"Positive feedback between transcriptional and kinase suppression in nematodes with extraordinary longevity and stress resistance","volume":"5","author":"Tazearslan","year":"2009","journal-title":"PLoS Genet."},{"key":"2023012711562986700_btu493-B19","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/nrm2190","article-title":"Stressing the role of FoxO proteins in lifespan and disease","volume":"8","author":"van der Horst","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023012711562986700_btu493-B20","doi-asserted-by":"crossref","first-page":"13987","DOI":"10.1073\/pnas.0801030105","article-title":"FOXO3A genotype is strongly associated with human longevity","volume":"105","author":"Willcox","year":"2008","journal-title":"Proc. Natl Acad. Sci. 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