{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:37:04Z","timestamp":1791319024175,"version":"4.3.1"},"reference-count":51,"publisher":"Elsevier BV","issue":"5","license":[{"start":{"date-parts":[[2008,3,1]],"date-time":"2008-03-01T00:00:00Z","timestamp":1204329600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2008,3,1]],"date-time":"2008-03-01T00:00:00Z","timestamp":1204329600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2013,8,22]],"date-time":"2013-08-22T00:00:00Z","timestamp":1377129600000},"content-version":"vor","delay-in-days":2000,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Molecular Cell"],"published-print":{"date-parts":[[2008,3]]},"DOI":"10.1016\/j.molcel.2007.12.023","type":"journal-article","created":{"date-parts":[[2008,4,11]],"date-time":"2008-04-11T15:38:36Z","timestamp":1207928316000},"page":"541-551","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":399,"title":["Loss of the Tuberous Sclerosis Complex Tumor Suppressors Triggers the Unfolded Protein Response to Regulate Insulin Signaling and Apoptosis"],"prefix":"10.1016","volume":"29","author":[{"given":"Umut","family":"Ozcan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lale","family":"Ozcan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erkan","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"D\u00fcvel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan D.","family":"Manning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6khan S.","family":"Hotamisligil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.molcel.2007.12.023_bib1","doi-asserted-by":"crossref","first-page":"9047","DOI":"10.1074\/jbc.275.12.9047","article-title":"The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)","volume":"275","author":"Aguirre","year":"2000","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.molcel.2007.12.023_bib2","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/ana.20211","article-title":"mTOR cascade activation distinguishes tubers from focal cortical dysplasia","volume":"56","author":"Baybis","year":"2004","journal-title":"Ann. Neurol."},{"key":"10.1016\/j.molcel.2007.12.023_bib3","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/sj.cdd.4401817","article-title":"Cellular response to endoplasmic reticulum stress: a matter of life or death","volume":"13","author":"Boyce","year":"2006","journal-title":"Cell Death Differ."},{"key":"10.1016\/j.molcel.2007.12.023_bib4","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/415092a","article-title":"IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA","volume":"415","author":"Calfon","year":"2002","journal-title":"Nature"},{"key":"10.1016\/j.molcel.2007.12.023_bib5","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/0092-8674(93)90648-A","article-title":"Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase","volume":"73","author":"Cox","year":"1993","journal-title":"Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib6","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1016\/j.febslet.2006.04.068","article-title":"The amino acid sensitive TOR pathway from yeast to mammals","volume":"580","author":"Dann","year":"2006","journal-title":"FEBS Lett."},{"key":"10.1016\/j.molcel.2007.12.023_bib7","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/S1097-2765(03)00220-X","article-title":"Insulin activation of Rheb, a mediator of mTOR\/S6K\/4E-BP signaling, is inhibited by TSC1 and 2","volume":"11","author":"Garami","year":"2003","journal-title":"Mol. Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib8","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0092-8674(02)00833-4","article-title":"Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action","volume":"110","author":"Hara","year":"2002","journal-title":"Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib9","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/16729","article-title":"Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase","volume":"397","author":"Harding","year":"1999","journal-title":"Nature"},{"key":"10.1016\/j.molcel.2007.12.023_bib10","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/S1097-2765(00)80330-5","article-title":"Perk is essential for translational regulation and cell survival during the unfolded protein response","volume":"5","author":"Harding","year":"2000","journal-title":"Mol. Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1083\/jcb.200403069","article-title":"The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins","volume":"166","author":"Harrington","year":"2004","journal-title":"J. Cell Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib12","doi-asserted-by":"crossref","first-page":"re15","DOI":"10.1126\/stke.2122003re15","article-title":"TOR signaling","volume":"2003","author":"Harris","year":"2003","journal-title":"Sci. STKE"},{"key":"10.1016\/j.molcel.2007.12.023_bib13","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1101\/gad.1212704","article-title":"Upstream and downstream of mTOR","volume":"18","author":"Hay","year":"2004","journal-title":"Genes Dev."},{"key":"10.1016\/j.molcel.2007.12.023_bib14","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature01137","article-title":"A central role for JNK in obesity and insulin resistance","volume":"420","author":"Hirosumi","year":"2002","journal-title":"Nature"},{"key":"10.1016\/j.molcel.2007.12.023_bib15","doi-asserted-by":"crossref","first-page":"S73","DOI":"10.2337\/diabetes.54.suppl_2.S73","article-title":"Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes","volume":"54","author":"Hotamisligil","year":"2005","journal-title":"Diabetes"},{"key":"10.1016\/j.molcel.2007.12.023_bib16","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"10.1016\/j.molcel.2007.12.023_bib17","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1126\/science.271.5249.665","article-title":"IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-\u03b1- and obesity-induced insulin resistance","volume":"271","author":"Hotamisligil","year":"1996","journal-title":"Science"},{"key":"10.1016\/j.molcel.2007.12.023_bib18","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/ncb839","article-title":"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling","volume":"4","author":"Inoki","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib19","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","article-title":"TSC2 mediates cellular energy response to control cell growth and survival","volume":"115","author":"Inoki","year":"2003","journal-title":"Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ng1494","article-title":"Dysregulation of the TSC-mTOR pathway in human disease","volume":"37","author":"Inoki","year":"2005","journal-title":"Nat. Genet."},{"key":"10.1016\/j.molcel.2007.12.023_bib21","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1210\/en.2004-0921","article-title":"Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance","volume":"146","author":"Khamzina","year":"2005","journal-title":"Endocrinology"},{"key":"10.1016\/j.molcel.2007.12.023_bib22","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0092-8674(02)00808-5","article-title":"mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery","volume":"110","author":"Kim","year":"2002","journal-title":"Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib23","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S1097-2765(03)00114-X","article-title":"GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR","volume":"11","author":"Kim","year":"2003","journal-title":"Mol. Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib24","first-page":"1206","article-title":"Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice","volume":"59","author":"Kobayashi","year":"1999","journal-title":"Cancer Res."},{"issue":"Spec No. 2","key":"10.1016\/j.molcel.2007.12.023_bib25","doi-asserted-by":"crossref","first-page":"R251","DOI":"10.1093\/hmg\/ddi260","article-title":"Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways","volume":"14","author":"Kwiatkowski","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"10.1016\/j.molcel.2007.12.023_bib26","doi-asserted-by":"crossref","first-page":"7448","DOI":"10.1128\/MCB.23.21.7448-7459.2003","article-title":"XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response","volume":"23","author":"Lee","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/gcc.20118","article-title":"Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models","volume":"42","author":"Lee","year":"2005","journal-title":"Genes Chromosomes Cancer"},{"key":"10.1016\/j.molcel.2007.12.023_bib28","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S1097-2765(02)00636-6","article-title":"Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control","volume":"10","author":"Loewith","year":"2002","journal-title":"Mol. Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib29","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2005.02.031","article-title":"Phosphorylation and functional inactivation of TSC2 by Erk: implications for tuberous sclerosis and cancer pathogenesis","volume":"121","author":"Ma","year":"2005","journal-title":"Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib30","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1097-2765(02)00568-3","article-title":"Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase\/akt pathway","volume":"10","author":"Manning","year":"2002","journal-title":"Mol. Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib31","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1101\/gad.1314605","article-title":"Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2","volume":"19","author":"Manning","year":"2005","journal-title":"Genes Dev."},{"key":"10.1016\/j.molcel.2007.12.023_bib32","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1152\/physrev.00015.2006","article-title":"Endoplasmic reticulum stress signaling in disease","volume":"86","author":"Marciniak","year":"2006","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.molcel.2007.12.023_bib33","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/0092-8674(93)90521-Q","article-title":"A transmembrane protein with a cdc2+\/CDC28\u2212 related kinase activity is required for signaling from the ER to the nucleus","volume":"74","author":"Mori","year":"1993","journal-title":"Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib34","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1172\/JCI7319","article-title":"Tsc2(+\/\u2212) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background","volume":"104","author":"Onda","year":"1999","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.molcel.2007.12.023_bib35","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1126\/science.1103160","article-title":"Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes","volume":"306","author":"Ozcan","year":"2004","journal-title":"Science"},{"key":"10.1016\/j.molcel.2007.12.023_bib36","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1126\/science.1128294","article-title":"Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes","volume":"313","author":"Ozcan","year":"2006","journal-title":"Science"},{"key":"10.1016\/j.molcel.2007.12.023_bib37","doi-asserted-by":"crossref","first-page":"13489","DOI":"10.1073\/pnas.0405659101","article-title":"Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase","volume":"101","author":"Roux","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.molcel.2007.12.023_bib38","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.ceb.2005.09.009","article-title":"Growing roles for the mTOR pathway","volume":"17","author":"Sarbassov","year":"2005","journal-title":"Curr. Opin. Cell Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib39","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"10.1016\/j.molcel.2007.12.023_bib40","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/ncb996","article-title":"Rheb promotes cell growth as a component of the insulin\/TOR signalling network","volume":"5","author":"Saucedo","year":"2003","journal-title":"Nat. Cell Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib41","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1146\/annurev.biochem.73.011303.074134","article-title":"The mammalian unfolded protein response","volume":"74","author":"Schroder","year":"2005","journal-title":"Annu. Rev. Biochem."},{"key":"10.1016\/j.molcel.2007.12.023_bib42","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.cub.2004.08.026","article-title":"Inappropriate activation of the TSC\/Rheb\/mTOR\/S6K cassette induces IRS1\/2 depletion, insulin resistance, and cell survival deficiencies","volume":"14","author":"Shah","year":"2004","journal-title":"Curr. Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib43","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0960-9822(03)00506-2","article-title":"Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb","volume":"13","author":"Tee","year":"2003","journal-title":"Curr. Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib44","doi-asserted-by":"crossref","first-page":"10741","DOI":"10.1073\/pnas.0603509103","article-title":"Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance","volume":"103","author":"Tuncman","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.molcel.2007.12.023_bib45","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1128\/MCB.26.1.63-76.2006","article-title":"Nutrients suppress phosphatidylinositol 3-kinase\/Akt via paptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation","volume":"26","author":"Tzatsos","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib46","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nature02866","article-title":"Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity","volume":"431","author":"Um","year":"2004","journal-title":"Nature"},{"key":"10.1016\/j.molcel.2007.12.023_bib47","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1126\/science.287.5453.664","article-title":"Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1","volume":"287","author":"Urano","year":"2000","journal-title":"Science"},{"key":"10.1016\/j.molcel.2007.12.023_bib48","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/ana.21058","article-title":"Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1","volume":"61","author":"Wang","year":"2007","journal-title":"Ann. Neurol."},{"key":"10.1016\/j.molcel.2007.12.023_bib49","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0092-8674(01)00611-0","article-title":"XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor","volume":"107","author":"Yoshida","year":"2001","journal-title":"Cell"},{"key":"10.1016\/j.molcel.2007.12.023_bib50","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/ncb999","article-title":"Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins","volume":"5","author":"Zhang","year":"2003","journal-title":"Nat. Cell Biol."},{"key":"10.1016\/j.molcel.2007.12.023_bib51","doi-asserted-by":"crossref","first-page":"pe4","DOI":"10.1126\/stke.2682005pe4","article-title":"Ser\/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance","volume":"2005","author":"Zick","year":"2005","journal-title":"Sci. STKE"}],"container-title":["Molecular Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S109727650800066X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S109727650800066X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:07:21Z","timestamp":1761091641000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S109727650800066X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,3]]},"references-count":51,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2008,3]]}},"alternative-id":["S109727650800066X"],"URL":"https:\/\/doi.org\/10.1016\/j.molcel.2007.12.023","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1103554.559622","asserted-by":"object"}]},"ISSN":["1097-2765"],"issn-type":[{"value":"1097-2765","type":"print"}],"subject":[],"published":{"date-parts":[[2008,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Loss of the Tuberous Sclerosis Complex Tumor Suppressors Triggers the Unfolded Protein Response to Regulate Insulin Signaling and Apoptosis","name":"articletitle","label":"Article Title"},{"value":"Molecular Cell","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.molcel.2007.12.023","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2008 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}