{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:02:44Z","timestamp":1791356564742,"version":"4.3.1"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"21","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,10,15]]},"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). First, coexpression of hamartin and tuberin repressed phosphorylation of 4E-BP1, resulting in increased association of 4E-BP1 with eIF4E; importantly, a mutant of\n                    <jats:italic>TSC2<\/jats:italic>\n                    derived from TSC patients was defective in repressing phosphorylation of 4E-BP1. Second, the activity of S6K1 was repressed by coexpression of hamartin and tuberin, but the activity of rapamycin-resistant mutants of S6K1 were not affected, implicating mTOR in the TSC-mediated inhibitory effect on S6K1. Third, hamartin and tuberin blocked the ability of amino acids to activate S6K1 within nutrient-deprived cells, a process that is dependent on mTOR. These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest that the formation of tumors within TSC patients may result from aberrantly high levels of mTOR-mediated signaling to downstream targets.\n                  <\/jats:p>","DOI":"10.1073\/pnas.202476899","type":"journal-article","created":{"date-parts":[[2002,10,15]],"date-time":"2002-10-15T12:43:03Z","timestamp":1034685783000},"page":"13571-13576","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":705,"title":["Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling"],"prefix":"10.1073","volume":"99","author":[{"given":"Andrew R.","family":"Tee","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Genetics Laboratory, Hematology Division, Brigham and Woman's Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane C.","family":"Fingar","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Genetics Laboratory, Hematology Division, Brigham and Woman's Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan D.","family":"Manning","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Genetics Laboratory, Hematology Division, Brigham and Woman's Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kwiatkowski","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Genetics Laboratory, Hematology Division, Brigham and Woman's Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewis C.","family":"Cantley","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Genetics Laboratory, Hematology Division, Brigham and Woman's Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Blenis","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Genetics Laboratory, Hematology Division, Brigham and Woman's Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2002,9,23]]},"reference":[{"key":"e_1_3_3_1_2","volume-title":"Developmental Perspectives in Psychiatry","author":"Gomez E R","year":"1999","unstructured":"E R Gomez, J R Sampson, V H Whittemore Developmental Perspectives in Psychiatry (Oxford Univ. Press, Oxford, 1999)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0294-193"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.10.1833"},{"key":"e_1_3_3_4_2","first-page":"4766","volume":"58","author":"Plank T L","year":"1998","unstructured":"T L Plank, R S Yeung, E P Henske Cancer Res 58, 4766\u20134770 (1998).","journal-title":"Cancer Res"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.6.1053"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00333-6"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.901101"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00568-3"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","unstructured":"Goncharova E. A. Goncharov D. A. Eszterhas A. Hunter D. S. Glassberg M. K. Yeung R. S. Walker C. L. Noonan D. Kwiatkowski D. J. Chou M. M. et al . (2002) J. Biol. Chem. 277 in press.","DOI":"10.1074\/jbc.M202678200"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.5.525"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.2480"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90643-Q"},{"key":"e_1_3_3_13_2","unstructured":"Martin K. A. & Blenis J. (2002) Adv. Cancer Res. 86 in press."},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.887201"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1042\/bst0290541"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063518"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00117-3"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00762-5"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.995802"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(99)80364-9"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006969200"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.25.2889"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.23.14484"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.2.1092"},{"key":"e_1_3_3_25_2","first-page":"2415","volume":"13","author":"Rousseau D","year":"1996","unstructured":"D Rousseau, A C Gingras, A Pause, N Sonenberg Oncogene 13, 2415\u20132420 (1996).","journal-title":"Oncogene"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/345544a0"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(98)80150-6"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.12.1721"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.46.29301"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.835000"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.845700"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.51.34496"}],"updated-by":[{"DOI":"10.1073\/pnas.2112628118","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T00:00:00Z","timestamp":1628467200000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.202476899","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T06:35:02Z","timestamp":1649831702000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.202476899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,9,23]]},"references-count":32,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2002,10,15]]}},"alternative-id":["10.1073\/pnas.202476899"],"URL":"https:\/\/doi.org\/10.1073\/pnas.202476899","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1001793.167408","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,9,23]]},"assertion":[{"value":"2002-08-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2002-09-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}