{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:39:47Z","timestamp":1791405587395,"version":"4.3.3"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"31","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,8,5]]},"abstract":"<jats:p>\n                    Activation of the phosphatidylinositol 3-kinase (PI3K)\/AKT signaling pathway is a frequent occurrence in human cancers and a major promoter of chemotherapeutic resistance. Inhibition of one downstream target in this pathway, mTORC1, has shown potential to improve chemosensitivity. However, the mechanisms and genetic modifications that confer sensitivity to mTORC1 inhibitors remain unclear. Here, we demonstrate that loss of TSC2 in the\n                    <jats:italic>E<\/jats:italic>\n                    \u03bc-\n                    <jats:italic>myc<\/jats:italic>\n                    murine lymphoma model leads to mTORC1 activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation. Tumors from\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    <jats:italic>E<\/jats:italic>\n                    \u03bc-\n                    <jats:italic>Myc<\/jats:italic>\n                    mice underwent rapid apoptosis upon blockade of mTORC1 by rapamycin. We identified myeloid cell leukemia sequence 1 (\n                    <jats:italic>Mcl-1<\/jats:italic>\n                    ), a\n                    <jats:italic>bcl-2<\/jats:italic>\n                    like family member, as a translationally regulated genetic determinant of mTORC1-dependent survival. Our results indicate that the extent by which rapamycin can modulate expression of\n                    <jats:italic>Mcl-1<\/jats:italic>\n                    is an important feature of the rapamycin response.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0804821105","type":"journal-article","created":{"date-parts":[[2008,7,29]],"date-time":"2008-07-29T23:24:28Z","timestamp":1217373868000},"page":"10853-10858","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":270,"title":["mTORC1 promotes survival through translational control of Mcl-1"],"prefix":"10.1073","volume":"105","author":[{"given":"John R.","family":"Mills","sequence":"first","affiliation":[{"name":"*Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Hippo","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Robert","sequence":"additional","affiliation":[{"name":"*Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel M. H.","family":"Chen","sequence":"additional","affiliation":[{"name":"*Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abba","family":"Malina","sequence":"additional","affiliation":[{"name":"*Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Ju","family":"Lin","sequence":"additional","affiliation":[{"name":"*Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Trojahn","sequence":"additional","affiliation":[{"name":"*Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Guido","family":"Wendel","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory and"},{"name":"Department of Cancer Biology and Genetics, Memorial Sloan\u2013Kettering, New York, NY 10021;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al","family":"Charest","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Institute, 750 Washington Street, Tufts\u2013New England Medical Center, Box 5609, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick T.","family":"Bronson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott C.","family":"Kogan","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California, San Francisco, CA 94143; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Nadon","sequence":"additional","affiliation":[{"name":"**McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, QC, Canada H3G 1Y6;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Housman","sequence":"additional","affiliation":[{"name":"Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott W.","family":"Lowe","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory and"},{"name":"Howard Hughes Medical Institute, Cold Spring Harbor, NY 11724;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Pelletier","sequence":"additional","affiliation":[{"name":"*Department of Biochemistry,"},{"name":"McGill Cancer Centre, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,8,5]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.05.008"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1212704"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130276"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2007.11.003"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.03.029"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2925"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0419"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02369"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.08.022"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317222"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/318533a0"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.20.2658"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200403069"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2006.10.007"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M603536200"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106148"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.20.2670"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1093903"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02067"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1604407"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03845"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5635"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00642-6"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-3018"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.09.006"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403784"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210679"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2004.06.054"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0804821105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:13:31Z","timestamp":1649787211000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0804821105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,8,5]]},"references-count":28,"journal-issue":{"issue":"31","published-print":{"date-parts":[[2008,8,5]]}},"alternative-id":["10.1073\/pnas.0804821105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0804821105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,8,5]]},"assertion":[{"value":"2008-05-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-08-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}