{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:57:12Z","timestamp":1791352632992,"version":"4.3.1"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,7,26]]},"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome characterized by benign tumors in multiple organs, including the brain and kidney. TSC-associated tumors exhibit hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), a direct inhibitor of autophagy. Autophagy can either promote or inhibit tumorigenesis, depending on the cellular context. The role of autophagy in the pathogenesis and treatment of the multisystem manifestations of TSC is unknown. We found that the combination of mTORC1 and autophagy inhibition was more effective than either treatment alone in inhibiting the survival of tuberin (TSC2)-null cells, growth of TSC2-null xenograft tumors, and development of spontaneous renal tumors in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice. Down-regulation of Atg5 induced extensive central necrosis in TSC2-null xenograft tumors, and loss of one allele of\n                    <jats:italic>Beclin1<\/jats:italic>\n                    almost completely blocked macroscopic renal tumor formation in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice. Surprisingly, given the finding that lowering autophagy blocks TSC tumorigenesis, genetic down-regulation of p62\/sequestosome 1 (SQSTM1), the autophagy substrate that accumulates in TSC tumors as a consequence of low autophagy levels, strongly inhibited the growth of TSC2-null xenograft tumors. These data demonstrate that autophagy is a critical component of TSC tumorigenesis, suggest that mTORC1 inhibitors may have autophagy-dependent prosurvival effects in TSC, and reveal two distinct therapeutic targets for TSC: autophagy and the autophagy target p62\/SQSTM1.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1104361108","type":"journal-article","created":{"date-parts":[[2011,7,12]],"date-time":"2011-07-12T02:10:10Z","timestamp":1310436610000},"page":"12455-12460","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":173,"title":["Tumorigenesis in tuberous sclerosis complex is autophagy and p62\/sequestosome 1 (SQSTM1)-dependent"],"prefix":"10.1073","volume":"108","author":[{"given":"Andrey","family":"Parkhitko","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;"},{"name":"Department of Molecular Biology, Russian State Medical University, Moscow 117997, Russia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faina","family":"Myachina","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasha A.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadijah M.","family":"Hindi","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Auricchio","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Karbowniczek","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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