{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:45:57Z","timestamp":1788896757847,"version":"build-2803163510"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"38","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,9,20]]},"abstract":"<jats:p>\n                    Converging evidence from the analysis of human brain tumors and genetically engineered mice has revealed that the mammalian target of rapamycin (mTOR) pathway is a central regulator of glial and glioma cell growth. In this regard, mutational inactivation of neurofibromatosis-1 (NF1), tuberous sclerosis complex (TSC), and PTEN genes is associated with glioma formation, such that pharmacologic inhibition of mTOR signaling results in attenuated tumor growth. This shared dependence on mTOR suggests that PTEN and NF1 (neurofibromin) glial growth regulation requires TSC\/Rheb (Ras homolog enriched in brain) control of mTOR function. In this report, we use a combination of genetic silencing in vitro and conditional mouse transgenesis approaches in vivo to demonstrate that neurofibromin regulates astrocyte cell growth and glioma formation in a TSC\/Rheb-independent fashion. First, we show that\n                    <jats:italic>Nf1<\/jats:italic>\n                    or\n                    <jats:italic>Pten<\/jats:italic>\n                    inactivation, but not\n                    <jats:italic>Tsc1<\/jats:italic>\n                    loss or Rheb overexpression, increases astrocyte cell growth in vitro. Second,\n                    <jats:italic>Nf1<\/jats:italic>\n                    -deficient increased mTOR signaling and astrocyte hyperproliferation is unaffected by Rheb shRNA silencing. Third, conditional\n                    <jats:italic>Tsc1<\/jats:italic>\n                    inactivation or Rheb overexpression in glial progenitors of\n                    <jats:italic>Nf1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice does not lead to glioma formation. Collectively, these findings establish TSC\/Rheb-independent mechanisms for mTOR-dependent glial cell growth control and gliomagenesis relevant to the design of therapies for individuals with glioma.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1019012108","type":"journal-article","created":{"date-parts":[[2011,9,6]],"date-time":"2011-09-06T22:38:14Z","timestamp":1315348694000},"page":"15996-16001","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":86,"title":["Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC\/Rheb-independent manner"],"prefix":"10.1073","volume":"108","author":[{"given":"Sutapa","family":"Banerjee","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikkilina R.","family":"Crouse","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Emnett","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Gianino","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Gutmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,9,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07385"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200507119"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205838200"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00568-3"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb840"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C300226200"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00220-X"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1110003"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00506-2"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb999"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.02.053"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00661"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb996"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb995"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20036"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.14.5100-5113.2002"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10283"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2487"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.171076798"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4058"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0503224102"},{"key":"e_1_3_3_22_2","first-page":"8573","article-title":"Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity","volume":"63","author":"Bajenaru ML","year":"2003","unstructured":"ML Bajenaru, et al., Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. 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