title: Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner.
abstract: 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 Nf1 or Pten inactivation, but not Tsc1 loss or Rheb overexpression, increases astrocyte cell growth in vitro. Second, Nf1-deficient increased mTOR signaling and astrocyte hyperproliferation is unaffected by Rheb shRNA silencing. Third, conditional Tsc1 inactivation or Rheb overexpression in glial progenitors of Nf1(+/-) 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.
authors: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Sutapa
authors: S
authors: Banerjee
authors: Nikkilina R
authors: NR
authors: Crouse
authors: Ryan J
authors: RJ
authors: Emnett
authors: Scott M
authors: SM
authors: Gianino
authors: David H
authors: DH
authors: Gutmann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D025542:Neurofibromin 1; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D020559:Monomeric GTP-Binding Proteins