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Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner.

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.

Pubmed ID: 21896734


  • Banerjee S
  • Crouse NR
  • Emnett RJ
  • Gianino SM
  • Gutmann DH


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

September 20, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: CA127008

Mesh Terms

  • Animals
  • Astrocytes
  • Blotting, Western
  • Brain
  • Cell Proliferation
  • Female
  • Glial Fibrillary Acidic Protein
  • Glioma
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Monomeric GTP-Binding Proteins
  • Neurofibromin 1
  • Neuropeptides
  • PTEN Phosphohydrolase
  • Primary Cell Culture
  • RNA Interference
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Proteins