title: Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.
abstract: Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.
authors: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Lauren T
authors: LT
authors: McGillicuddy
authors: Jody A
authors: JA
authors: Fromm
authors: Pablo E
authors: PE
authors: Hollstein
authors: Sara
authors: S
authors: Kubek
authors: Rameen
authors: R
authors: Beroukhim
authors: Thomas
authors: T
authors: De Raedt
authors: Bryan W
authors: BW
authors: Johnson
authors: Sybil M G
authors: SM
authors: Williams
authors: Phioanh
authors: P
authors: Nghiemphu
authors: Linda M
authors: LM
authors: Liau
authors: Tim F
authors: TF
authors: Cloughesy
authors: Paul S
authors: PS
authors: Mischel
authors: Annabel
authors: A
authors: Parret
authors: Jeanette
authors: J
authors: Seiler
authors: Gerd
authors: G
authors: Moldenhauer
authors: Klaus
authors: K
authors: Scheffzek
authors: Anat O
authors: AO
authors: Stemmer-Rachamimov
authors: Charles L
authors: CL
authors: Sawyers
authors: Cameron
authors: C
authors: Brennan
authors: Ludwine
authors: L
authors: Messiaen
authors: Ingo K
authors: IK
authors: Mellinghoff
authors: Karen
authors: K
authors: Cichowski
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D011905:Genes, ras; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics*; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins