Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.
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.
McGillicuddy
Lauren T
LT
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Fromm
Jody A
JA
Hollstein
Pablo E
PE
Kubek
Sara
S
Beroukhim
Rameen
R
De Raedt
Thomas
T
Johnson
Bryan W
BW
Williams
Sybil M G
SM
Nghiemphu
Phioanh
P
Liau
Linda M
LM
Cloughesy
Tim F
TF
Mischel
Paul S
PS
Parret
Annabel
A
Seiler
Jeanette
J
Moldenhauer
Gerd
G
Scheffzek
Klaus
K
Stemmer-Rachamimov
Anat O
AO
Sawyers
Charles L
CL
Brennan
Cameron
C
Messiaen
Ludwine
L
Mellinghoff
Ingo K
IK
Cichowski
Karen
K
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
D025542:Neurofibromin 1; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins