Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Cell. 2009 Jul 7;16(1):44-54. doi: 10.1016/j.ccr.2009.05.009.

Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.

Author information

1
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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.

PMID:
19573811
PMCID:
PMC2897249
DOI:
10.1016/j.ccr.2009.05.009
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center