Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in Gliomagenesis

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2009 Jul 4

PMID 19573811

Citations 89

Authors

Lauren T McGillicuddy

Jody A Fromm

Pablo E Hollstein

Sara Kubek

Rameen Beroukhim

Thomas De Raedt

Bryan W Johnson

Sybil M G Williams

Phioanh Nghiemphu

Linda M Liau

Tim F Cloughesy

Paul S Mischel

Annabel Parret

Jeanette Seiler

Gerd Moldenhauer

Klaus Scheffzek

Anat O Stemmer-Rachamimov

Charles L Sawyers

Cameron Brennan

Ludwine Messiaen

Ingo K Mellinghoff

Karen Cichowski

Affiliations

Soon will be listed here.

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.

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