1. Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in Gliomagenesis
- Author
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Linda M. Liau, Lauren T. McGillicuddy, G. Moldenhauer, Jody A. Fromm, Charles L. Sawyers, Sara Kubek, Bryan W. Johnson, Annabel H. A. Parret, Thomas De Raedt, Karen Cichowski, Sybil M. Genther Williams, Ludwine Messiaen, Paul S. Mischel, Rameen Beroukhim, Cameron Brennan, Klaus Scheffzek, Timothy F. Cloughesy, Anat Stemmer-Rachamimov, Jeanette Seiler, Pablo E. Hollstein, Ingo K. Mellinghoff, and Phioanh L. Nghiemphu
- Subjects
Proteasome Endopeptidase Complex ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Neurofibromatosis 1 ,Down-Regulation ,CELLCYCLE ,Biology ,medicine.disease_cause ,Article ,3T3 cells ,law.invention ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,law ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,neoplasms ,Gene ,Protein Kinase C ,Protein kinase C ,030304 developmental biology ,0303 health sciences ,Mutation ,Neurofibromin 1 ,Cell Biology ,3T3 Cells ,Glioma ,Cell cycle ,Genes, p53 ,nervous system diseases ,3. Good health ,Genes, ras ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,ras Proteins ,Cancer research ,Suppressor ,Glioblastoma ,Carcinogenesis - Abstract
SummaryLoss-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.
- Published
- 2009
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