Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis Journal Article
| Authors: | McGillicuddy, L. T.; Fromm, J. A.; Hollstein, P. E.; Kubek, S.; Beroukhim, R.; De Raedt, T.; Johnson, B. W.; Williams, S. M. G.; Nghiemphu, P.; Liau, L. M.; Cloughesy, T. F.; Mischel, P. S.; Parret, A.; Seiler, J.; Moldenhauer, G.; Scheffzek, K.; Stemmer-Rachamimov, A. O.; Sawyers, C. L.; Brennan, C.; Messiaen, L.; Mellinghoff, I. K.; Cichowski, K. |
| Article 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. © 2009 Elsevier Inc. All rights reserved. |
| Keywords: | controlled study; human cell; mutation; nonhuman; glioma; animal cell; mouse; animals; mice; neurofibromatosis 1; proteasome endopeptidase complex; embryo; protein degradation; down-regulation; enzyme activation; chemosensitivity; protein p53; carcinogenesis; molecular mechanics; cancer inhibition; glioblastoma; neurofibromin; gene loss; neurofibromin 1; cellcycle; protein kinase c; gene inactivation; ras proteins; genes, ras; genes, tumor suppressor; 3t3 cells; genes, p53 |
| Journal Title: | Cancer Cell |
| Volume: | 16 |
| Issue: | 1 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2009-07-07 |
| Start Page: | 44 |
| End Page: | 54 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2009.05.009 |
| PUBMED: | 19573811 |
| PROVIDER: | scopus |
| PMCID: | PMC2897249 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 12" - "Export Date: 30 November 2010" - "CODEN: CCAEC" - "Source: Scopus" |
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