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Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc.

TitleGliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc.
Publication TypeJournal Article
Year of Publication2012
AuthorsKim HSug, Woolard K, Lai C, Bauer PO, Maric D, Song H, Li A, Kotliarova S, Zhang W, Fine HA
JournalCancer Res
Volume72
Issue22
Pagination6065-75
Date Published2012 Nov 15
ISSN1538-7445
KeywordsAnimals, Apoptosis, Brain Neoplasms, Cyclin-Dependent Kinase Inhibitor p16, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Female, Glioblastoma, Male, Mice, Mice, Knockout, Neural Stem Cells, Proto-Oncogene Proteins c-myc, PTEN Phosphohydrolase, Signal Transduction, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases
Abstract

Glioblastoma multiforme is the most common type of primary malignant brain tumor and may arise from a cell with neural stem-like properties. Deregulation of the retinoblastoma, phosphoinositide-3 kinase (PI3K), and p53 pathways are molecular hallmarks of this disease. Recent work has shown that p53(-/-)Pten(-/-) mice form gliomas in a c-Myc-dependent manner. To explore the role of the INK4A/ARF locus and Pten deletions in gliomagenesis, we generated Pten(-/-)Ink4a/Arf(-/-) mouse neural stem cells (mNSC) and such cells were highly proliferative, self-renewing, relatively refractory to differentiation, and induced both low- and high-grade glioma formation in vivo. In contrast to p53(-/-) Pten(-/-) mNSCs, however, Pten(-/-)Ink4a/Arf(-/-) mNSCs do not express appreciable levels of c-Myc in vitro, although glioma stem cells derived from thesecells did. Sequencing of Pten(-/-)Ink4a/Arf(-/-) mNSC-derived tumors revealed spontaneous mutations in Tp53 in vivo with subsequent downregulation of Fbxw7. Expression of p53 mutants in Pten(-/-)Ink4a/Arf(-/-) mNSC or knockdown of Fbxw7 resulted in reexpression of c-Myc with enhanced Pten(-/-)Ink4a/Arf(-/-) mNSC tumorigenecity. We propose that p53 mutations contribute to gliomagenesis by both allowing the overexpression of c-Myc through downregulation of Fbxw7 and by protecting against c-Myc-induced apoptosis.

DOI10.1158/0008-5472.CAN-12-2594
Alternate JournalCancer Res.
PubMed ID22986743
Grant List / / Intramural NIH HHS / United States