Title | Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Kim HSug, Woolard K, Lai C, Bauer PO, Maric D, Song H, Li A, Kotliarova S, Zhang W, Fine HA |
Journal | Cancer Res |
Volume | 72 |
Issue | 22 |
Pagination | 6065-75 |
Date Published | 2012 Nov 15 |
ISSN | 1538-7445 |
Keywords | Animals, 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. |
DOI | 10.1158/0008-5472.CAN-12-2594 |
Alternate Journal | Cancer Res. |
PubMed ID | 22986743 |
Grant List | / / Intramural NIH HHS / United States |