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 cellswere 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.
ASJC Scopus subject areas
- Cancer Research