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

Hong Sug Kim, Kevin D Woolard, Chen Lai, Peter O. Bauer, Dragan Maric, Hua Song, Aiguo Li, Svetlana Kotliarova, Wei Zhang, Howard A. Fine

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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 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.

Original languageEnglish (US)
Pages (from-to)6065-6075
Number of pages11
JournalCancer Research
Volume72
Issue number22
DOIs
StatePublished - Nov 15 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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