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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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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Neural Stem Cells
Stem Cells
Glioma
Down-Regulation
Mutation
1-Phosphatidylinositol 4-Kinase
Retinoblastoma
Glioblastoma
Brain Neoplasms
Apoptosis
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc. / Kim, Hong Sug; Woolard, Kevin D; Lai, Chen; Bauer, Peter O.; Maric, Dragan; Song, Hua; Li, Aiguo; Kotliarova, Svetlana; Zhang, Wei; Fine, Howard A.

In: Cancer Research, Vol. 72, No. 22, 15.11.2012, p. 6065-6075.

Research output: Contribution to journalArticle

Kim, Hong Sug ; Woolard, Kevin D ; Lai, Chen ; Bauer, Peter O. ; Maric, Dragan ; Song, Hua ; Li, Aiguo ; Kotliarova, Svetlana ; Zhang, Wei ; Fine, Howard A. / Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc. In: Cancer Research. 2012 ; Vol. 72, No. 22. pp. 6065-6075.
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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.",
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AU - Kim, Hong Sug

AU - Woolard, Kevin D

AU - Lai, Chen

AU - Bauer, Peter O.

AU - Maric, Dragan

AU - Song, Hua

AU - Li, Aiguo

AU - Kotliarova, Svetlana

AU - Zhang, Wei

AU - Fine, Howard A.

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