Loss of Arf Causes Tumor Progression of PDGFB-induced Oligodendroglioma

Oncogene. 2007 Sep 20;26(43):6289-96. doi: 10.1038/sj.onc.1210455. Epub 2007 Apr 16.


In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a-/- mice and Ink4a-Arf-/- mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Disease Progression
  • Mice
  • Mice, Knockout
  • Oligodendroglioma / genetics
  • Oligodendroglioma / metabolism*
  • Oligodendroglioma / pathology*
  • Proto-Oncogene Proteins c-sis / genetics
  • Proto-Oncogene Proteins c-sis / metabolism*
  • Signal Transduction
  • Survival Rate
  • Tissue Culture Techniques


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proto-Oncogene Proteins c-sis