Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma
2007 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 43, 6289-6296 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 26, no 43, 6289-6296 p.
oligodendroglioma, PDGF, mouse model, Ink4a, Arf, p70S6K
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-10833DOI: 10.1038/sj.onc.1210455ISI: 000249583300005PubMedID: 17438529OAI: oai:DiVA.org:uu-10833DiVA: diva2:38601