Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence.

SOX5 is a member of the high-mobility group superfamily of architectural non-histone proteins involved in gene regulation and maintenance of chromatin structure in a wide variety of developmental processes. Sox5 was identified as a brain tumor locus in a retroviral insertional mutagenesis screen of platelet-derived growth factor B (PDGFB)-induced mouse gliomas. Here we have investigated the role of Sox5 in PDGFB-induced gliomagenesis in mice. We show that Sox5 can suppress PDGFB-induced glioma development predominantly upon Ink4a-loss. In human glioma cell lines and tissues, we found very low levels of SOX5 compared with normal brain. Overexpression of Sox5 in human glioma cells led to a reduction in clone formation and inhibition of proliferation. Combined expression of Sox5 and PDGFB in primary brain cell cultures caused decreased proliferation and an increased number of senescent cells in the Ink4a-/- cells only. Protein analyses showed a reduction in the amount and activation of Akt and increased levels of p27(Kip1) upon Sox5 expression that was dominant to PDGFB signaling and specific to Ink4a-/- cells. Upon inhibition of p27(Kip1), the effects of Sox5 on proliferation and senescence could be reversed. Our data suggest a novel pathway, where Sox5 may suppress the oncogenic effects of PDGFB signaling during glioma development by regulating p27(Kip1) in a p19(Arf)-dependent manner, leading to acute cellular senescence.

Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma.

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.