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

Oncogene volume 28, pages 1537–1548 (2009)Cite this article

Abstract

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 p27Kip1 upon Sox5 expression that was dominant to PDGFB signaling and specific to Ink4a−/− cells. Upon inhibition of p27Kip1, 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 p27Kip1 in a p19Arf-dependent manner, leading to acute cellular senescence.

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Acknowledgements

We thank Veronique Lefebvre for the Sox5 cDNA, Fredrik Pontén for supplying the normal and tumor tissue microarrays, and Umashankar Singh for advice on siRNA. This work has been supported by grants from the Swedish Cancer Society, the Swedish Research Council and Association for International Cancer Research, and by donations in the memory of Joacim Bonnevier. ET has been supported by postdoctoral grants from the Swedish Research Council, the Swedish Society for Medical Research and the Swedish Cancer Society.

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  1. D Bråsäter

    Present address: 3Current address: ICON Clinical Research, PO Box 728, Gårsdvägen 18, SE-169 27 Solna, Sweden.,

  2. E Tchougounova and Y Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    E Tchougounova, Y Jiang, D Bråsäter, N Lindberg, M Kastemar, A Asplund, B Westermark & L Uhrbom

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Correspondence to L Uhrbom.

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Tchougounova, E., Jiang, Y., Bråsäter, D. et al. Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence. Oncogene 28, 1537–1548 (2009). https://doi.org/10.1038/onc.2009.9

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