title: Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence.
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 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.
authors.affiliation: Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Tchougounova
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.forename: D
authors.initials: D
authors.lastname: Bråsäter
authors.forename: N
authors.initials: N
authors.lastname: Lindberg
authors.forename: M
authors.initials: M
authors.lastname: Kastemar
authors.forename: A
authors.initials: A
authors.lastname: Asplund
authors.forename: B
authors.initials: B
authors.lastname: Westermark
authors.forename: L
authors.initials: L
authors.lastname: Uhrbom
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D005910:Glioma / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D051379:Mice; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000502:physiology*; D055755:SOXD Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C436291:CDKN1B protein, human; C493961:Cdkn1b protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047908:Intracellular Signaling Peptides and Proteins; D020574:Proto-Oncogene Proteins c-sis; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors; C089186:Sox5 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27