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• W2041822919 abstract "High-grade gliomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority of these tumors. Resistance to genotoxic modalities in p53-positive gliomas is generally attributed to attenuation of p53 functions by mutations of other components within the p53 signaling axis, such as p14Arf, MDM2, and ATM, but this explanation is not entirely satisfactory. We show here that the central nervous system (CNS)-restricted transcription factor Olig2 affects a key posttranslational modification of p53 in both normal and malignant neural progenitors and thereby antagonizes the interaction of p53 with promoter elements of multiple target genes. In the absence of Olig2 function, even attenuated levels of p53 are adequate for biological responses to genotoxic damage. High-grade gliomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority of these tumors. Resistance to genotoxic modalities in p53-positive gliomas is generally attributed to attenuation of p53 functions by mutations of other components within the p53 signaling axis, such as p14Arf, MDM2, and ATM, but this explanation is not entirely satisfactory. We show here that the central nervous system (CNS)-restricted transcription factor Olig2 affects a key posttranslational modification of p53 in both normal and malignant neural progenitors and thereby antagonizes the interaction of p53 with promoter elements of multiple target genes. In the absence of Olig2 function, even attenuated levels of p53 are adequate for biological responses to genotoxic damage. Olig2 promotes survival of neural progenitors under genotoxic stress Acetylation of p53 is suppressed by Olig2 p53 association to its target promoters is affected in the presence of Olig2 Olig2 requirement for glioma formation is p53 dependent The data show how a molecular mechanism for sustaining the replication competent state of neural progenitors at early times in CNS development has been co-opted by high-grade glioma. The bHLH transcription factor Olig2 opposes p53 functions in both normal and malignant neural progenitor cells via modulation of posttranslational modifications of p53. The findings shed light on developmental origins of these tumors and may have practical overtones for targeted therapy. The p53 tumor suppressor gene and its downstream effectors play a multifaceted role in protection from cellular stress, genotoxic damage, and inappropriate mitogenic cues (Brugarolas et al., 1995Brugarolas J. Chandrasekaran C. Gordon J.I. Beach D. Jacks T. Hannon G.J. Radiation-induced cell cycle arrest compromised by p21 deficiency.Nature. 1995; 377: 552-557Crossref PubMed Scopus (1118) Google Scholar, el-Deiry et al., 1993el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. WAF1, a potential mediator of p53 tumor suppression.Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7726) Google Scholar, Prives and Hall, 1999Prives C. Hall P.A. The p53 pathway.J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1207) Google Scholar). Activation of p53 transcriptional functions by any of these biological events results in transient growth arrest, permanent growth arrest or programmed cell death (Brugarolas et al., 1995Brugarolas J. Chandrasekaran C. Gordon J.I. Beach D. Jacks T. Hannon G.J. Radiation-induced cell cycle arrest compromised by p21 deficiency.Nature. 1995; 377: 552-557Crossref PubMed Scopus (1118) Google Scholar, el-Deiry et al., 1993el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. WAF1, a potential mediator of p53 tumor suppression.Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7726) Google Scholar, Prives and Hall, 1999Prives C. Hall P.A. The p53 pathway.J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1207) Google Scholar, Wynford-Thomas, 1999Wynford-Thomas D. Cellular senescence and cancer.J. Pathol. 1999; 187: 100-111Crossref PubMed Scopus (134) Google Scholar, Zilfou and Lowe, 2009Zilfou J.T. Lowe S.W. Tumor suppressive functions of p53.Cold Spring Harb. Perspect. Biol. 2009; 1: a001883Crossref Scopus (358) Google Scholar). One key effector of p53 biological responses is the cell cycle inhibitor protein p21WAF1/CIP1 (hereafter called “p21”) encoded by CDKN1A. CDKN1A is a direct transcriptional target of p53 and ablation of CDKN1A can phenocopy some, though not all, aspects of p53 loss of function (Sherr and Roberts, 1999Sherr C.J. Roberts J.M. CDK inhibitors: positive and negative regulators of G1-phase progression.Genes Dev. 1999; 13: 1501-1512Crossref PubMed Scopus (4936) Google Scholar). Recent studies on the production of induced pluripotent stem (iPS) cells highlight a hitherto unappreciated oppositional relationship between p53, p21 and the stem cell phenotype (Hong et al., 2009Hong H. Takahashi K. Ichisaka T. Aoi T. Kanagawa O. Nakagawa M. Okita K. Yamanaka S. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.Nature. 2009; 460: 1132-1135Crossref PubMed Scopus (1007) Google Scholar, Kawamura et al., 2009Kawamura T. Suzuki J. Wang Y.V. Menendez S. Morera L.B. Raya A. Wahl G.M. Belmonte J.C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming.Nature. 2009; 460: 1140-1144Crossref PubMed Scopus (850) Google Scholar, Li et al., 2009Li H. Collado M. Villasante A. Strati K. Ortega S. Canamero M. Blasco M.A. Serrano M. The Ink4/Arf locus is a barrier for iPS cell reprogramming.Nature. 2009; 460: 1136-1139Crossref PubMed Scopus (767) Google Scholar, Marion et al., 2009Marion R.M. Strati K. Li H. Murga M. Blanco R. Ortega S. Fernandez-Capetillo O. Serrano M. Blasco M.A. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity.Nature. 2009; 460: 1149-1153Crossref PubMed Scopus (804) Google Scholar, Utikal et al., 2009Utikal J. Polo J.M. Stadtfeld M. Maherali N. Kulalert W. Walsh R.M. Khalil A. Rheinwald J.G. Hochedlinger K. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells.Nature. 2009; 460: 1145-1148Crossref PubMed Scopus (669) Google Scholar). Ablation of p53 greatly enhances the efficiency of iPS formation from normal fibroblast cells and p21 is an important component of this outcome (Hong et al., 2009Hong H. Takahashi K. Ichisaka T. Aoi T. Kanagawa O. Nakagawa M. Okita K. Yamanaka S. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.Nature. 2009; 460: 1132-1135Crossref PubMed Scopus (1007) Google Scholar, Kawamura et al., 2009Kawamura T. Suzuki J. Wang Y.V. Menendez S. Morera L.B. Raya A. Wahl G.M. Belmonte J.C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming.Nature. 2009; 460: 1140-1144Crossref PubMed Scopus (850) Google Scholar, Li et al., 2009Li H. Collado M. Villasante A. Strati K. Ortega S. Canamero M. Blasco M.A. Serrano M. The Ink4/Arf locus is a barrier for iPS cell reprogramming.Nature. 2009; 460: 1136-1139Crossref PubMed Scopus (767) Google Scholar). The iPS work resonates with earlier studies showing that targeted disruption of either p53 (Meletis et al., 2006Meletis K. Wirta V. Hede S.M. Nister M. Lundeberg J. Frisen J. p53 suppresses the self-renewal of adult neural stem cells.Development. 2006; 133: 363-369Crossref PubMed Scopus (324) Google Scholar) or Cdkn1a (Kippin et al., 2005Kippin T.E. Martens D.J. van der Kooy D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity.Genes Dev. 2005; 19: 756-767Crossref PubMed Scopus (339) Google Scholar) compromises the relative quiescence of neural progenitors and accelerates self-renewal in the mouse. If the p53:p21 regulatory axis suppresses self-renewal, how do stem cells in the general, and neural stem cells in the particular, suppress these functions during development and tissue repair? The molecular mechanism of p53:p21 suppression would likely involve proteins that are unique to uncommitted progenitor cell types because global disruption of p53 functions gives rise to an oncogenic phenotype (Donehower et al., 1992Donehower L.A. Harvey M. Slagle B.L. McArthur M.J. Montgomery Jr., C.A. Butel J.S. Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.Nature. 1992; 356: 215-221Crossref PubMed Scopus (3904) Google Scholar, Harvey et al., 1993Harvey M. McArthur M.J. Montgomery Jr., C.A. Butel J.S. Bradley A. Donehower L.A. Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice.Nat. Genet. 1993; 5: 225-229Crossref PubMed Scopus (476) Google Scholar). For neural progenitors, the bHLH transcription factor Olig2 is a plausible candidate, based on expression and functional studies. During CNS development, Olig2 is expressed in progenitor cells that give rise to neurons and to myelinating oligodendrocytes (Lu et al., 2002Lu Q.R. Sun T. Zhu Z. Ma N. Garcia M. Stiles C.D. Rowitch D.H. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection.Cell. 2002; 109: 75-86Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar, Takebayashi et al., 2002Takebayashi H. Nabeshima Y. Yoshida S. Chisaka O. Ikenaka K. The basic helix-loop-helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages.Curr. Biol. 2002; 12: 1157-1163Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar, Zhou and Anderson, 2002Zhou Q. Anderson D.J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification.Cell. 2002; 109: 61-73Abstract Full Text Full Text PDF PubMed Scopus (783) Google Scholar). In the postnatal brain, Olig2 is expressed in transit amplifying type C neural progenitors of the subventricular zone that give rise to olfactory neurons and oligodendrocytes (Hack et al., 2004Hack M.A. Sugimori M. Lundberg C. Nakafuku M. Gotz M. Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6.Mol. Cell. Neurosci. 2004; 25: 664-678Crossref PubMed Scopus (222) Google Scholar, Menn et al., 2006Menn B. Garcia-Verdugo J.M. Yaschine C. Gonzalez-Perez O. Rowitch D. Alvarez-Buylla A. Origin of oligodendrocytes in the subventricular zone of the adult brain.J. Neurosci. 2006; 26: 7907-7918Crossref PubMed Scopus (705) Google Scholar). Olig2 is also expressed in NG2-positive glia, which is the most prevalent cycling progenitor cell type in the postnatal brain (Jackson et al., 2006Jackson E.L. Garcia-Verdugo J.M. Gil-Perotin S. Roy M. Quinones-Hinojosa A. VandenBerg S. Alvarez-Buylla A. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling.Neuron. 2006; 51: 187-199Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, Ligon et al., 2006Ligon K.L. Kesari S. Kitada M. Sun T. Arnett H.A. Alberta J.A. Anderson D.J. Stiles C.D. Rowitch D.H. Development of NG2 neural progenitor cells requires Olig gene function.Proc. Natl. Acad. Sci. USA. 2006; 103: 7853-7858Crossref PubMed Scopus (164) Google Scholar, Magnus et al., 2007Magnus T. Coksaygan T. Korn T. Xue H. Arumugam T.V. Mughal M.R. Eckley D.M. Tang S.C. Detolla L. Rao M.S. et al.Evidence that nucleocytoplasmic Olig2 translocation mediates brain-injury-induceddifferentiation of glial precursors to astrocytes.J. Neurosci. Res. 2007; 85: 2126-2137Crossref PubMed Scopus (68) Google Scholar). A pathological correlate of Olig2 expression in healthy neural progenitors is seen in primary cancers of the CNS where OLIG2 is expressed in 100% of diffuse gliomas irrespective of grade (Ligon et al., 2004Ligon K.L. Alberta J.A. Kho A.T. Weiss J. Kwaan M.R. Nutt C.L. Louis D.N. Stiles C.D. Rowitch D.H. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas.J. Neuropathol. Exp. Neurol. 2004; 63: 499-509Crossref PubMed Scopus (311) Google Scholar). Beyond merely marking malignant astrocytomas, Olig2 expression is required for tumor formation in a genetically relevant murine model of high-grade human glioma (Ligon et al., 2007Ligon K.L. Huillard E. Mehta S. Kesari S. Liu H. Alberta J.A. Bachoo R.M. Kane M. Louis D.N. Depinho R.A. et al.Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma.Neuron. 2007; 53: 503-517Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). Malignant gliomas are notoriously resistant to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority of adult high-grade primary gliomas (Cancer Genome Atlas Research Network, 2008Cancer Genome Atlas Research NetworkComprehensive genomic characterization defines human glioblastoma genes and core pathways.Nature. 2008; 455: 1061-1068Crossref PubMed Scopus (5204) Google Scholar). Resistance to genotoxic modalities in p53-positive gliomas has been attributed to attenuation of p53 functions by genetic or epigenetic changes within a p53 signaling axis that includes the p14Arf, MDM2, and ATM gene products (Nakamura et al., 2001Nakamura M. Watanabe T. Klangby U. Asker C. Wiman K. Yonekawa Y. Kleihues P. Ohgaki H. p14ARF deletion and methylation in genetic pathways to glioblastomas.Brain Pathol. 2001; 11: 159-168Crossref PubMed Scopus (204) Google Scholar, Cancer Genome Atlas Research Network, 2008Cancer Genome Atlas Research NetworkComprehensive genomic characterization defines human glioblastoma genes and core pathways.Nature. 2008; 455: 1061-1068Crossref PubMed Scopus (5204) Google Scholar, Parsons et al., 2008Parsons D.W. Jones S. Zhang X. Lin J.C. Leary R.J. Angenendt P. Mankoo P. Carter H. Siu I.M. Gallia G.L. et al.An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4176) Google Scholar, Reifenberger et al., 1993Reifenberger G. Liu L. Ichimura K. Schmidt E.E. Collins V.P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations.Cancer Res. 1993; 53: 2736-2739PubMed Google Scholar). However, CNS lineage-specific factors that inhibit p53 pathways have not been reported. In this study, we investigated the potential function for Olig2 as an antagonist of p53 function in normal and malignant neural progenitors. As shown in Figure 1A , normal neural progenitors (wild-type for both Olig2 and p53) can form secondary neurospheres within 5 days after exposure to radiation. The Olig2 null counterparts of these cells are significantly more sensitive to radiation. The same differential sensitivity to genotoxic damage is observed in cells treated with Temozolomide, a genotoxic drug that is now a standard-of-care chemotherapeutic agent for adult patients with recurrent high-grade glioma (see Figure S1 available online). Loss of Olig2 impacts both the number of secondary neurospheres and the total number of cells in these secondary neurosphere assays (Figures 1B and 1C). Cell cycle arrest (as monitored by BrdU uptake) and to a lesser extent programmed cell death (as monitored by cleaved caspase 3) contribute to the differential sensitivity of Olig2 null cells (Figures 1D and 1E). Experiments summarized in Figure 2 document an oppositional relationship between Olig2 and p53. In one set of studies, we intercrossed Olig2-tva-cre+/− driver mice (Schuller et al., 2008Schuller U. Heine V.M. Mao J. Kho A.T. Dillon A.K. Han Y.G. Huillard E. Sun T. Ligon A.H. Qian Y. et al.Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma.Cancer Cell. 2008; 14: 123-134Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar) and p53 conditional null (p53fl/fl) mice to obtain neural progenitors that were null for p53 and either null or heterozygous for Olig2 function. As shown (Figures 2A, 2D, and 2E) Olig2 status is irrelevant to radiation sensitivity in cells wherein p53 has been genetically ablated. In a second set of experiments, we used the carboxy-terminal dominant-negative fragment of (p53DD) to block p53 transcriptional functions. As indicated (Figures 2B, 2D, and 2E), ablation of Olig2 does not rescue radiosensitivity in the presence of dominant-negative p53. In a third set of experiments, we treated Olig2-positive cells with a p53 agonist (Nutlin, an Mdm2 inhibitor) (Vassilev et al., 2004Vassilev L.T. Vu B.T. Graves B. Carvajal D. Podlaski F. Filipovic Z. Kong N. Kammlott U. Lukacs C. Klein C. et al.In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Science. 2004; 303: 844-848Crossref PubMed Scopus (3515) Google Scholar). As indicated (Figures 2C–2E), we show that Nutlin-mediated stabilization of p53 promotes radiosensitivity in the presence of Olig2. Thus, the oppositional relationship between Olig2 and p53 is symmetrical. To explore biological functions of Olig2 in p53-positive gliomas, we began with genetically accessible murine models. We prepared neurosphere cultures from p16/p19−/− mice (p19 being the mouse ortholog of human p14) and then transduced these cells with a constitutively active mutation of the epidermal growth factor receptor (EGFRvIII) identified originally in human glioblastoma. At a genetic level, these murine “tumor neurospheres” emulate the “classic” group of human gliomas (p16/p14−/−;mutant EGFR; wild-type p53) (Verhaak et al., 2010Verhaak R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. et al.Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.Cancer Cell. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (4306) Google Scholar) and form invasive tumors that recapitulate the histopathology of high-grade human gliomas when engrafted into the brains of SCID mice (Bachoo et al., 2002Bachoo R.M. Maher E.A. Ligon K.L. Sharpless N.E. Chan S.S. You M.J. Tang Y. DeFrances J. Stover E. Weissleder R. et al.Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis.Cancer Cell. 2002; 1: 269-277Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar, Ligon et al., 2007Ligon K.L. Huillard E. Mehta S. Kesari S. Liu H. Alberta J.A. Bachoo R.M. Kane M. Louis D.N. Depinho R.A. et al.Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma.Neuron. 2007; 53: 503-517Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). As expected, p16/p19−/− neurospheres are attenuated relative to wild-type neurospheres with respect to the level of activated p53 protein that can be detected following gamma irradiation (Figure 3A ). However, in secondary neurosphere assays, p16/p19−/− neurospheres and wild-type neurospheres are equally tolerant of gamma irradiation. Ablation of Olig2 function unmasks a radiosensitive phenotype (Figures 3B–3E). Thus, the major contributor to the radioresistance phenotype of normal and malignant neural progenitors is Olig2 status rather than p16Ink4a/p19Arf. Additional experiments with the murine tumor neurospheres recapitulate the oppositional relationship between Olig2 and p53. The expression of p53DD restores radiation resistance in the absence of Olig2 whereas stabilization of p53 with Nutlin promotes radiosensitivity in the presence of Olig2 (Figure 4).Figure 4Olig2-Mediated Radiation Resistance in Tumor Progenitor Cells Is Dependent on p53 StatusShow full caption(A) Suppression of p53 function. An expression vector encoding a dominant negative mutant of p53 (p53DD) was transduced into Olig2−/− p16/p19−/−; EGFRvIII tumor neurospheres as described in the text. These cells, together with vector controls were irradiated as shown. Secondary neurosphere assays were counted at day 5 posttreatment. Scale bars = 100 μm.(B) Enhancement of p53 function. Olig2+/+ tumor neurospheres were treated with 0.25 μM Nutlin (an Mdm2 inhibitor) or DMSO control for 16 hr and then exposed to 2 Gy of radiation. Secondary neurosphere assays were counted at day 5 postirradiation. Scale bars = 100 μm.(C) Quantitation of percentage of secondary neurospheres formed in treated samples as compared with untreated samples.(D) Quantitation of percentage of viable cells after radiation treatment as compared with untreated control samples. For both graphs, the data are compiled from three independent experiments. ∗∗∗p < 0.001, ∗∗p < 0.01. Error bars indicate SEM.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Suppression of p53 function. An expression vector encoding a dominant negative mutant of p53 (p53DD) was transduced into Olig2−/− p16/p19−/−; EGFRvIII tumor neurospheres as described in the text. These cells, together with vector controls were irradiated as shown. Secondary neurosphere assays were counted at day 5 posttreatment. Scale bars = 100 μm. (B) Enhancement of p53 function. Olig2+/+ tumor neurospheres were treated with 0.25 μM Nutlin (an Mdm2 inhibitor) or DMSO control for 16 hr and then exposed to 2 Gy of radiation. Secondary neurosphere assays were counted at day 5 postirradiation. Scale bars = 100 μm. (C) Quantitation of percentage of secondary neurospheres formed in treated samples as compared with untreated samples. (D) Quantitation of percentage of viable cells after radiation treatment as compared with untreated control samples. For both graphs, the data are compiled from three independent experiments. ∗∗∗p < 0.001, ∗∗p < 0.01. Error bars indicate SEM. All primary human gliomas express OLIG2 protein (Ligon et al., 2004Ligon K.L. Alberta J.A. Kho A.T. Weiss J. Kwaan M.R. Nutt C.L. Louis D.N. Stiles C.D. Rowitch D.H. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas.J. Neuropathol. Exp. Neurol. 2004; 63: 499-509Crossref PubMed Scopus (311) Google Scholar, Ligon et al., 2007Ligon K.L. Huillard E. Mehta S. Kesari S. Liu H. Alberta J.A. Bachoo R.M. Kane M. Louis D.N. Depinho R.A. et al.Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma.Neuron. 2007; 53: 503-517Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). Accordingly, for human gliomas, we conducted shRNA knockdown experiments to extend our observation of Olig2:p53 cross-antagonistic interactions. As shown in Figure 5, OLIG2 promotes survival of two radiation-treated human glioma neurosphere lines that are wild-type for p53 (the BT37 and BT112 lines). However, OLIG2 knockdown is without effect in human glioma cells wherein p53 function has been genetically ablated (BT70 line). Notably, OLIG2 knockdown does not impair survival of any of the human cells in the absence of radiation treatment. Previous studies have shown that Olig gene function is required in order for murine tumor neurospheres to form intracranial tumors in SCID mice (Ligon et al., 2007Ligon K.L. Huillard E. Mehta S. Kesari S. Liu H. Alberta J.A. Bachoo R.M. Kane M. Louis D.N. Depinho R.A. et al.Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma.Neuron. 2007; 53: 503-517Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). In the absence of Olig1/2, these cells engraft and survive for at least 70 days, but they do not proliferate to form tumors (Ligon et al., 2007Ligon K.L. Huillard E. Mehta S. Kesari S. Liu H. Alberta J.A. Bachoo R.M. Kane M. Louis D.N. Depinho R.A. et al.Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma.Neuron. 2007; 53: 503-517Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). Experiments summarized in Figure 6 indicate that the Olig2 requirement for proliferation in vivo is another manifestation of the Olig2:p53 oppositional relationship for both mouse and human glioma cell types. In the murine tumor neurospheres, even a single copy of the p53 gene is sufficient to suppress tumor formation in the absence of Olig2. The requirement for Olig2 is overcome by removing both copies of p53 (Figure 6A). We do note, however, that Olig2 heterozygous, p53 null tumors develop more quickly than their Olig2 null counterparts (p < 0.003) raising the possibility of some p53-independent functions that contribute to tumor growth (Figure 6A). Predictably, the histopathology of p53 null tumors that form in the absence of Olig2 is quite different from that of the Olig2-positive/p53-positive tumors that more closely emulate the human disease. In particular, the Olig2 null tumors have a much greater proportion of GFAP-positive cells and a near complete absence of cells that express oligodendrocyte (PDGFRα) and neuronal (Tuj1) progenitor-associated markers (Figure 6B). Intracranial growth of p53-positive human gliomas is likewise promoted by OLIG2. As indicated in Figure 6C, shRNA knockdown of OLIG2 reduces the penetrance and significantly extends the latency of two different p53-positive glioma neurosphere lines. Moreover, the tumors that eventually do arise from implants of the p53-positive lines show expression of endogenous OLIG2 protein (Figure 6D). By contrast, penetrance and latency of a p53 null human glioma line show no significant responses to OLIG2 knockdown (Figure 6C). Moreover, the p53 mutant tumors proliferate in the absence of OLIG2 expression (Figure 6E). As noted with the genetically defined mouse tumor neurospheres, there is a trend (not rising to statistical significance) for OLIG2 to accelerate tumor development from p53 mutant human glioma cells suggesting additional p53-independent functions for growth in vivo (Figure 6C). How might Olig2 oppose p53 biological functions? As indicated in Figure 7A and Figure S2, Olig2 does not affect the overall abundance of p53 protein in either control or irradiated cells. Likewise, Olig2 status is irrelevant to basal or radiation-induced p53 phosphorylation in any of these cell types. However, as shown in Figure 7B, Olig2 suppresses the acetylation of p53 in both normal and malignant murine neural progenitors and in human glioma neurosphere lines. Coincident with p53 hypoacetylation, Olig2 suppresses both basal and radiation-induced interactions of p53 with several well-characterized p53 target genes (Cdkn1a, Wig1, Bax, and Mdm2) as shown by chromatin immune precipitation experiments. Again, this Olig2-mediated suppression of p53 gene targeting is seen in both normal and malignant murine neural progenitors and in human glioma neurosphere cells (Figure 7C). In summary, Olig2 acts upon a key posttranslational modification of p53 protein itself to suppress downstream genetic and biological responses (Figure 7D). The mechanisms that regulate p53-mediated biological responses to DNA damage are complex (for reviews, see Hollstein and Hainaut, 2010Hollstein M. Hainaut P. Massively regulated genes: the example of TP53.J. Pathol. 2010; 220: 164-173PubMed Google Scholar, Riley et al., 2008Riley T. Sontag E. Chen P. Levine A. Transcriptional control of human p53-regulated genes.Nat. Rev. Mol. Cell Biol. 2008; 9: 402-412Crossref PubMed Scopus (1374) Google Scholar, Vogelstein et al., 2000Vogelstein B. Lane D. Levine A.J. Surfing the p53 network.Nature. 2000; 408: 307-310Crossref PubMed Scopus (5527) Google Scholar, Vousden and Prives, 2009Vousden K.H. Prives C. Blinded by the Light: The Growing Complexity of p53.Cell. 2009; 137: 413-431Abstract Full Text Full Text PDF PubMed Scopus (2108) Google Scholar). Activation of p53 stimulates the expression of some genes and suppresses the expression of others depending upon cell type, time point of measurement and extent of DNA damage (Fei et al., 2002Fei P. Bernhard E.J. El-Deiry W.S. Tissue-specific induction of p53 targets in vivo.Cancer Res. 2002; 62: 7316-7327PubMed Google Scholar, Kannan et al., 2001Kannan K. Amariglio N. Rechavi G. Jakob-Hirsch J. Kela I. Kaminski N. Getz G. Domany E. Givol D. DNA microarrays identification of primary and secondary target genes regulated by p53.Oncogene. 2001; 20: 2225-2234Crossref PubMed Scopus (283) Google Scholar, Wei et al., 2006Wei C.L. Wu Q. Vega V.B. Chiu K.P. Ng P. Zhang T. Shahab A. Yong H.C. Fu Y. Weng Z. et al.A global map of p53 transcription-factor binding sites in the human genome.Cell. 2006; 124: 207-219Abstract Full Text Full Text PDF PubMed Scopus (898) Google Scholar). The biological impact of diminished DNA targeting was examined in detail for one p53 target gene, namely, CDKN1A. As indicated in Figures 8A , 8B, and Figure S3, Olig2 suppresses radiation-induced expression of p21 in some, but not all of the cell types studied here. The expression of p21 is regulated by a wide range of cellular cues including growth factors and activated oncogenes (Gartel and Tyner, 1999Gartel A.L. Tyner A.L. Transcriptional regulation of the p21(WAF1/CIP1) gene.Exp. Cell Res. 1999; 246: 280-289Crossref PubMed Scopus (566) Google Scholar, Olson et al., 1998Olson M.F. Paterson H.F. Marshall C.J. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1.Nature. 1998; 394: 295-299Crossref PubMed Scopus (400) Google Scholar). Although the sample size is small, the ability of Olig2 to oppose radiation-induced expression of p21 appears to correlate with EGFR status. In the two mouse lines and one human line that express wild-type EGFR at physiologic levels, Olig2 opposes the i" @default.
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• W2041822919 modified "2023-10-12" @default.
• W2041822919 title "The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant Glioma" @default.
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• W2041822919 doi "https://doi.org/10.1016/j.ccr.2011.01.035" @default.
• W2041822919 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3070398" @default.
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