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dc.contributor.authorZheng, Hongwuen_US
dc.contributor.authorYing, Haoqiangen_US
dc.contributor.authorYan, Haiyanen_US
dc.contributor.authorKimmelman, Alec C.en_US
dc.contributor.authorHiller, David J.en_US
dc.contributor.authorChen, An-Jouen_US
dc.contributor.authorPerry, Samuel R.en_US
dc.contributor.authorTonon, Giovannien_US
dc.contributor.authorChu, Gerald C.en_US
dc.contributor.authorDing, Zhihuen_US
dc.contributor.authorStommel, Jayne M.en_US
dc.contributor.authorDunn, Katherine L.en_US
dc.contributor.authorWiedemeyer, Ruprechten_US
dc.contributor.authorYou, Mingjian J.en_US
dc.contributor.authorBrennan, Cameronen_US
dc.contributor.authorWang, Y. Alanen_US
dc.contributor.authorLigon, Keith L.en_US
dc.contributor.authorWong, Wing H.en_US
dc.contributor.authorChin, Lyndaen_US
dc.contributor.authorDePinho, Ronald A.en_US
dc.date.accessioned2014-07-07T17:03:14Z
dc.date.issued2014en_US
dc.identifier.citationZheng, H., H. Ying, H. Yan, A. C. Kimmelman, D. J. Hiller, A. Chen, S. R. Perry, et al. 2014. “P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation.” Nature 455 (7216): 1129-1133. doi:10.1038/nature07443. http://dx.doi.org/10.1038/nature07443.en
dc.identifier.issn0028-0836en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12406668
dc.description.abstractGlioblastoma (GBM) is a highly lethal brain tumor presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as high-grade disease that typically harbors EGFR, Pten and Ink4a/Arf mutations, and the secondary GBM subtype evolves from the slow progression of low-grade disease that classically possesses PDGF and p53 events1–3. Here, we show that concomitant CNS-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with striking clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted p53 and Pten mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of p53 as well the expected Pten mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives elevated c-Myc levels and its associated signature. Functional studies validated increased c-Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of p53-Pten null NSCs as well as tumor neurospheres (TNSs) derived from this model. c-Myc also serves to maintain robust tumorigenic potential of p53-Pten null TNSs. These murine modeling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumor suppressor mutation profile in human primary GBM and establish c-Myc as a key target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/nature07443en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051433/pdf/en
dash.licenseLAAen_US
dc.titleP53 and Pten control neural and glioma stem/progenitor cell renewal and differentiationen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalNatureen
dash.depositing.authorKimmelman, Alec C.en_US
dc.date.available2014-07-07T17:03:14Z
dc.identifier.doi10.1038/nature07443*
dash.authorsorderedfalse
dash.contributor.affiliatedDunn, Katherine L.
dash.contributor.affiliatedKimmelman, Alec C.
dash.contributor.affiliatedLigon, Keith


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