Cited by 767Glioma Diagnosis and TreatmentCancer-related Molecular PathwaysNeurogenesis and neuroplasticity mechanisms

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p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation

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Zheng, Hongwu, Ying, Haoqiang, Yan, Haiyan, Kimmelman, Alec C., Hiller, David J., Chen, An-Jou, Perry, Samuel R., Tonon, Giovanni, Chu, Gerald C., Ding, Zhihu, Stommel, Jayne M., Dunn, Katherine L., Wiedemeyer, Ruprecht, You, Mingjian J., Brennan, Cameron, Wang, Y. Alan, Ligon, Keith L., Wong, Wing H., Chin, Lynda, DePinho, Ronald A.·2008·Nature

DOI 10.1038/nature07443PMC PMC4051433

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Abstract

Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as 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 increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.

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Authors: Zheng, H., Ying, H., Yan, H., Kimmelman, A. C., Hiller, D. J., Chen, A.-J., Perry, S. R., Tonon, G., Chu, G. C., Ding, Z., Stommel, J. M., Dunn, K. L., Wiedemeyer, R., You, M. J., Brennan, C., Wang, Y. A., Ligon, K. L., Wong, W. H., Chin, L., & DePinho, R. A.
Affiliations: Harvard University (US)
Stanford University (US)
Memorial Sloan Kettering Cancer Center (US)
Brigham and Women's Hospital (US)
Corresponding author: DePinho, Ronald A.
ORCID: Zheng, Hongwu
Ying, Haoqiang
Yan, Haiyan
Kimmelman, Alec C.
Hiller, David J.
Tonon, Giovanni
Stommel, Jayne M.
Dunn, Katherine L.
You, Mingjian J.
Brennan, Cameron
Wang, Y. Alan
Ligon, Keith L.
Wong, Wing H.
DePinho, Ronald A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2008-10
Volume: 455
Issue: 7216
Pages: 1129-1133
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07443
PMC: PMC4051433
OpenAlex: W2109610561
Cited by: 767
References: 37
Citations by year: 2026: 12 · 2025: 20 · 2024: 32 · 2023: 41 · 2022: 33 · 2021: 32 · 2020: 41 · 2019: 33 · 2018: 35 · 2017: 38 · 2016: 39 · 2015: 46 · 2014: 47 · 2013: 61 · 2012: 76
FWCI: 27.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
Funders: National Cancer Institute (R01 CA99041, R01CA099041, U01CA84313, 5P01CA95616, U01CA084313, P01CA095616)
Topics: Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: p53, PTEN, glioblastoma, neural stem cells, glioma stem cells, c-Myc, tumor suppressor inactivation, cell differentiation, cell renewal, TP53 mutation, PTEN mutation, gene expression profiling, promoter analysis, EGFR, neurofibromatosis type 1, RB1, ATM, APC
MeSH terms: Animals, Brain Neoplasms, Cell Differentiation, Gene Expression Regulation, Glioblastoma, Glioma, Humans, Immunohistochemistry, Neurons, Neoplastic Stem Cells, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Cell Proliferation, PTEN Phosphohydrolase, Mice

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p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation

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