The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although TP53 mutations are oncogenic in GBM, other genes, such as PTEN must also be mutated to drive GBM progression [28].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [28]
Experimental — accuracy not yet measuredIn the citing paper
“Similarly, the chronic cellular damage that leads to liver cirrhosis results in shortened telomeres, anaphase bridges and a dramatically increased risk of liver cancer (131-134).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [133]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673
The 2007 WHO Classification of Tumours of the Central Nervous System
Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., Scheithauer, B. W., & Kleihues, P. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0243-4 · Cited by 15,675
In silico prediction of protein-protein interactions in human macrophages
Souiai, O., Guerfali, F. Z., Miled, S. B., Brun, C., & Benkahla, A. (2014) · BMC Research Notes · doi:10.1186/1756-0500-7-157 · Cited by 10,785
Significance analysis of microarrays applied to the ionizing radiation response
Tusher, V. G., Tibshirani, R., & Chu, G. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091062498 · Cited by 10,568
Self-citationErratum to: The 2007 WHO classification of tumours of the central nervous system
Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., Scheithauer, B. W., & Kleihues, P. (2007) · Zurich Open Repository and Archive (University of Zurich) · doi:10.5167/uzh-156115 · Cited by 4,435
Model-based analysis of oligonucleotide arrays: Expression index computation and outlier detection.
Li, C., & Wong, W. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.1.31 · Cited by 3,133
Self-citationClarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C., Jamieson, C., Jones, D. L., Visvader, J., Weissman, I. L., & Wahl, G. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-3126 · Cited by 3,124
Ben‐Porath, I., Thomson, M., Carey, V. J., Ge, R., Bell, G. W., Regev, A., & Weinberg, R. A. (2008) · Nature Genetics · doi:10.1038/ng.127 · Cited by 2,571
Malignant astrocytic glioma: genetics, biology, and paths to treatment
Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., et al. (2007) · Genes & Development · doi:10.1101/gad.1596707 · Cited by 2,316
Self-citationMultiple Ras-dependent phosphorylation pathways regulate Myc protein stabilityPreprint
Sears, R. C., Nuckolls, F., Haura, E. B., Taya, Y., Tamai, K., & Nevins, J. R. (2000) · Genes & Development · doi:10.1101/gad.836800 · Cited by 1,411
Cited by
Sorted by citations
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043
Self-citationCancer stem cells in glioblastoma
Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. L., & Rich, J. N. (2015) · Genes & Development · doi:10.1101/gad.261982.115 · Cited by 1,520
Unravelling mechanisms of p53-mediated tumour suppression
Bieging-Rolett, K. T., Mello, S. S., & Attardi, L. D. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3711 · Cited by 1,459
Exciting New Advances in Neuro-Oncology: The Avenue to a Cure for Malignant Glioma
Van Meir, E. G., Hadjipanayis, C. G., Norden, A. D., Shu, H. K., Wen, P. Y., & Olson, J. J. (2010) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.20069 · Cited by 1,372
HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer
David, C. J., Chen, M., Assanah, M., Canoll, P., & Manley, J. L. (2010) · Nature · doi:10.1038/nature08697 · Cited by 1,179
Metadata
- 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
- Venue
- Nature
- Published
- 2008-10
- Volume
- 455
- Issue
- 7216
- Pages
- 1129-1133
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
