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PMID: 18948956 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature ·Vol. 455 ·No. 7216 ·2008-10-23 ·Pages 1129-33

Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, Chu GC, Ding Z, Stommel JM, Dunn KL, Wiedemeyer R, You MJ, Brennan C, Wang YA, Ligon KL, Wong WH, Chin L, DePinho RA

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.

MeSH Terms
Animals Brain Neoplasms/genetics,pathology Cell Differentiation Cell Proliferation Gene Expression Regulation Glioblastoma/genetics,pathology Glioma/genetics,pathology Humans Immunohistochemistry Mice Neoplastic Stem Cells/metabolism,pathology Neurons/metabolism,pathology PTEN Phosphohydrolase/genetics,metabolism Proto-Oncogene Proteins c-myc/genetics,metabolism Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
Myc protein, mouse Proto-Oncogene Proteins c-myc Tumor Suppressor Protein p53 PTEN Phosphohydrolase PTEN protein, human Pten protein, mouse
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Zheng Hongwu
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
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
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature07443
Published
2008-10-23
Pages
1129-33
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4051433
Subset
IM
Grants
NCI NIH HHS · U01 CA084313 · United States
NCI NIH HHS · R01 CA099041-05 · United States
NCI NIH HHS · R01 CA099041 · United States
NCI NIH HHS · P01 CA095616 · United States
NCI NIH HHS · P01 CA095616-01A19003 · United States
NCI NIH HHS · U01 CA84313 · United States
NCI NIH HHS · R01CA99041 · United States
NCI NIH HHS · 5P01CA95616 · United States
External Links
PubMed source DOI: 10.1038/nature07443 PMC Full Text View journal details
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