Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma

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. (2008) Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harbor Symposia on Quantitative Biology, 73. pp. 427-37. ISSN 0091-7451

URL: http://www.ncbi.nlm.nih.gov/pubmed/19150964
DOI: 10.1101/sqb.2008.73.047

Abstract

Glioblastoma (GBM) is a highly lethal primary brain cancer with hallmark features of diffuse invasion, intense apoptosis resistance and florid necrosis, robust angiogenesis, and an immature profile with developmental plasticity. In the course of assessing the developmental consequences of central nervous system (CNS)-specific deletion of p53 and Pten, we observed a penetrant acute-onset malignant glioma phenotype with striking clinical, pathological, and molecular resemblance to primary GBM in humans. This primary, as opposed to secondary, GBM presentation in the mouse prompted genetic analysis of human primary GBM samples that revealed combined p53 and Pten mutations as the most common tumor suppressor defects in primary GBM. On the mechanistic level, the "multiforme" histopathological presentation and immature differentiation marker profile of the murine tumors motivated transcriptomic promoter-binding element and functional studies of neural stem cells (NSCs), which revealed that dual, but not singular, inactivation of p53 and Pten promotes cellular c-Myc activation. This increased c-Myc activity is associated not only with impaired differentiation, enhanced self-renewal capacity of NSCs, and tumor-initiating cells (TICs), but also with maintenance of TIC tumorigenic potential. Together, these murine studies have provided a highly faithful model of primary GBM, revealed a common tumor suppressor mutational pattern in human disease, and established c-Myc as a key component of p53 and Pten cooperative actions in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal, and tumorigenic potential.

Item Type: Paper
Uncontrolled Keywords: Animals Brain Neoplasms/*genetics/*pathology Cell Differentiation/genetics Cell Proliferation Cell Transformation, Neoplastic/genetics Disease Models, Animal *Genes, myc *Genes, p53 Glioblastoma/*genetics/*pathology Humans Mice Mice, Mutant Strains Mice, Transgenic Models, Neurological Mutation Neoplastic Stem Cells/*pathology PTEN Phosphohydrolase/*genetics Species Specificity
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > differentiation
diseases & disorders > cancer > cancer types > glioblastoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
CSHL Authors:
Communities: CSHL labs > Zheng lab
Depositing User: Matt Covey
Date: 2008
Date Deposited: 22 Aug 2014 19:25
Last Modified: 22 Aug 2014 19:25
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30705

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