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


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.
Title: Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma
Conference Title: 73rd Cold Spring Harbor Symposium on Quantitative Biology
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. ©2008 Cold Spring Harbor Laboratory Press.
Keywords: gene mutation; genetics; mutation; nonhuman; conference paper; brain tumor; brain neoplasms; protein function; cell proliferation; mouse; animal; mouse mutant; animals; mice; biological model; mice, mutant strains; cell renewal; neural stem cell; cell differentiation; pathology; protein p53; transgenic mouse; mice, transgenic; cell transformation, neoplastic; disease model; cancer inhibition; tumor suppressor gene; species specificity; neoplastic stem cells; cell transformation; glioblastoma; myc protein; genes, myc; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; cancer stem cell; pten phosphohydrolase; murinae; species difference; pten protein, mouse; disease models, animal; pten protein, human; oncogene myc; genes, p53; models, neurological
Journal Title Cold Spring Harbor Symposia on Quantitative Biology
Volume: 73
Conference Dates: 2008 May 28-Jun 3
Conference Location: Cold Spring Harbor, NY
ISBN: 0091-7451
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2008-01-01
Start Page: 427
End Page: 437
Language: English
DOI: 10.1101/sqb.2008.73.047
PUBMED: 19150964
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 13" - "Export Date: 17 November 2011" - "CODEN: CSHSA" - "Source: Scopus"
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  1. Cameron Brennan
    226 Brennan