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The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability

Overholtzer, Michael and Rao, Pulivarthi H. and Favis, Reyna and Lu, Xin-Yan and Elowitz, Michael B. and Barany, Francis and Ladanyi, Marc and Gorlick, Richard and Levine, Arnold J. (2003) The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proceedings of the National Academy of Sciences of the United States of America, 100 (20). pp. 11547-11552. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:OVEpnas03

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Abstract

The p53 gene is a critical tumor suppressor that is inactivated in a majority of cancers. The central role of p53 in response to stresses such as DNA damage, hypoxia, and oncogene activation underlies this high frequency of negative selection during tumorigenic transformation. Mutations in p53 disrupt checkpoint responses to DNA damage and result in the potential for destabilization of the genome. Consistent with this, p53 mutant cells have been shown to accumulate genomic alterations in cell culture, mouse models, and some human tumors. The relationship between p53 mutation and genomic instability in human osteosarcoma is addressed in this report. Similar to some other primary human tumors, the mutation of p53 correlates significantly with the presence of high levels of genomic instability in osteosarcomas. Surprisingly, osteosarcomas harboring an amplification of the HDM2 oncogene, which inhibits the tumor-suppressive properties of p53, do not display high levels of genomic instability. These results demonstrate that the inactivation of p53 in osteosarcomas directly by mutation versus indirectly by HDM2 amplification may have different cellular consequences with respect to the stability of the genome.


Item Type:Article
Additional Information:Copyright © 2003 by the National Academy of Sciences. Contributed by Arnold J. Levine, July 31, 2003. Published online before print September 12, 2003, 10.1073/pnas.1934852100. We thank members of the Levine Laboratory for helpful discussions, especially Drs. Kenan Onel, Archontoula Stoffel, Shengkan Jin, and Gareth Bond and Christine Walsh.
Subject Keywords:WILD-TYPE P53; POLYMERASE-CHAIN-REACTION; GENE AMPLIFICATION; TUMOR-SUPPRESSOR; HOMOLOGOUS RECOMBINATION; FRAUMENI-SYNDROME; MDM-2 ONCOGENE; BLADDER-CANCER; CELL CARCINOMA; MICE
Record Number:CaltechAUTHORS:OVEpnas03
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:OVEpnas03
Alternative URL:http://dx.doi.org/10.1073/pnas.1934852100
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1471
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Jan 2006
Last Modified:26 Dec 2012 08:44

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