Nucleic Acids Research, Vol 26, Issue 15 3453-3459, Copyright © 1998 by Oxford University Press
J Momand, D Jung, S Wilczynski and J Niland
The p53 tumor suppressor gene is inactivated in human tumors by several
distinct mechanisms. The best characterized inactivation mechanisms are:
(i) gene mutation; (ii) p53 protein association with viral proteins; (iii)
p53 protein association with the MDM2 cellular oncoprotein. The MDM2 gene
has been shown to be abnormally up-regulated in human tumors and tumor cell
lines by gene amplification, increased transcript levels and enhanced
translation. This communication presents a brief review of the spectrum of
MDM2 abnormalities in human tumors and compares the tissue distribution of
MDM2 amplification and p53 mutation frequencies. In this study, 3889
samples from tumors or xenografts from 28 tumor types were examined for
MDM2 amplification from previously published sources. The overall frequency
of MDM2 amplification in these human tumors was 7%. Gene amplification was
observed in 19 tumor types, with the highest frequency observed in soft
tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%).
Tumors which showed a higher incidence of MDM2 amplification than p53
mutation were soft tissue tumors, testicular germ cell cancers and
neuro-blastomas. Data from studies where both MDM2 amplification and p53
mutations were analyzed within the same samples showed that mutations in
these two genes do not generally occur within the same tumor. In these
studies, 29 out of a total of 33 MDM2 amplification- positive tumors had
wild-type p53. We hypothesize that heretofore uncharacterized carcinogens
favor MDM2 amplification over p53 mutations in certain tumor types. A
database listing the MDM2 gene amplifications is available on the World
Wide Web at http://www. infosci.coh.org/mdm2 . Charts of MDM2 amplification
frequencies and comparisons with p53 genetic alterations are also available
at this Web site.
REVIEWS
The MDM2 gene amplification database
Department of Cell and Tumor Biology, Beckman Research Institute, National Medical Center, 1450 East Duarte Road, Duarte, CA 91010-3000, USA. jmomand@coh.org
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|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
G. L. Bond, W. Hu, and A. Levine A Single Nucleotide Polymorphism in the MDM2 Gene: From a Molecular and Cellular Explanation to Clinical Effect Cancer Res., July 1, 2005; 65(13): 5481 - 5484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
 |
|
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|
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|
|
|
|
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|
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|
|
Z. Zhang, H. Wang, G. Prasad, M. Li, D. Yu, J. A. Bonner, S. Agrawal, and R. Zhang Radiosensitization by Antisense Anti-MDM2 Mixed-Backbone Oligonucleotide in in Vitro and in Vivo Human Cancer Models Clin. Cancer Res., February 15, 2004; 10(4): 1263 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. T. Vassilev, B. T. Vu, B. Graves, D. Carvajal, F. Podlaski, Z. Filipovic, N. Kong, U. Kammlott, C. Lukacs, C. Klein, et al. In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 Science, February 6, 2004; 303(5659): 844 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
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K. Onel and C. Cordon-Cardo MDM2 and Prognosis Mol. Cancer Res., January 1, 2004; 2(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Perry Mdm2 in the Response to Radiation Mol. Cancer Res., January 1, 2004; 2(1): 9 - 19. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 C.-M. Kang, H.-N. Cho, J.-M. Ahn, S.-S. Lee, D.-I. Jeoung, C.-K. Cho, S. Bae, S.-J. Lee, and Y.-S. Lee Alteration of gene expression during radiation-induced resistance and tumorigenesis in NIH3T3 cells revealed by cDNA microarrays: involvement of MDM2 and CDC25B Carcinogenesis, January 1, 2004; 25(1): 123 - 132. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
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|
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|
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|
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S. Bartl, J. Ban, H. Weninger, G. Jug, and H. Kovar A small nuclear RNA, hdm365, is the major processing product of the human mdm2 gene Nucleic Acids Res., February 15, 2003; 31(4): 1136 - 1147. [Abstract] [Full Text] [PDF]
|
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|
|
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M. Sanchez-Beato, A. Sanchez-Aguilera, and M. A. Piris Cell cycle deregulation in B-cell lymphomas Blood, February 15, 2003; 101(4): 1220 - 1235. [Abstract] [Full Text] [PDF]
|
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|
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|
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|
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D. Polsky, K. Melzer, C. Hazan, K. S. Panageas, K. Busam, M. Drobnjak, H. Kamino, J. G. Spira, A. W. Kopf, A. Houghton, et al. HDM2 Protein Overexpression and Prognosis in Primary Malignant Melanoma J Natl Cancer Inst, December 4, 2002; 94(23): 1803 - 1806. [Abstract] [Full Text] [PDF]
|
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|
|
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|
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|
 |
|
 J. A. Knauf, L. S. Ward, Y. E. Nikiforov, M. Nikiforova, E. Puxeddu, M. Medvedovic, T. Liron, D. Mochly-Rosen, and J. A. Fagin Isozyme-Specific Abnormalities of PKC in Thyroid Cancer: Evidence for Post-Transcriptional Changes in PKC Epsilon J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2150 - 2159. [Abstract] |