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[Cancer Research 54, 794-799, February 1, 1994]
© 1994 American Association for Cancer Research

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Molecular Abnormalities of mdm2 and p53 Genes in Adult Soft Tissue Sarcomas1

Carlos Cordon-Cardo2, Esther Latres, Marija Drobnjak, Maria R. Oliva, Daphna Pollack, James M. Woodruff, Vincent Marechal, Jiandong Chen, Murray F. Brennan and Arnold J. Levine

Departments of Pathology [C. C-C., E. L., M. D., M. R. O., J. M. W.], Biostatistics and Epidemiology [D. P.], and Surgery [M. F. B.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Department of Molecular Biology-Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544-1014 [V. M., J. C., A. J. L.]

Genetic alterations in the p53 and mdm2 genes have been reported to occur in soft tissue sarcomas. This study was designed to determine the prevalence and potential clinical value of detected molecular abnormalities and altered patterns of expression of mdm2 and p53 genes in adult soft tissue sarcomas.

A cohort of 211 soft tissue sarcomas from adults that were both clinically and pathologically well characterized was analyzed. Monoclonal antibodies directed against mdm2 and p53 proteins were used to measure overexpression of these proteins in the nuclei of cells from sections of these tumors. Seventy-six of 207 tumors had abnormally high levels of mdm2 proteins and 56 of 211 tumors overexpressed p53 protein. Twenty-two cases had abnormally high levels of both mdm2 and p53 proteins based upon immunoreactivity with these antibodies. There was a striking statistically significant correlation between the overexpression of p53 and mdm2 proteins in the same tumor and poor survival (P < 0.05) of the patients.

A group of 73 soft tissue sarcomas was chosen for analysis using Southern blots, single strand conformation polymorphisms, and direct DNA sequencing to confirm mdm2 gene amplifications and p53 mutations and correlate these with the results of the immunoreactivities. The overexpression of p53 and mdm2 proteins in the nuclei of tumor cells did not always correlate well with gene amplification at the mdm2 locus or mutation at the p53 gene. The possible reasons for these discrepancies are discussed.

1 Supported by National Cancer Institute Grant CA-47179 (C. C-C., J. M. W., M. F. B.).

2 To whom requests for reprints should be addressed.

Received 8/10/93. Accepted 11/19/93.




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BloodHome page
M. Urashima, G. Teoh, D. Chauhan, A. Ogata, S. Shirahama, C. Kaihara, M. Matsuzaki, H. Matsushima, M. Akiyama, Y. Yuza, et al.
MDM2 Protein Overexpression Inhibits Apoptosis of TF-1 Granulocyte-Macrophage Colony-Stimulating Factor-Dependent Acute Myeloblastic Leukemia Cells
Blood, August 1, 1998; 92(3): 959 - 967.
[Abstract] [Full Text] [PDF]


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Mol. Cell. Biol.Home page
T. Juven-Gershon, O. Shifman, T. Unger, A. Elkeles, Y. Haupt, and M. Oren
The Mdm2 Oncoprotein Interacts with the Cell Fate Regulator Numb
Mol. Cell. Biol., July 1, 1998; 18(7): 3974 - 3982.
[Abstract] [Full Text]


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J Oncol Pharm PractHome page
E. Perz and J. G. Kuhn
Review : p53 in the pathogenesis, diagnosis, and treatment of cancer
Journal of Oncology Pharmacy Practice, June 1, 1998; 4(2): 75 - 102.
[Abstract] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
O. V. Volpert, J. Lawler, and N. P. Bouck
A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1
PNAS, May 26, 1998; 95(11): 6343 - 6348.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
L. Chen, S. Agrawal, W. Zhou, R. Zhang, and J. Chen
Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage
PNAS, January 6, 1998; 95(1): 195 - 200.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
T. Leveillard and B. Wasylyk
The MDM2 C-terminal Region Binds to TAFII250 and Is Required for MDM2 Regulation of the Cyclin A Promoter
J. Biol. Chem., December 5, 1997; 272(49): 30651 - 30661.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
L. Chen, V. Marechal, J. Moreau, A. J. Levine, and J. Chen
Proteolytic Cleavage of the mdm2 Oncoprotein during Apoptosis
J. Biol. Chem., September 5, 1997; 272(36): 22966 - 22973.
[Abstract] [Full Text] [PDF]


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BloodHome page
G. Teoh, M. Urashima, A. Ogata, D. Chauhan, J. A. DeCaprio, S. P. Treon, R. L. Schlossman, and K. C. Anderson
MDM2 Protein Overexpression Promotes Proliferation and Survival of Multiple Myeloma Cells
Blood, September 1, 1997; 90(5): 1982 - 1992.
[Abstract] [Full Text] [PDF]


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INT J SURG PATHOLHome page
T. Naka, Y. Iwamoto, N. Shinohara, H. Chuman, and M. Tsuneyoshi
p53 Accumulation in Malignant Bone Tumors: An Immunohistochemical Analysis of 217 Cases
International Journal of Surgical Pathology, July 1, 1997; 5(1-2): 1 - 9.
[Abstract] [PDF]


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Genes Dev.Home page
K Lundgren, R Montes de Oca Luna, Y B McNeill, E P Emerick, B Spencer, C R Barfield, G Lozano, M P Rosenberg, and C A Finlay
Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53.
Genes & Dev., March 15, 1997; 11(6): 714 - 725.
[Abstract] [PDF]


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ScienceHome page
P. H. Kussie, S. Gorina, V. Marechal, B. Elenbaas, J. Moreau, A. J. Levine, and N. P. Pavletich
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Science, November 8, 1996; 274(5289): 948 - 953.
[Abstract] [Full Text]


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INT J SURG PATHOLHome page
K. Devaney, S. L. Abbondanzo, K. M. Shekitka, R. B. Wolov, and D. E. Sweet
p53 Protein and Proliferating Cell Nuclear Antigen (PCNA) Expression in Small Round Cell Tumors of Bone and Adjacent Soft Tissue: A Study of 60 Cases
International Journal of Surgical Pathology, April 1, 1995; 2(4): 259 - 267.
[Abstract] [PDF]


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NEJMHome page
D. Esrig, D. Elmajian, S. Groshen, J. A. Freeman, J. P. Stein, S.-C. Chen, P. W. Nichols, D. G. Skinner, P. A. Jones, and R. J. Cote
Accumulation of Nuclear p53 and Tumor Progression in Bladder Cancer
N. Engl. J. Med., November 10, 1994; 331(19): 1259 - 1264.
[Abstract] [Full Text]


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Genes Dev.Home page
Y Barak, E Gottlieb, T Juven-Gershon, and M Oren
Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential.
Genes & Dev., August 1, 1994; 8(15): 1739 - 1749.
[Abstract] [PDF]


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Cold Spring Harb Symp Quant BiolHome page
S.W. Lowe, S. Bodis, N. Bardees, A. McClatchey, L. Remington, H.E. Ruley, D.E. Fisher, T. Jacks, J. Pelletier, and D.E. Housman
Apoptosis and the Prognostic Significance of p53 Mutation
Cold Spring Harb Symp Quant Biol, January 1, 1994; 59(0): 419 - 426.
[Abstract] [PDF]


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Cold Spring Harb Symp Quant BiolHome page
K.M. Dameron, O.V. Volpert, M.A. Tainsky, and N. Bouck
The p53 Tumor Suppressor Gene Inhibits Angiogenesis by Stimulating the Production of Thrombospondin
Cold Spring Harb Symp Quant Biol, January 1, 1994; 59(0): 483 - 489.
[Abstract] [PDF]


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J. Biol. Chem.Home page
Y. Peng, L. Chen, C. Li, W. Lu, S. Agrawal, and J. Chen
Stabilization of the MDM2 Oncoprotein by Mutant p53
J. Biol. Chem., February 23, 2001; 276(9): 6874 - 6878.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
T. Buschmann, Y. Lin, N. Aithmitti, S. Y. Fuchs, H. Lu, L. Resnick-Silverman, J. J. Manfredi, Z.'e. Ronai, and X. Wu
Stabilization and Activation of p53 by the Coactivator Protein TAFII31
J. Biol. Chem., April 20, 2001; 276(17): 13852 - 13857.
[Abstract] [Full Text] [PDF]




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