Abstract
The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a transgene to create mice that overexpress Mdm2. The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Transformation, Neoplastic*
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Chimera
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Crosses, Genetic
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Female
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Gene Deletion
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Genes, p53*
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Heterozygote
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Mice, Transgenic
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Neoplasm Proteins / metabolism
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Neoplasms, Experimental / genetics*
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Neoplasms, Experimental / pathology
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Nuclear Proteins*
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Promoter Regions, Genetic
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Transcription, Genetic
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Tumor Suppressor Protein p53 / metabolism
Substances
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MAS1 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2