Overexpression of Mdm2 in Mice Reveals a p53-Independent Role for Mdm2 in Tumorigenesis

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-12, Vol.95 (26), p.15608-15612
Main Authors: Jones, Stephen N., Hancock, Amy R., Vogel, Hannes, Donehower, Lawrence A., Bradley, Allan
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cancer
Cell growth
Cell lines
Cell Transformation, Neoplastic
Chimera
Cosmids
Crosses, Genetic
Female
Fibroblasts
Gene Deletion
Genes
Genes, p53
Heterozygote
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Transgenic
Neoplasm Proteins - metabolism
Neoplasms, Experimental - genetics
Neoplasms, Experimental - pathology
Nuclear Proteins
Promoter Regions, Genetic
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-mdm2
Rodents
Sarcoma
Transcription, Genetic
Transgenes
Transgenic animals
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.26.15608