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-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.
Jones
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Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA. steve.jones@banyan.ummed.edu
Hancock
A R
AR
Vogel
H
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Donehower
L A
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Bradley
A
A
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002678:Chimera; D003433:Crosses, Genetic; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2