Loss of one but not two mdm2 null alleles alters the tumour spectrum in p53 null mice.
The transcriptional activity of the p53 tumour suppressor is inhibited by binding to MDM2. The in vivo significance of this interaction was established in mdm2 null mice. Embryonic lethality due to loss of mdm2 is completely rescued by deletion of p53, indicating that the lethality is due to inability to down-modulate p53 function. The production of mice null for both p53 and mdm2 led to an assessment of the role of MDM2 in tumour development. Tumour latency and spectrum in p53 null mice were monitored in the presence or absence of mdm2. Two unusual findings resulted: tumour latency in p53 null/mdm2 heterozygous mice was longer than in p53/mdm2 double-null mice; and the incidence of sarcomas was higher in p53 null/mdm2 heterozygous mice than in p53 null or p53/mdm2 double-null mice. These data raise the possibility that heterozygosity at the mdm2 locus in the absence of p53 affects the development of tumours of mesenchymal origin.
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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TJ
McDonnell
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Montes de Oca Luna
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Cho
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Amelse
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Chavez-Reyes
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Lozano
D000818:Animals; D005260:Female; D016158:Genes, p53; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D012513:Sarcoma, Experimental / Q000235:genetics / Q000473:pathology; D018243:Teratocarcinoma / Q000235:genetics; D013724:Teratoma / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2