Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo.
Mdm2 and Mdm4 are critical negative regulators of p53. A large body of evidence indicates that elevated expression of either Mdm2 or Mdm4 may favor tumor formation by inhibiting p53 tumor suppression function. To explore this possibility in vivo, we generated conditional Mdm2 and Mdm4 transgenic mice. We show that although both transgenes are designed to be expressed ubiquitously and at comparable levels, only the Mdm4 transgenic protein is produced at high levels in vivo. In contrast, exogenous Mdm2 is constitutively degraded in a proteasome-dependent manner, indicating that cells are equipped with efficient mechanisms that prevent Mdm2 accumulation in vivo. Mice that are homozygous for the Mdm4 transgene die during embryogenesis owing to severe vascular maturation defects. Importantly, this lethality is not rescued on a p53-null background, indicating that high levels of Mdm4 impact on a pathway(s) other than p53 that controls vascular and embryonic development. Mice expressing a single copy of the Mdm4 transgene are viable and, surprisingly, are not prone to spontaneous, radiation-induced or Eμ-myc-induced tumor formation. The findings have clear implications for cancer etiology as well as for cancer therapy.
De Clercq
Sarah
S
Laboratory for Molecular Cancer Biology, Department of Biomedical Molecular Biology, VIB-UGent, Technologiepark, B-9052 Ghent, Belgium.
Gembarska
Agnieszka
A
Denecker
Geertrui
G
Maetens
Marion
M
Naessens
Michael
M
Haigh
Katharina
K
Haigh
Jody J
JJ
Marine
Jean-Christophe
JC
D000818:Animals; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D000939:Epitopes; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D000939:Epitopes; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases