Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development.
We report here the characterization of a mutant mouse line with a specific gene trap event in the Mdm4 locus. Absence of Mdm4 expression results in embryonic lethality (10.5 days postcoitum [dpc]), which was rescued by transferring the Mdm4 mutation into a Trp53-null background. Mutant embryos were characterized by overall growth deficiency, anemia, improper neural tube closure, and dilation of lateral ventricles. In situ analysis demonstrated increased levels of p21(CIP1/Waf1) and lower levels of Cyclin E and proliferating cell nuclear antigen expression. Consistent with lack of 5-bromo-2'-deoxyuridine incorporation, these data suggest a block of mutant embryo cells in the G(1) phase of the cell cycle. Accordingly, Mdm4-deficient mouse embryonic fibroblasts manifested a greatly reduced proliferative capacity in culture. Moreover, extensive p53-dependent cell death was specifically detected in the developing central nervous system of the Mdm4 mutant embryos. These findings unambiguously assign a critical role for Mdm4 as a negative regulator of p53 and suggest that Mdm4 could contribute to neoplasias retaining wild-type Trp53. Finally, we provide evidence indicating that Mdm4 plays no role on cell proliferation or cell cycle control that is distinct from its ability to modulate p53 function.
Migliorini
Domenico
D
Department of Experimental Oncology, European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy.
Lazzerini Denchi
Eros
E
Danovi
Davide
D
Jochemsen
Aart
A
Capillo
Manuela
M
Gobbi
Alberto
A
Helin
Kristian
K
Pelicci
Pier Giuseppe
PG
Marine
Jean-Christophe
JC
D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D001973:Bromodeoxyuridine; D016923:Cell Death / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities*; D005347:Fibroblasts / Q000166:cytology; D016193:G1 Phase; D005804:Genes, Lethal; D020547:Lateral Ventricles / Q000002:abnormalities; D051379:Mice; D008817:Mice, Mutant Strains; D009436:Neural Tube Defects / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012249:Rhombencephalon / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
C493957:Cdkn1a protein, mouse; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C461497:Mdm4 protein, mouse; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D001973:Bromodeoxyuridine