title: Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Migliorini
authors.forename: Eros
authors.initials: E
authors.lastname: Lazzerini Denchi
authors.forename: Davide
authors.initials: D
authors.lastname: Danovi
authors.forename: Aart
authors.initials: A
authors.lastname: Jochemsen
authors.forename: Manuela
authors.initials: M
authors.lastname: Capillo
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
mesh_terms: 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
chemical_list: 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