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.
|Titolo:||Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development|
PELICCI, PIER GIUSEPPE (Penultimo)
|Parole Chiave:||Bromodeoxyuridine; Lateral Ventricles; Neural Tube Defects; Ubiquitin-Protein Ligases; Animals; Proliferating Cell Nuclear Antigen; Tumor Suppressor Protein p53; Proto-Oncogene Proteins c-mdm2; Fibroblasts; Phenotype; Nuclear Proteins; Abnormalities, Multiple; G1 Phase; Embryo, Mammalian; Genes, Lethal; Cyclins; Cell Division; Rhombencephalon; Spinal Cord; Cyclin-Dependent Kinase Inhibitor p21; Mice; Mice, Mutant Strains; Proto-Oncogene Proteins; Cells, Cultured; Neurons; Cell Death; Cyclin E|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||ago-2002|
|Digital Object Identifier (DOI):||10.1128/MCB.22.15.5527-5538.2002|
|Appare nelle tipologie:||01 - Articolo su periodico|