TY - JOUR
T1 - Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development.
AU - Migliorini, Domenico
AU - Lazzerini Denchi, Eros
AU - Danovi, Davide
AU - Jochemsen, Aart
AU - Capillo, Manuela
AU - Gobbi, Alberto
AU - Helin, Kristian
AU - Pelicci, Pier Giuseppe
AU - Marine, Jean-Christophe
N1 - Keywords: Abnormalities, Multiple; Animals; Bromodeoxyuridine; Cell Death; Cell Division; Cells, Cultured; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Embryo, Mammalian; Fibroblasts; G1 Phase; Genes, Lethal; Lateral Ventricles; Mice; Mice, Mutant Strains; Neural Tube Defects; Neurons; Nuclear Proteins; Phenotype; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Rhombencephalon; Spinal Cord; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
M3 - Journal article
C2 - 12101245
SN - 0270-7306
VL - 22
SP - 5527
EP - 5538
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 15
ER -