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首页> 外文期刊>Molecular and Cellular Biology >Mdm4 (Mdmx) Regulates p53-Induced Growth Arrest and Neuronal Cell Death during Early Embryonic Mouse Development
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Mdm4 (Mdmx) Regulates p53-Induced Growth Arrest and Neuronal Cell Death during Early Embryonic Mouse Development

机译：Mdm4（Mdmx）调节早期胚胎小鼠发育过程中p53诱导的生长停滞和神经元细胞死亡。

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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 p21CIP1/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 G1 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.
机译：我们在这里报告在 Mdm4 基因座中具有特定基因捕获事件的突变小鼠系的特征。 Mdm4表达的缺失会导致胚胎致死率（死后10.5天），可通过将 Mdm4 突变转移到 Trp53 -null背景中来挽救。突变的胚胎的特征是整体生长不足，贫血，神经管闭合不当和侧脑室扩张。原位分析表明， p21 CIP1 / Waf1 的水平升高，而 Cyclin E 的水平降低，并增殖了细胞核抗原。与缺乏5-溴-2'-脱氧尿苷掺入一致，这些数据表明在细胞周期的G 1 期中有一组突变的胚胎细胞。因此，缺乏Mdm4的小鼠胚胎成纤维细胞在培养物中表现出大大降低的增殖能力。此外，在 Mdm4 突变体胚胎发育中的中枢神经系统中特异性检测到广泛的p53依赖性细胞死亡。这些发现清楚地表明Mdm4作为p53的负调节剂具有关键作用，并暗示Mdm4可能有助于保留野生型 Trp53 的肿瘤形成。最后，我们提供的证据表明Mdm4在细胞增殖或细胞周期控制中没有作用，这与其调节p53功能的能力不同。

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