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首页> 外文期刊>Molecular and Cellular Biology >Widespread Overexpression of Epitope-Tagged Mdm4 Does Not Accelerate Tumor Formation In Vivo
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Widespread Overexpression of Epitope-Tagged Mdm4 Does Not Accelerate Tumor Formation In Vivo

机译：抗原表位标记的Mdm4的广泛过量表达不会加速体内肿瘤形成。

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Mdm2 and Mdm4 are critical negative regulators of p53. A large body of evidence indicates that elevated expression of either Mdm2 or Mdm4 may favor tumor formation by inhibiting p53 tumor suppression function. To explore this possibility in vivo, we generated conditional Mdm2 and Mdm4 transgenic mice. We show that although both transgenes are designed to be expressed ubiquitously and at comparable levels, only the Mdm4 transgenic protein is produced at high levels in vivo. In contrast, exogenous Mdm2 is constitutively degraded in a proteasome-dependent manner, indicating that cells are equipped with efficient mechanisms that prevent Mdm2 accumulation in vivo. Mice that are homozygous for the Mdm4 transgene die during embryogenesis owing to severe vascular maturation defects. Importantly, this lethality is not rescued on a p53-null background, indicating that high levels of Mdm4 impact on a pathway(s) other than p53 that controls vascular and embryonic development. Mice expressing a single copy of the Mdm4 transgene are viable and, surprisingly, are not prone to spontaneous, radiation-induced or Eμ-myc-induced tumor formation. The findings have clear implications for cancer etiology as well as for cancer therapy.
机译：Mdm2和Mdm4是p53的关键负调控因子。大量证据表明，Mdm2或Mdm4的表达升高可能通过抑制p53肿瘤抑制功能而促进肿瘤形成。为了探索这种体内可能性，我们产生了条件性Mdm2和Mdm4转基因小鼠。我们表明，尽管两个转基因都被设计为在普遍水平和相当水平表达，但只有Mdm4转基因蛋白在体内高水平产生。相比之下，外源性Mdm2以蛋白酶体依赖性方式组成性降解，表明细胞具有阻止Mdm2体内积累的有效机制。 Mdm4 转基因纯合子的小鼠由于严重的血管成熟缺陷而在胚胎发生过程中死亡。重要的是，这种致死性在 p53 -null背景下无法挽救，这表明高水平的Mdm4会影响除控制血管和胚胎发育的p53以外的其他途径。表达 Mdm4 转基因单拷贝的小鼠是可行的，而且令人惊讶的是，它们不容易自发，辐射诱导或由Eμ- myc 诱导肿瘤形成。该发现对癌症病因学和癌症治疗具有明显的意义。

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