The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces tumorigenesis
The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces tumorigenesis
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DOI：
10.1093/emboj/17.9.2513
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发表时间：
1998-05-01
期刊：
影响因子：
11.4
通讯作者：
Deb, SP
中科院分区：
文献类型：
--
作者：
Brown, DR;Thomas, CA;Deb, SP
人癌蛋白MDM 2（hMDM 2）在多种人类肿瘤中过表达。如果扩增，mdm 2基因可以增强小鼠细胞的致瘤潜力。在此，我们提供的证据表明，全长的人或小鼠MDM 2从各自的cDNA表达可以抑制NIH 3 T3和正常人二倍体细胞的G（0）/G（1）-S相转变。该蛋白含有一个以上的细胞周期抑制结构域，不与p53相互作用结构域重叠。缺失细胞周期抑制结构域的hMDM 2缺失突变体可在NIH 3 T3细胞中稳定表达，增强其致瘤潜力。hMDM 2的致瘤结构域与p53相互作用结构域重叠。一些肿瘤衍生的细胞，如Saos-2、H1299或U-2 OS，对hMDM 2的生长抑制作用相对不敏感。这些观察结果表明，hMDM 2过表达在致癌刺激的反应将诱导正常细胞的生长停滞。hMDM 2诱导的G（0）/G（1）阻滞的消除或失活可能有助于肿瘤发生的步骤之一。
The human oncoprotein MDM2 (hMDM2) overexpresses in various human tumors. If amplified, the mdm2 gene can enhance the tumorigenic potential of murine cells. Here, we present evidence to show that the full-length human or mouse MDM2 expressed from their respective cDNA can inhibit the G(0)/G(1)-S phase transition of NIH 3T3 and normal human diploid cells. The protein harbors more than one cell-cycle-inhibitory domain that does not overlap with the p53-interaction domain. Deletion mutants of hMDM2 that lack the cell-cycle-inhibitory domains can be stably expressed in NIH 3T3 cells, enhancing their tumorigenic potential, The tumorigenic domain of hMDM2 overlaps with the p53-interaction domain. Some tumor-derived cells, such as Saos-2, H1299 or U-2OS, are relatively insensitive to the growth-inhibitory effects of hMDM2. These observations suggest that hMDM2 overexpression in response to oncogenic stimuli would induce growth arrest in normal cells. Elimination or inactivation of the hMDM2-induced G(0)/G(1) arrest may contribute to one of the steps of tumorigenesis.