Brown D R, Thomas C A, Deb S P
Department of Microbiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284, USA.
EMBO J. 1998 May 1;17(9):2513-25. doi: 10.1093/emboj/17.9.2513.
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 G0/G1-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 G0/G1 arrest may contribute to one of the steps of tumorigenesis.
人类癌蛋白MDM2（hMDM2）在多种人类肿瘤中过表达。如果mdm2基因扩增，可增强鼠细胞的致瘤潜能。在此，我们提供证据表明，从各自的cDNA表达的全长人或小鼠MDM2可抑制NIH 3T3细胞和正常人二倍体细胞的G0/G1-S期转变。该蛋白含有多个细胞周期抑制结构域，这些结构域与p53相互作用结构域不重叠。缺乏细胞周期抑制结构域的hMDM2缺失突变体可在NIH 3T3细胞中稳定表达，增强其致瘤潜能。hMDM2的致瘤结构域与p53相互作用结构域重叠。一些肿瘤来源的细胞，如Saos-2、H1299或U-2OS，对hMDM2的生长抑制作用相对不敏感。这些观察结果表明，致癌刺激导致的hMDM2过表达会使正常细胞生长停滞。hMDM2诱导的G0/G1期停滞的消除或失活可能是肿瘤发生的步骤之一。
