Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Nucleic Acids Res. 1995 Jul 25;23(14):2584-92. doi: 10.1093/nar/23.14.2584.
The mdm2 gene is a target for transcriptional activation by the p53 tumor suppressor gene product. Previous work has revealed that the mouse mdm2 gene contains two promoters: one is located upstream to the gene and is active in the absence of p53, the other resides within the first intron and requires p53 for transcriptional activity. To determine whether this unique promoter activation pattern is biologically important, we investigated the structure and function of the corresponding region of the human mdm2 (hmdm2) gene. We report here that the hmdm2 gene also contains an intronic, p53-dependent promoter. The structural features of this promoter are highly conserved between mouse and man, as opposed to the lack of conservation of the first exon. This promoter is triggered in vivo in the presence of activated wild type p53, leading to the production of novel mRNA species. The intronic hmdm2 promoter contains two tandem p53 binding elements. Deletion analysis suggests that optimal promoter activity requires the simultaneous binding of p53 to both elements; this may serve to prevent premature triggering of the promoter by p53.
mdm2基因是p53肿瘤抑制基因产物进行转录激活的靶点。先前的研究表明，小鼠mdm2基因含有两个启动子：一个位于基因上游，在没有p53的情况下具有活性；另一个位于第一个内含子内，转录活性需要p53。为了确定这种独特的启动子激活模式在生物学上是否重要，我们研究了人类mdm2（hmdm2）基因相应区域的结构和功能。我们在此报告，hmdm2基因也含有一个内含子依赖性的、依赖p53的启动子。与第一个外显子缺乏保守性相反，该启动子的结构特征在小鼠和人类之间高度保守。在激活的野生型p53存在的情况下，该启动子在体内被触发，导致产生新的mRNA种类。内含子hmdm2启动子包含两个串联的p53结合元件。缺失分析表明，最佳启动子活性需要p53同时与两个元件结合；这可能有助于防止p53过早触发启动子。
