Montes de Oca Luna R, Wagner D S, Lozano G
Department of Molecular Genetics, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Nature. 1995 Nov 9;378(6553):203-6. doi: 10.1038/378203a0.
The gene p53 encodes a transcriptional activator of genes involved in growth arrest, DNA repair and apoptosis. Loss of p53 function contributes to tumour development in vivo. The transcriptional activation function of p53 is inactivated by interaction with the mdm2 gene product. Amplification of mdm2 has been observed in 36% of human sarcomas, indicating that it may represent an alternative mechanism of preventing p53 function in tumour development. To study mdm2 function in vivo, we generated an mdm2 null allele by homologous recombination. Mdm2 null mice are not viable, and further analysis revealed embryonic lethality around implantation. To examine the importance of the interaction of MDM2 with p53 in vivo, we crossed mice heterozygous for mdm2 and p53 and obtained progeny homozygous for both p53 and mdm2 null alleles. Rescue of the mdm2-/- lethality in a p53 null background suggests that a critical in vivo function of MDM2 is the negative regulation of p53 activity.
基因p53编码一种参与生长停滞、DNA修复和细胞凋亡的基因转录激活因子。p53功能的丧失在体内促进肿瘤发展。p53的转录激活功能通过与mdm2基因产物相互作用而失活。在36%的人类肉瘤中观察到mdm2的扩增，这表明它可能是肿瘤发展过程中阻止p53功能的一种替代机制。为了在体内研究mdm2的功能，我们通过同源重组产生了一个mdm2无效等位基因。mdm2基因敲除小鼠无法存活，进一步分析显示在着床前后出现胚胎致死。为了在体内检测MDM2与p53相互作用的重要性，我们将mdm2和p53杂合的小鼠进行杂交，获得了p53和mdm2无效等位基因均为纯合的后代。在p53基因敲除背景下挽救mdm2 - / - 的致死性表明，MDM2在体内的一个关键功能是对p53活性的负调控。
