Jones S N, Roe A E, Donehower L A, Bradley A
Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature. 1995 Nov 9;378(6553):206-8. doi: 10.1038/378206a0.
The Mdm2 proto-oncogene was originally identified as one of several genes contained on a mouse double minute chromosome present in a transformed derivative of 3T3 cells. Overexpression of Mdm2 can immortalize primary cultures of rodent fibroblasts. Human MDM2 is amplified in 30-40% of sarcomas, and is overexpressed in leukaemic cells. The Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor protein and inhibits p53-mediated transregulation of gene expression. Because Mdm2 expression increases in response to p53, Mdm2-p53 binding may autoregulate Mdm2 expression and modulate the activity of p53 in the cell. We have created Mdm2-null and Mdm2/p53-null mice to determine whether Mdm2 possesses developmental functions in addition to the ability to complex with p53, and to investigate the biological role of Mdm2-p53 complex formation in development. Mice deficient for Mdm2 die early in development. In contrast, mice deficient for both Mdm2 and p53 develop normally and are viable. These results suggest that a critical role of Mdm2 in development is the regulation of p53 function.
Mdm2原癌基因最初被鉴定为存在于3T3细胞转化衍生物中的小鼠双微小染色体上所含的几个基因之一。Mdm2的过表达可使啮齿动物成纤维细胞的原代培养永生化。在30% - 40%的肉瘤中人类MDM2基因会扩增，并且在白血病细胞中过表达。Mdm2癌蛋白与p53肿瘤抑制蛋白形成复合物，并抑制p53介导的基因表达的反式调节。由于Mdm2的表达会因p53而增加，Mdm2 - p53结合可能会自动调节Mdm2的表达并调节细胞中p53的活性。我们已培育出Mdm2基因敲除和Mdm2/p53双基因敲除小鼠，以确定Mdm2除了与p53形成复合物的能力外是否还具有发育功能，并研究Mdm2 - p53复合物形成在发育中的生物学作用。缺乏Mdm2的小鼠在发育早期死亡。相比之下，同时缺乏Mdm2和p53的小鼠发育正常且可存活。这些结果表明，Mdm2在发育中的关键作用是调节p53的功能。
