Jones S N, Hancock A R, Vogel H, Donehower L A, Bradley A
Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15608-12. doi: 10.1073/pnas.95.26.15608.
The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a transgene to create mice that overexpress Mdm2. The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.
Mdm2原癌基因在人类肉瘤中扩增至高拷贝数，并在多种其他人类癌症中过表达。由于Mdm2蛋白与p53肿瘤抑制蛋白形成复合物并下调p53功能，因此推测Mdm2的致癌潜能是p53依赖性的。为了在小鼠中模拟这些情况，我们使用了整个Mdm2基因，在其天然启动子区域的转录控制下，作为转基因来创建过表达Mdm2的小鼠。转基因小鼠易发生自发性肿瘤形成，在有或没有功能性p53的情况下，Mdm2转基因小鼠中观察到的肉瘤发生率表明，除了Mdm2介导的p53失活外，Mdm2在肿瘤发生中还存在p53非依赖性作用。
