Dudgeon Crissy, Kek Calvina, Demidov Oleg N, Saito Shin-ichi, Fernandes Kenneth, Diot Alexandra, Bourdon Jean-Christophe, Lane David P, Appella Ettore, Fornace Albert J, Bulavin Dmitry V
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Cancer Res. 2006 Mar 15;66(6):2928-36. doi: 10.1158/0008-5472.CAN-05-2063.
Activation of apoptosis is believed to be critical for the role of p53 as a tumor suppressor. Here, we report a new mouse strain carrying a human p53 transgene in the mouse p53-null background. Expression of human p53 in these mice was comparable with wild-type murine p53; however, transactivation, induction of apoptosis, and G(1)-S checkpoint, but not transrepression or regulation of a centrosomal checkpoint, were deregulated. Although multiple functions of p53 were abrogated, mice carrying the human p53 transgene did not show early onset of tumors as typically seen for p53-null mice. In contrast, human p53 in the p53-null background did not prevent accelerated tumor development after genotoxic or oncogenic stress. Such behavior of human p53 expressed at physiologic levels in transgenic cells could be explained by unexpectedly high binding with Mdm2. By using Nutlin-3a, an inhibitor of the interaction between Mdm2 and p53, we were able to partially reconstitute p53 transactivation and apoptosis in transgenic cells. Our findings indicate that the interaction between p53 and Mdm2 controls p53 transcriptional activity in homeostatic tissues and regulates DNA damage- and oncogene-induced, but not spontaneous, tumorigenesis.
凋亡的激活被认为对于p53作为肿瘤抑制因子的作用至关重要。在此，我们报道了一种新的小鼠品系，其在小鼠p53基因缺失的背景下携带人p53转基因。这些小鼠中人p53的表达与野生型小鼠p53相当；然而，反式激活、凋亡诱导和G(1)-S期检查点功能失调，但反式抑制或中心体检查点的调控功能未失调。尽管p53的多种功能被废除，但携带人p53转基因的小鼠并未像p53基因缺失小鼠那样出现肿瘤的早期发生。相反，在p53基因缺失背景下的人p53并不能防止基因毒性或致癌应激后肿瘤的加速发展。转基因细胞中生理水平表达的人p53的这种行为可以通过其与Mdm2意外高的结合来解释。通过使用Mdm2与p53相互作用的抑制剂Nutlin-3a，我们能够在转基因细胞中部分重建p53的反式激活和凋亡功能。我们的研究结果表明，p53与Mdm2之间的相互作用在稳态组织中控制p53的转录活性，并调节DNA损伤和癌基因诱导而非自发的肿瘤发生。
