Tissue-specific inactivation of p53 tumor suppression in the mouse
Tissue-specific inactivation of p53 tumor suppression in the mouse
复制标题
DOI：
10.1101/gad.10.7.826
复制
发表时间：
1996-04-01
影响因子：
10.5
通讯作者：
VanDyke, T
中科院分区：
文献类型：
--
作者：
Bowman, T;Symonds, H;VanDyke, T
p53基因是人类癌症中结构和功能基因突变的最常见靶点。因此，相当大的努力已经致力于映射p53的功能结构域，就其对体内肿瘤发生的影响。研究表明，p53的羧基末端结构域足以进行体外转化。为了确定是否可以使用反式显性负性p53蛋白在体内引发组织特异性p53无效效应，我们测试了羧基末端p53片段（氨基酸302-390）是否可以在已建立的肿瘤进展模型中消除p53依赖性凋亡。我们先前在转基因小鼠模型中发现p53依赖性凋亡的丧失加速了脑肿瘤的发生。在这里，我们表明，同样的效果可以引起表达显性负性p53蛋白组织特异性野生型p53的存在下。在该模型中，pRb功能被破坏并共表达p53羧基末端显性负性片段（p53 DD）的转基因小鼠发生了模拟p53遗传缺失的侵袭性脑肿瘤。我们发现内源性p53与p53 DD复合，其失活导致细胞凋亡减少和肿瘤发生加速。这些研究建立了体内组织特异性敲除p53功能的机制。
The p53 gene is the most frequent target of structural and functional genetic mutations in human cancer. Thus, considerable effort has been devoted to mapping the functional domains of p53 with regard to their impact on tumorigenesis in vivo. Studies have shown that the carboxy-terminal domain of p53 is sufficient for transformation in vitro. To determine whether a transdominant-negative p53 protein could be used to elicit a tissue-specific p53-null effect in vivo, we tested whether a carboxy-terminal p53 fragment (amino acids 302-390) could abolish p53-dependent apoptosis in an established tumor progression model. We showed previously that loss of p53-dependent apoptosis accelerates brain tumorigenesis in a transgenic mouse model. Here, we show that the same effect can be elicited by expressing a dominant-negative p53 protein tissue specifically in the presence of wild-type p53. Transgenic mice in which pRb function has been disrupted and that coexpress a p53 carboxy-terminal dominant-negative fragment (p53DD) develop aggressive brain tumors mimicking genetic loss of p53 in this model. Inactivation of endogenous p53, which we show to be complexed with p53DD, results in a reduction in apoptosis and acceleration of tumorigenesis. These studies establish a mechanism for tissue-specific knock out of p53 function in vivo.