Bowman T, Symonds H, Gu L, Yin C, Oren M, Van Dyke T
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27299, USA.
Genes Dev. 1996 Apr 1;10(7):826-35. doi: 10.1101/gad.10.7.826.
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.
p53基因是人类癌症中结构和功能基因突变最常见的靶点。因此，人们投入了大量精力来绘制p53的功能结构域，以了解它们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在体外诱导转化。为了确定反式显性负性p53蛋白是否可用于在体内引发组织特异性p53缺失效应，我们测试了羧基末端p53片段（氨基酸302 - 390）是否能在已建立的肿瘤进展模型中消除p53依赖性凋亡。我们之前表明，在转基因小鼠模型中，p53依赖性凋亡的缺失会加速脑肿瘤的发生。在此，我们表明，在野生型p53存在的情况下，通过组织特异性表达显性负性p53蛋白也能产生相同的效果。在该模型中，pRb功能已被破坏且共表达p53羧基末端显性负性片段（p53DD）的转基因小鼠会发展出侵袭性脑肿瘤，类似于p53基因缺失的情况。我们发现内源性p53与p53DD形成复合物，其失活会导致凋亡减少和肿瘤发生加速。这些研究建立了一种在体内组织特异性敲除p53功能的机制。
