Li B, Kittrell F S, Medina D, Rosen J M
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030-3498, USA.
Mol Carcinog. 1995 Oct;14(2):75-83. doi: 10.1002/mc.2940140203.
Murine p53 containing an Arg-->Leu substitution at amino acid 172 possesses many properties characteristic of wild-type p53, including the ability to induce p21/WAF/Cip1 and apoptosis. To determine if p53-dependent apoptosis plays a critical role in mammary tumorigenesis, transgenic mice were generated in which the expression of this mutant p53 protein was targeted to the mammary gland by using the rat whey acidic protein gene promoter. Mice bearing pituitary isografts were treated with 7,12-dimethylbenz[a]anthracene (DMBA) and examined for mammary tumor development. Mice overexpressing the p53 transgene exhibited a statistically significant increase in apoptosis in the mammary gland and a statistically significant decrease in the incidence of DMBA-induced mammary tumors. No difference in tumor incidence was observed in mice without pituitary isografts who were treated with DMBA, because the transgene is not overexpressed in the absence of hormone stimulation provided by the pituitary isograft. The unexpected wild-type properties of the 172Arg-->Leu mutant p53, including its ability to stimulate apoptosis, make it a possible candidate for use in gene therapy protocols.
在第172位氨基酸处含有精氨酸到亮氨酸替换的小鼠p53具有许多野生型p53的特性，包括诱导p21/WAF/Cip1和凋亡的能力。为了确定p53依赖的凋亡在乳腺肿瘤发生中是否起关键作用，构建了转基因小鼠，通过使用大鼠乳清酸性蛋白基因启动子将这种突变p53蛋白的表达靶向乳腺。对携带垂体同基因移植瘤的小鼠用7,12 - 二甲基苯并[a]蒽（DMBA）处理，并检查乳腺肿瘤的发生情况。过表达p53转基因的小鼠乳腺中的凋亡有统计学显著增加，DMBA诱导的乳腺肿瘤发生率有统计学显著降低。在没有垂体同基因移植瘤且用DMBA处理的小鼠中未观察到肿瘤发生率的差异，因为在没有垂体同基因移植瘤提供的激素刺激时转基因不会过度表达。172位精氨酸到亮氨酸突变体p53出人意料的野生型特性，包括其刺激凋亡的能力，使其成为基因治疗方案中可能的候选者。
