Transgenic mice with p53-responsive lacZ: P53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo
Transgenic mice with p53-responsive lacZ: P53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo
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DOI：
10.1093/emboj/16.6.1391
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发表时间：
1997-03-17
期刊：
影响因子：
11.4
通讯作者：
Gudkov, AV
中科院分区：
文献类型：
--
作者：
Komarova, EA;Chernov, MV;Gudkov, AV
为了分析参与p53依赖的转录激活在正常发育和响应DNA损伤在体内，我们创建了转基因小鼠与lacZ报告基因的控制下的p53响应启动子。五个独立的菌株表现出类似的模式的转基因表达。在未处理的动物中，lacZ表达仅限于胚胎和新生小鼠的发育中的神经系统，并且在成年大脑中强烈下降。γ射线照射或阿霉素处理诱导lacZ在早期胚胎的大部分细胞中以及在成年小鼠的脾脏、胸腺和小肠中表达。转基因表达是p53依赖性的，并与强p53积累的位点相吻合。与其他成年组织和晚期胚胎不同，lacZ表达组织和早期胚胎的特征在于高水平的p53 mRNA表达，并通过大量凋亡细胞死亡对DNA损伤作出反应。对p53缺失小鼠的分析表明，这种凋亡是p53依赖的。这些数据表明，p53活性，监测报告lacZ转基因，是体内的辐射和药物敏感性的决定因素，并表明组织和阶段特异性的p53调节在mRNA表达水平的重要性。
To analyze the involvement of p53-dependent transcriptional activation in normal development and in response to DNA damage in vivo, we created transgenic mice with a lacZ reporter gene under the control of a p53-responsive promoter. Five independent strains showed similar patterns of transgene expression. In untreated animals, lacZ expression was limited to the developing nervous system of embryos and newborn mice and was strongly decreased in the adult brain. gamma-irradiation or adriamycin treatment induced lacZ expression in the majority of cells of early embryos and in the spleen, thymus and small intestine in adult mice. Transgene expression was p53 dependent and coincided with the sites of strong p53 accumulation. The lacZ-expressing tissues and early embryos, unlike other adult tissues and late embryos, are characterized by high levels of p53 mRNA expression and respond to DNA damage by massive apoptotic cell death, Analysis of p53-null mice showed that this apoptosis is p53 dependent. These data suggest that p53 activity, monitored by the reporter lacZ transgene, is the determinant of radiation and drug sensitivity in vivo and indicate the importance of tissue and stage specificity of p53 regulation at the level of mRNA expression.