The genetic basis of tissue responses to ionizing radiation
The genetic basis of tissue responses to ionizing radiation
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DOI：
10.1259/bjr/60507340
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发表时间：
2007-01-01
影响因子：
2.6
通讯作者：
Wright, E. G.
中科院分区：
文献类型：
--
作者：
Lindsay, K. J.;Coates, P. J.;Wright, E. G.
哺乳动物细胞对电离辐射的反应可能直接受到遗传的影响，并且可以鉴定出细胞放射敏感性不同的小鼠品系。利用 C57BL/6 辐射抗性和 DBA/2 辐射敏感小鼠品系来帮助阐明电离辐射早期反应所涉及的机制。对 p53 通路的研究揭示了这些小鼠品系之间 p53 及其下游靶标的表达和活性的差异。辐射抗性C57BL/6菌株表现出早期p53反应并优先上调促凋亡Bax，而辐射敏感DBA/2菌株表现出较晚、更长的p53反应和细胞周期蛋白依赖性激酶抑制剂p21的更高表达。这两种小鼠品系还表现出显着不同水平的脾辐射诱导的细胞凋亡，抗辐射的 C57BL/6 的细胞凋亡细胞是辐射敏感的小鼠的两倍。这些数据为细胞凋亡遗传连锁分析提供了定量终点。连锁分析的初步结果表明，三个不同的位点可能参与驱动小鼠品系表现出的不同细胞凋亡表型。此外，我们还确定了电离辐射反应所涉及的机制是否可能以组织特异性方式发挥作用。在连锁分析中，结肠和小肠细胞凋亡评分与脾脏数据的比较显示几乎没有相关性，表明细胞凋亡水平具有组织特异性。通过使用二维凝胶电泳系统进一步说明了结肠和小肠的组织特异性。这揭示了暴露于电离辐射之前和之后肠道组织之间 p53 磷酸化的不同模式。这里讨论的数据将有助于我们理解辐射反应所涉及的基因和机制。
The response of mammalian cells to ionizing radiation can be directly influenced by genetics, and mouse strains can be identified that differ in their cellular radiosensitivity. The C57BL/6 radiation resistant and DBA/2 radiation susceptible mouse strains were utilized to aid the elucidation of the mechanisms involved in the early response to ionizing radiation. Investigation of the p53 pathway revealed differences in the expression and activity of p53 and its downstream targets between these mouse strains. The radiation resistant C57BL/6 strain showed an early p53 response and preferentially upregulated pro-apoptotic Bax, whereas the radiation sensitive DBA/2 strain exhibited a later, more prolonged p53 response and a greater expression of the cyclin dependent kinase inhibitor p21. These two mouse strains also showed significantly different levels of splenic radiation-induced apoptosis, the radiation resistant C57BL/6 scoring twofold more apoptotic cells than its radiation sensitive counterpart. These data provided a quantitative endpoint for an apoptosis genetic linkage analysis. The preliminary results of the linkage analysis indicated that three distinct loci may be involved in driving the different apoptosis phenotypes exhibited by the mouse strains. Moreover, we ascertained whether the mechanisms involved in the response to ionizing radiation may work in a tissue-specific fashion. In the linkage analysis, comparison of apoptosis scores in the colon and small intestine with data from the spleen showed little correlation suggesting that levels of apoptosis are tissuespecific. Tissue-specificity in the colon and small intestine was further illustrated by work with a 2D gel electrophoresis system. This revealed different patterns of p53 phosphorylation between the intestinal tissues both before and after exposure to ionizing radiation. The data discussed here will aid our understanding of the genes and mechanisms involved in radiation responses.