Tissue-specific p53 responses to ionizing radiation and their genetic modification: the key to tissue-specific tumour susceptibility?
Tissue-specific p53 responses to ionizing radiation and their genetic modification: the key to tissue-specific tumour susceptibility?
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DOI：
10.1002/path.1456
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发表时间：
2003-11-01
影响因子：
7.3
通讯作者：
Wright, EG
中科院分区：
文献类型：
--
作者：
Coates, PJ;Lorimore, SA;Wright, EG
尽管对潜在的机制知之甚少，但对肿瘤发生和治疗剂存在组织特异性反应，并且这些反应受遗传因素影响。电离辐射是一种重要的肿瘤发生和治疗剂，有大量证据表明这种组织依赖性和基因型依赖性反应。由于p53肿瘤抑制蛋白是细胞对辐射反应的主要决定因素，本研究已调查是否修改的p53通路有助于组织依赖性和基因型依赖性的反应，使用近交系小鼠。在照射C57 BL/6和DBA/2小鼠的造血和上皮细胞的反应的比较显示，在不同的细胞类型和相同类型的不同细胞中的p53和凋亡反应的显着差异，反映了在整个生物体中操作的损伤反应的复杂性。这些数据表明，p53介导的上调Bax是脾细胞凋亡的主要决定因素，但不是在肠，而p53介导的诱导p21（waf 1）在脾中起着抗凋亡的作用，但不是在肠。它还表明，p53的稳定和差异反式激活活动对Bax或p21（waf 1）的影响，遗传因素的作用，在组织特异性的方式。ATM的分析，一个潜在的调解人的差异p53激活，表明这一关键调节辐射反应优先诱导上皮细胞，但不太可能占基因修饰的p53或凋亡反应的小鼠品系研究。在p53或DNA-PKcs基因的多态性也不太可能解释这里报道的遗传修饰。有许多p53通路的进一步的潜在修饰剂，但回交和互交小鼠的分析表明，基因负责这些体内反应的复杂修饰可以通过连锁分析来确定。这种方法有可能揭示涉及p53通路的新的或意想不到的相互作用，这些相互作用决定了辐射暴露的短期和长期影响以及组织特异性反应和肿瘤易感性的基础。版权所有（C）2003约翰威利父子有限公司。
Although little is understood of the underlying mechanisms, there are tissue-specific responses to tumourigenic and therapeutic agents and these responses are influenced by genetic factors. Ionizing radiation is an important tumourigenic and therapeutic agent for which there is substantial evidence for such tissue-dependent and genotype-dependent responses. Because the p53 tumour suppressor protein is a major determinant of cellular responses to radiation, the present study has investigated whether modification of the p53 pathway contributes to tissue-dependent and genotype-dependent responses using inbred strains of mice. Comparison of responses in haemopoietic and epithelial cells in irradiated C57BL/6 and DBA/2 mice revealed significant differences in p53 and apoptotic responses in different cell types and in different cells of the same type, reflecting the complexity of damage responses operating in the whole organism. The data suggest that p53-mediated up-regulation of Bax is a major determinant of apoptosis in the spleen, but not in the intestine, whereas p53-mediated induction of p21(waf1) plays an anti-apoptotic role in the spleen, but not in the intestine. It is also shown that p53 stabilization and differential transactivational activities towards Bax or p21(waf1) are influenced by genetic factors that act in a tissue-specific manner. Analysis of ATM, a potential mediator of differential p53 activation, indicates that this key regulator of radiation responses is preferentially induced in epithelial cells, but is unlikely to account for genetic modification of p53 or apoptotic responses in the mouse strains studied. Polymorphisms in the p53 or DNA-PKcs genes are also unlikely to account for the genetic modifications that are reported here. There are numerous further potential modifiers of the p53 pathway, but analysis of backcross and inter-cross mice demonstrates that genes responsible for the complex modification of these in vivo responses can be identified by linkage analysis. This approach has the potential to reveal new or unexpected interactions involving the p53 pathway that determine both short-term and long-term effects of radiation exposure and the basis of tissue-specific responses and tumour susceptibility. Copyright (C) 2003 John Wiley Sons, Ltd.