The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death
The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death
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DOI：
10.1038/sj.cdd.4401415
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发表时间：
2004-09-01
影响因子：
12.4
通讯作者：
Franceschi, C
中科院分区：
文献类型：
--
作者：
Bonafé, M;Salvioli, S;Franceschi, C
在人类P53基因的第72密码子上存在一种常见的精氨酸到脯氨酸的多态。在这项研究中，我们发现从精氨酸等位基因纯合子百岁老人和六十岁老人(Arg+)分离的成纤维细胞和淋巴细胞经历了比从Pro+等位基因携带者(Pro+)获得的细胞更高程度的氧化应激诱导的凋亡。在研究30岁人群的细胞时，Arg+和Pro+在凋亡敏感性上的差异并不显著。此外，我们发现百岁老人的Arg+和Pro+细胞在P53蛋白和P53/MDM2复合体的构成水平以及氧化应激诱导的P53/Bclxl复合体和线粒体定位的P53的水平上存在差异。一直以来，所有这些差异在30岁的人的细胞中都不那么明显。最后，我们调查了一组受急性心肌缺血影响的老年患者(66-99岁)中P53密码子72基因型在体内的功能相关性，急性心肌缺血是一种临床情况，体内细胞死亡发生。我们发现，与Pro+患者相比，Arg+患者肌钙蛋白I和CK-MB水平升高，这两个血清标志物与缺血损伤的程度相关。综上所述，这些数据表明，P53密码子72的多态在老年人的细胞凋亡易感性中具有遗传决定的变异性，这在与年龄相关的病理条件，如心肌缺血的背景下具有潜在的相关作用。
A common arginine to proline polymorphism is harboured at codon 72 of the human p53 gene. In this investigation, we found that fibroblasts and lymphocytes isolated from arginine allele homozygote centenarians and sexagenarians (Arg+) undergo an oxidative-stress-induced apoptosis at a higher extent than cells obtained from proline allele carriers (Pro+). At variance, the difference in apoptosis susceptibility between Arg+ and Pro+ is not significant when cells from 30-year-old people are studied. Further, we found that Arg+ and Pro+ cells from centenarians differ in the constitutive levels of p53 protein and p53/MDM2 complex, as well as in the levels of oxidative stress-induced p53/Bcl-xL complex and mitochondria-localised p53. Consistently, all these differences are less evident in cells from 30-year-old people. Finally, we investigated the in vivo functional relevance of the p53 codon 72 genotype in a group of old patients (66-99 years of age) affected by acute myocardial ischaemia, a clinical condition in which in vivo cell death occurs. We found that Arg+ patients show increased levels of Troponin I and CK-MB, two serum markers that correlate with the extent of the ischaemic damage in comparison to Pro+ patients. In conclusion, these data suggest that p53 codon 72 polymorphism contributes to a genetically determined variability in apoptotic susceptibility among old people, which has a potentially relevant role in the context of an age-related pathologic condition, such as myocardial ischaemia.