Regional analysis of p35 mutations in rheumatoid arthritis synovium
Regional analysis of p35 mutations in rheumatoid arthritis synovium
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DOI：
10.1073/pnas.152333199
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发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
Firestein, GS
中科院分区：
文献类型：
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作者：
Yamanishi, Y;Boyle, DL;Firestein, GS
p53肿瘤抑制蛋白在细胞周期调节、DNA修复和细胞凋亡中起核心作用。最近的研究表明，DNA损伤和p53基因的体细胞突变可能发生在许多组织中，包括皮肤、结肠和滑膜。虽然在类风湿性关节炎（RA）滑膜组织和滑膜细胞中已经证实了p53基因的体细胞突变，但没有关于p53突变的位置或程度的信息。通过显微解剖RA滑膜组织切片，我们观察到大量的p53过渡突变，这是氧化应激引起的特征性DNA损伤。p53突变和asp53 mRNA表达主要位于滑膜内膜，而非滑膜下层（P < 0.01）。在一些显微解剖区域观察到p53突变子簇，提示寡克隆扩增。由于IL-6基因的表达受野生型p53的调控，因此采用real-time PCR技术对微解剖组织中IL-6 mRNA的表达进行定量分析。p53高突变率区域的IL-6 mRNA含量显著高于低突变率区域（P < 0.02）。显微解剖结果表明，炎症性氧化应激可诱导RA滑膜组织中p53突变。这一过程，如暴露在阳光下的皮肤和发炎的结肠上皮，为一些突变克隆提供了选择性生长优势。含有p53突变的相对低百分比的细胞可以潜在地影响邻近细胞，并通过促炎细胞因子的作用增强炎症。
The p53 tumor suppressor protein plays a central role in cell cycle regulation, DNA repair, and apoptosis. Recent studies indicate that DNA damage and somatic mutations in the p53 gene can occur because of genotoxic stress in many tissues, including the skin, colon, and synovium. Although somatic mutations in the p53 gene have been demonstrated in rheumatoid arthritis (RA) synovial tissue and synoviocytes, no information is available on the location or extent of p53 mutations. Using microdissected RA synovial tissue sections, we observed abundant p53 transition mutations, which are characteristic DNA damage caused by oxidative stress. p53 mutations, as well asp53 mRNA expression, were located mainly in the synovial intimal lining rather than the sublining (P < 0.01). Clusters of p53 mutant subdones were observed in some microdissected regions, suggesting oligoclonal expansion. Because IL-6 gene expression is regulated by wildtype p53, IL-6 mRNA expression in microdissected tissues was quantified by using real-time PCR. The regions with high rates of p53 mutations contained significantly greater amounts of IL-6 mRNA compared with the low mutation samples (P < 0.02). The microdissection findings suggest that p53 mutations are induced in RA synovial tissues by inflammatory oxidative stress. This process, as in sun-exposed skin and inflamed colonic epithelium, provides some of the mutant clones with a selective growth advantage. A relatively low percentage of cells containing p53 mutations can potentially affect neighboring cells and enhance inflammation through the elaboration of proinflammatory cytokines.