CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in response to butyric acid
CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in response to butyric acid
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DOI：
10.1007/s00535-010-0355-9
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发表时间：
2011-03-01
影响因子：
6.3
通讯作者：
Okayasu, Isao
中科院分区：
文献类型：
--
作者：
Yoshida, Tsutomu;Sekine, Tsukasa;Okayasu, Isao
在溃疡性结肠炎（UC）中，在患者的粘膜中显著检测到多变梭杆菌，并且由细菌大量产生的丁酸（BA）激活p53系统并诱导上皮细胞凋亡，如我们先前报道的。然而，BA和p53之间的联系的积极因素还有待澄清。在此，我们确定了一个基因的BA激活特异性在UC相关的癌细胞系，并确定其激活的p53的机制。cDNA微阵列分析的基础上Percellome（每细胞标准化）的方法进行BA刺激的UC相关的癌症和散发性结直肠癌细胞系在模拟结肠上皮UC的条件下。为了验证芯片的结果，分子，生物化学，和组织病理学分析performed.We发现CBP/p300相互作用的反式激活因子与谷氨酸/天冬酰胺丰富的羧基末端结构域2（CITED 2）被特异性上调UC相关的癌细胞系BA治疗，在mRNA和蛋白质表达水平。CITED 2可诱导p53乙酰化和p53依赖性凋亡，伴随CBP/p300结合。BA依赖性细胞凋亡抑制剂的单羧酸转运蛋白-1和siRNA的p53。在UC的炎症灶中，组织学上明显的炎症活动与CITED 2的表达显著相关，在体外模拟UC的条件下，基于Percellome方法的cDNA微阵列鉴定CITED 2为UC相关蛋白。CITED 2的激活可能通过激活p53诱导粘膜细胞凋亡和糜烂，因此在UC中将肠道细菌与粘膜炎症联系起来方面发挥关键作用。
In ulcerative colitis (UC), Fusobacterium varium is significantly detected in patients' mucosa, and butyric acid (BA), abundantly produced by the bacterium, activates the p53 system and induces epithelial apoptosis, as we previously reported. However, factors active in the link between BA and p53 have yet to be clarified. Here, we identified a gene activated by BA specifically in UC-associated cancer cell lines and ascertained the mechanism of its activation of p53.cDNA microarray analysis based on the Percellome (per cell normalization) method was performed on BA-stimulated UC-associated cancers and sporadic colorectal cancer cell lines under conditions mimicking colonic epithelium UC. For validation of microarray results, molecular, biochemical, and histopathological analyses were performed.We found the CBP/p300-interacting transactivator with glutamic acid/asparagine-rich carboxy-terminal domain 2 (CITED2) to be specifically upregulated in UC-associated cancer cell lines by BA treatment, at both mRNA and protein expression levels. CITED2 could be shown to induce p53 acetylation and p53-dependent apoptosis, accompanied by binding of CBP/p300. BA-dependent apoptosis was suppressed by an inhibitor of monocarboxylate transporter-1 and an siRNA for p53. In inflammatory foci of UC, histologically evident inflammatory activity and CITED2 expression were significantly correlated.CITED2 was identified as UC-associated protein by cDNA microarray based on the Percellome method under UC-mimicking conditions in vitro. CITED2 activation may induce mucosal apoptosis and erosion by activating p53 and thus play a critical role in linking enteric bacteria with mucosal inflammation in UC.