p53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis.
p53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis.
复制标题
DOI：
10.1053/j.gastro.2011.05.032
复制
发表时间：
2011-09
期刊：
影响因子：
29.4
通讯作者：
Barrett TA
中科院分区：
文献类型：
--
作者：
Dirisina R;Katzman RB;Goretsky T;Managlia E;Mittal N;Williams DB;Qiu W;Yu J;Chandel NS;Zhang L;Barrett TA
炎症性肠病（IBD）与肠上皮细胞（IEC）凋亡增加有关。肿瘤抑制基因p53的突变出现在从结肠炎到癌症进展的早期阶段。我们研究了p53及其靶点p53上调的凋亡调节因子（p53-upregulated modulator of apoptosis，p53-A）在炎症诱导的IEC凋亡中的作用。在小鼠粘膜炎症模型中诱导细胞凋亡。在野生型、p53−/−、Bid−/−、Bim−/−、p53−/−、巴克−/−、Bak A −/−和Noxa−/−小鼠中评估IEC对急性T细胞活化的反应。分别在葡聚糖硫酸钠（DSS）1或3个周期后，在小鼠中测量IEC对急性和慢性结肠炎的反应。通过TUNEL染色和测量半胱氨酸蛋白酶3和9的活性来评估细胞凋亡;在患有和不患有溃疡性结肠炎的患者的结肠组织中评估p53和p53蛋白A的水平。人和小鼠结肠炎组织下隐窝内均出现肠上皮细胞凋亡。用抗CD 3或3个周期的DSS诱导结肠炎增加结肠隐窝IEC中的细胞凋亡和p53和p53 A蛋白水平。在p53−/−和p53 A −/−小鼠中，IEC的凋亡显著减少，但炎症没有减少。与对照组相比，结肠炎小鼠和UC患者的炎症粘膜组织中p53和p54 A的水平升高。p53−/−小鼠IEC中PUMA的诱导表明PUMA介导的细胞凋亡不依赖于p53。在小鼠和人类中，结肠炎症通过p53依赖性和非依赖性机制诱导IEC的凋亡; CCLA还激活与结肠炎相关的内在凋亡途径。
Inflammatory bowel disease (IBD) is associated with increased apoptosis of intestinal epithelial cells (IECs). Mutations in the tumor suppressor p53 appear during early stages of progression from colitis to cancer. We investigated the role of p53 and its target, p53-upregulated modulator of apoptosis (PUMA), in inflammation-induced apoptosis of IECs. Apoptosis was induced in mouse models of mucosal inflammation. Responses of IECs to acute, T-cell activation were assessed in wild-type, p53−/−, Bid−/−, Bim−/−, Bax3−/−, Bak−/−, PUMA−/−, and Noxa−/− mice. Responses of IECs to acute and chronic colitis were measured in mice following 1 or 3 cycles of dextran sulfate sodium (DSS), respectively. Apoptosis was assessed by TUNEL staining and measuring activity of caspases 3 and 9; levels of p53 and PUMA were assessed in colon tissue from patients with and without ulcerative colitis. Apoptosis of IECs occurred in the lower crypts of colitic tissue from humans and mice. Colitis induction with anti-CD3 or 3 cycles of DSS increased apoptosis and protein levels of p53 and PUMA in colonic crypt IECs. In p53−/− and PUMA−/− mice, apoptosis of IECs was significantly reduced but inflammation was not. Levels of p53 and PUMA were increased in inflamed mucosal tissues of mice with colitis and in patients with UC, compared with controls. Induction of PUMA in IECs of p53−/− mice indicated that PUMA-mediated apoptosis was independent of p53. In mice and humans, colon inflammation induces apoptosis of IECs via p53-dependent and -independent mechanisms; PUMA also activates an intrinsic apoptosis pathway associated with colitis.
登录
查看更多内容
影响因子：
2.5
作者：
Croitoru, K;Zhou, PF
通讯作者：
Zhou, PF
影响因子：
29.4
作者：
BRENTNALL, TA;CRISPIN, DA;BURMER, GC
通讯作者：
BURMER, GC
影响因子：
2.8
作者：
Goodman, JE;Hofseth, LJ;Harris, CC
通讯作者：
Harris, CC
影响因子：
8.8
作者：
Ijiri, K;Potten, C S
通讯作者：
Potten, C S
影响因子：
8
作者：
Merritt, AJ;Allen, TD;Hickman, JA
通讯作者：
Hickman, JA