Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis.
Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis.
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DOI：
10.1053/j.gastro.2010.05.037
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发表时间：
2010-09
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：
Lee G;Goretsky T;Managlia E;Dirisina R;Singh AP;Brown JB;May R;Yang GY;Ragheb JW;Evers BM;Weber CR;Turner JR;He XC;Katzman RB;Li L;Barrett TA
慢性溃疡性结肠炎（CUC）隐窝结构扭曲的机制尚不清楚。数据表明，Akt信号通过磷酸化Ser552位点（P-β-catenin552）与Wnt协同激活肠干细胞和祖细胞中的β-catenin。我们研究了肠道炎症中akt介导的β-连环蛋白激活是否需要磷酸肌苷激酶（PI3K）。PI3K的IA类亚基有条件地从小鼠肠上皮细胞中删除。对小鼠（I-pik3r1KO）进行急性炎症诱导，并用生化和组织学方法对其肠道进行分析。研究了化学阻断PI3K对结肠炎IL-10−/−小鼠的影响。检查患者的活检样本。与野生型小鼠相比，I-pik3r1KO小鼠肠道干细胞和祖细胞中t细胞介导的Akt和β-catenin信号通路减少，隐窝上皮细胞增殖受限。生化分析表明，PI3K-Akt信号传导增加了细胞核总β-catenin和P-β-catenin552水平，并降低了与降解相关的n端β-catenin的磷酸化。IL-10−/−小鼠中PI3K的抑制可损害结肠炎诱导的上皮细胞Akt和β-catenin的活化，减少祖细胞的扩增，防止发育不良。与对照样本相比，人类样本中含有P-β-catenin552的祖细胞数量增加，CUC、结肠炎相关癌症、管状腺瘤和散发性结直肠癌中β-catenin552靶基因mRNA表达增加。炎症过程中，PI3K-Akt信号通路与Wnt协同增加β-catenin信号通路。在CUC到CAC的过程中，pi3k诱导和akt介导的β-catenin信号是祖细胞活化所必需的；这些因素可能作为结肠发育不良转化的生物标志物。
Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that Akt signaling cooperates with Wnt to activate β-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-β-catenin552). We investigated whether phosphoinositide 3- kinase (PI3K) is required for Akt-mediated activation of β-catenin during intestinal inflammation. The class IA subunit of PI3K was conditionally deleted from intestinal epithelial cells in mice. Acute inflammation was induced in these mice (I-pik3r1KO) and their intestines were analyzed by biochemical and histological methods. The effects of chemically blocking PI3K in colitic IL-10−/− mice were examined. Biopsy samples from patients were examined. Compared to wild type mice, I-pik3r1KO mice had reduced T-cell–mediated Akt and β-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3K–Akt signaling increased nuclear total β-catenin and P-β-catenin552 levels and reduced phosphorylation of N-terminal β-catenin, which is associated with degradation. PI3K inhibition in IL-10−/− mice impaired colitis-induced epithelial Akt and β-catenin activation, reduced progenitor cell expansion, and prevented dysplasia. Human samples had increased numbers of progenitor cells with P-β-catenin552 throughout expanded crypts and increased mRNA expression of β-catenin target genes in CUC, colitis-associated cancer, tubular adenomas, and sporadic colorectal cancer, compared with control samples. PI3K–Akt signaling cooperates with Wnt to increase β-catenin signaling during inflammation. PI3K-induced and Akt-mediated β-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC; these factors might be used as biomarkers of dysplastic transformation in the colon.
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影响因子：
29.4
作者：
Dekaney, CM;Rodriguez, JM;Henning, SJ
通讯作者：
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DOI：
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发表时间：
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