کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3298523 | 1209906 | 2008 | 18 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Intestinal Deletion of Pofut1 in the Mouse Inactivates Notch Signaling and Causes Enterocolitis
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کلمات کلیدی
GSIMLNHRPGALTCVANICDBSA - BSAbovine serum albumin - آلبومین سرم گاوHES - او هستgut-associated lymphoid tissue - باکتری لنفوئیدی مرتبط با رودهNotch intracellular domain - دامنه درون سلولی Notchγ-secretase inhibitor - مهارکننده γ-اسیدhairy and enhancer of split - مودار و تقویت کننده تقسیم بندیpolymerase chain reaction - واکنش زنجیره ای پلیمرازPCR - واکنش زنجیرهٔ پلیمرازHorseradish peroxidase - پراکسیداز هوررادیشmesenteric lymph nodes - گره های لنفاوی مزانتریک
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
بیماریهای گوارشی
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چکیده انگلیسی
Background & Aims: Notch downstream targets are fundamental to intestinal cell lineage commitment and are suggested as therapeutic targets for colon cancer cells. However, the role of endogenous Notch signaling through receptor-ligand interaction, and effects of its longer term down-regulation on intestinal homeostasis, are unclear. Methods: To address these issues, the gene encoding protein O-fucosyltransferase 1, an enzyme required for Notch ligand binding and thus activation of all Notch receptors, was deleted in the mouse intestinal and colonic epithelium, through Villin-Cre-mediated recombination. Results: Pofut1 deletion inactivated Notch signaling, giving rise to smaller but viable mice. These mice exhibited a large increase in all intestinal secretory cell lineages, which accumulated in the crypts, resulting in crypt hyperplasia. Although proliferating cells were largely reduced in the colon, the transit amplifying compartment was maintained in the upper crypts of the intestinal mucosa. By 9 months, these perturbations in cell maturation altered mucus-associated gut microbiota and caused chronic intestinal inflammation, with evidence of bacterial translocation to the mesenteric lymph nodes, macrophage, and T-lymphocyte infiltration, and Th1/Th17 immune response. Dysplastic foci were also observed in Pofut1-deficient small intestine with occasional progression to tumor formation. Conclusions: Mucus hypersecretion upon Pofut1 inactivation is accompanied by alteration of the mucus-associated flora, which likely contributes to the development of enterocolitis. Therefore, these data identify important potential complications in strategies to target Notch signaling in therapeutic approaches to colon cancer.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 135, Issue 3, September 2008, Pages 849-860.e6
Journal: Gastroenterology - Volume 135, Issue 3, September 2008, Pages 849-860.e6
نویسندگان
Sandra Guilmeau, Marta Flandez, Laura Bancroft, Rani S. Sellers, Benjamin Tear, Pamela Stanley, Leonard H. Augenlicht,