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Regulation of colonic epithelial cell homeostasis by mTORC1
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Journal Article
Regulation of colonic epithelial cell homeostasis by mTORC1
2020
Overview
Cell signaling important for homeostatic regulation of colonic epithelial cells (CECs) remains poorly understood. Mammalian target of rapamycin complex 1 (mTORC1), a protein complex that contains the serine-threonine kinase mTOR, mediates signaling that underlies the control of cellular functions such as proliferation and autophagy by various external stimuli. We here show that ablation of tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, specifically in intestinal epithelial cells of mice resulted in increased activity of mTORC1 of, as well as increased proliferative activity of, CECs. Such Tsc2 ablation also reduced the population of Lgr5-positive colonic stem cells and the expression of Wnt target genes in CECs. The stimulatory phosphorylation of the kinase Akt and inhibitory phosphorylation of glycogen synthase kinase 3β were both markedly decreased in the colon of the Tsc2 conditional knockout (CKO) mice. Development of colonic organoids with cryptlike structures was enhanced for Tsc2 CKO mice compared with control mice. Finally, Tsc2 CKO mice manifested increased susceptibility to dextran sulfate sodium–induced colitis. Our results thus suggest that mTORC1 activity promotes the proliferation of, as well as the expression of Wnt target genes in, CECs and thereby contributes to colonic organogenesis and homeostasis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Ablation
/ Animals
/ Cell Proliferation - genetics
/ Cell Proliferation - physiology
/ Colitis
/ Colon
/ Dextran
/ Epithelial Cells - physiology
/ Genetic Predisposition to Disease
/ Glycogen
/ Glycogen Synthase Kinase 3 beta - metabolism
/ Humanities and Social Sciences
/ Kinases
/ Mechanistic Target of Rapamycin Complex 1 - metabolism
/ Mechanistic Target of Rapamycin Complex 1 - physiology
/ Protein-serine/threonine kinase
/ Science
/ Signal Transduction - genetics
/ Signal Transduction - physiology
/ Tuberous Sclerosis Complex 2
