title: TSC2/mTORC1 signaling controls Paneth and goblet cell differentiation in the intestinal epithelium.
abstract: The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the intestinal epithelium, with a marked decrease in the goblet and Paneth cell lineages. Conversely, treatment of mice with either Notch inhibitor dibenzazepine (DBZ) or mTORC1 inhibitor rapamycin significantly attenuated the reduction of goblet and Paneth cells. Accordingly, knockdown of TSC2 activated, whereas knockdown of mTOR or treatment with rapamycin decreased, the activity of Notch signaling in the intestinal cell line LS174T. Importantly, our findings demonstrate that TSC2/mTORC1 signaling contributes to the maintenance of intestinal epithelium homeostasis by regulating Notch activity.
authors: Markey Cancer Center, The University of Kentucky, Lexington, KY, USA.
authors: Y
authors: Y
authors: Zhou
authors: 1] Markey Cancer Center, The University of Kentucky, Lexington, KY, USA [2] Department of Surgery, The University of Kentucky, Lexington, KY, USA.
authors: P
authors: P
authors: Rychahou
authors: 1] Markey Cancer Center, The University of Kentucky, Lexington, KY, USA [2] Department of Surgery, The University of Kentucky, Lexington, KY, USA.
authors: Q
authors: Q
authors: Wang
authors: Markey Cancer Center, The University of Kentucky, Lexington, KY, USA.
authors: H L
authors: HL
authors: Weiss
authors: 1] Markey Cancer Center, The University of Kentucky, Lexington, KY, USA [2] Department of Surgery, The University of Kentucky, Lexington, KY, USA.
authors: B M
authors: BM
authors: Evers
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D020397:Goblet Cells / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008822:Mice, Transgenic; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D019879:Paneth Cells / Q000166:cytology* / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases; D000072056:Transcription Factor HES-1; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C489734:Hes1 protein, mouse; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse
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