title: Nuclear factor of activated T-cells 5 increases intestinal goblet cell differentiation through an mTOR/Notch signaling pathway.
abstract: The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis that is regulated by multiple signaling pathways. Previously, we have shown that the nuclear factor of activated T-cells 5 (NFAT5) is involved in the regulation of intestinal enterocyte differentiation. Here we show that treatment with sodium chloride (NaCl), which activates NFAT5 signaling, increased mTORC1 repressor regulated in development and DNA damage response 1 (REDD1) protein expression and inhibited mTOR signaling; these alterations were attenuated by knockdown of NFAT5. Knockdown of NFAT5 activated mammalian target of rapamycin (mTOR) signaling and significantly inhibited REDD1 mRNA expression and protein expression. Consistently, overexpression of NFAT5 increased REDD1 expression. In addition, knockdown of REDD1 activated mTOR and Notch signaling, whereas treatment with mTOR inhibitor rapamycin repressed Notch signaling and increased the expression of the goblet cell differentiation marker mucin 2 (MUC2). Moreover, knockdown of NFAT5 activated Notch signaling and decreased MUC2 expression, while overexpression of NFAT5 inhibited Notch signaling and increased MUC2 expression. Our results demonstrate a role for NFAT5 in the regulation of mTOR signaling in intestinal cells. Importantly, these data suggest that NFAT5 participates in the regulation of intestinal homeostasis via the suppression of mTORC1/Notch signaling pathway.
authors: Markey Cancer Center, University of Kentucky, Lexington, KY 40536.
authors: Yuning
authors: Y
authors: Zhou
authors: Markey Cancer Center, University of Kentucky, Lexington, KY 40536 Department of Surgery, University of Kentucky, Lexington, KY 40536.
authors: Qingding
authors: Q
authors: Wang
authors: Markey Cancer Center, University of Kentucky, Lexington, KY 40536.
authors: Heidi L
authors: HL
authors: Weiss
authors: Markey Cancer Center, University of Kentucky, Lexington, KY 40536 Department of Surgery, University of Kentucky, Lexington, KY 40536 mark.evers@uky.edu.
authors: B Mark
authors: BM
authors: Evers
mesh_terms: D018938:Caco-2 Cells; D002454:Cell Differentiation; D020397:Goblet Cells / Q000502:physiology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D055262:Mucin-2 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: C469991:DDIT4 protein, human; C524625:MUC2 protein, human; D055262:Mucin-2; C118125:NFAT5 protein, human; D051880:Receptors, Notch; D014157:Transcription Factors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases