title: Glucosamine-induced OGT activation mediates glucose production through cleaved Notch1 and FoxO1, which coordinately contributed to the regulation of maintenance of self-renewal in mouse embryonic stem cells.
abstract: We aimed to study the relationship between glucosamine and FoxO1/Notch in gluconeogenesis and maintenance of mouse embryonic stem cell (mESC) self-renewal. Glucosamine (GlcN) increased glucose production and gluconeogenic enzyme (G6Pase and PEPCK) expression. GlcN also increased the percentage of cells in S phase, number of cells, and the protein expression of cell cycle regulatory proteins that were blocked by 3-mercaptopicolinic acid (gluconeogenesis inhibitor) or glucose transporter (GLUT) 1 neutralizing antibody. GlcN increased the O-GlcNAc transferase (OGT)-dependent protein O-GlcNAc level. Moreover, inhibition of OGT (by ST045849) decreased glucose production. GlcN enhanced the expression of OGT-dependent O-GlcNAcylated Notch1 and then increased the translocation of cleaved Notch1 to the nucleus. Moreover, GlcN stimulated the translocation of O-GlcNAcylated FoxO1 to the nucleus. GlcN increased the binding between cleaved Notch1 and FoxO1 with CSL, a transcription factor, which was blocked by L-685,458 (γ-secretase inhibitor) or ST045849, respectively. Simultaneous blockage of cleaved Notch1 and FoxO1 also decreased the expression of G6Pase and PEPCK more significantly than that by inhibition of cleaved Notch1 alone or FoxO1 alone. In addition, GlcN maintained the undifferentiation status while depletion of Notch1 and FoxO1 for 3 days decreased Oct4 and SSEA-1 expression and alkaline phosphatase activity or increased the mRNA expression of GATA4, Tbx5, Cdx2, and Fgf5. In conclusion, GlcN-induced OGT activation mediated glucose production through cleaved Notch1 and FoxO1, which contributed to the regulation of maintenance of self-renewal in mESCs.
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University , Seoul, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeon
authors.forename: Han Na
authors.initials: HN
authors.lastname: Suh
authors.forename: Mi Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ryu
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D005943:Gluconeogenesis; D005944:Glucosamine / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006031:Glycosylation; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C497762:Notch1 protein, mouse; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; D005944:Glucosamine
references.citation: J Clin Invest. 2007 Sep;117(9):2477-85
references.pmid: 17717603
references.citation: J Biol Chem. 2005 Sep 23;280(38):32944-56
references.pmid: 16027160
references.citation: J Biol Chem. 2009 Feb 20;284(8):5148-57
references.pmid: 19103600
references.citation: Exp Cell Res. 2008 Jul 1;314(11-12):2238-48
references.pmid: 18570920
references.citation: J Biol Chem. 2008 Jun 20;283(25):17721-30
references.pmid: 18436531
references.citation: J Biol Chem. 2008 Dec 19;283(51):35486-95
references.pmid: 18948267
references.citation: Am J Physiol Cell Physiol. 2008 Jun;294(6):C1509-20
references.pmid: 18367586
references.citation: J Biol Chem. 2012 Sep 28;287(40):33615-28
references.pmid: 22859309
references.citation: Nature. 2013 Oct 17;502(7471):372-6
references.pmid: 24077098
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10804-9
references.pmid: 15249677
references.citation: Am J Pathol. 2003 Nov;163(5):1873-85
references.pmid: 14578187
references.citation: Nat Med. 2011 Jul 31;17(8):961-7
references.pmid: 21804540
references.citation: J Assist Reprod Genet. 1995 Feb;12(2):97-105
references.pmid: 7670281
references.citation: PLoS One. 2012;7(5):e37427
references.pmid: 22629392
references.citation: Mol Endocrinol. 2009 Jun;23(6):827-37
references.pmid: 19264844
references.citation: Glycobiology. 2010 Aug;20(8):931-49
references.pmid: 20368670
references.citation: Nat Rev Mol Cell Biol. 2013 Feb;14(2):83-97
references.pmid: 23325358
references.citation: Sci STKE. 2005 Nov 29;2005(312):re13
references.pmid: 16317114
references.citation: J Biol Chem. 2005 Feb 18;280(7):5307-17
references.pmid: 15557334
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: J Biol Chem. 2008 Jun 13;283(24):16283-92
references.pmid: 18420577
references.citation: FEBS Lett. 2008 Mar 5;582(5):829-34
references.pmid: 18280254
references.citation: Mol Cell Biol. 2005 Jul;25(14):6031-46
references.pmid: 15988017
references.citation: PLoS One. 2012;7(10):e47231
references.pmid: 23056614
references.citation: FASEB J. 2006 Jan;20(1):157-9
references.pmid: 16293708
references.citation: Biochim Biophys Acta. 2006 May-Jun;1761(5-6):599-617
references.pmid: 16781888
references.citation: Cell Stem Cell. 2012 Jul 6;11(1):62-74
references.pmid: 22608532
references.citation: Brain Tumor Pathol. 2011 Feb;28(1):1-12
references.pmid: 21274750
references.citation: J Reprod Fertil. 1993 Sep;99(1):87-95
references.pmid: 8283458
references.citation: Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E974-80
references.pmid: 18728220
references.citation: J Clin Invest. 2001 Nov;108(9):1341-8
references.pmid: 11696579
references.citation: Nat Genet. 2006 Apr;38(4):431-40
references.pmid: 16518401
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12222-6
references.pmid: 11050244
references.citation: Nat Cell Biol. 2011 Jul 31;13(9):1092-9
references.pmid: 21804543
references.citation: Nature. 2007 Apr 26;446(7139):1017-22
references.pmid: 17460662
references.citation: Acta Naturae. 2010 Jul;2(3):30-46
references.pmid: 22649650
references.citation: Kidney Int Suppl. 2000 Sep;77:S13-8
references.pmid: 10997685
references.citation: Dev Cell. 2009 May;16(5):633-47
references.pmid: 19460341
references.citation: Aging Cell. 2012 Jun;11(3):439-48
references.pmid: 22314054
references.citation: Stem Cells Dev. 2013 Nov 15;22(22):2975-89
references.pmid: 23815613
references.citation: J Biol Chem. 2010 Nov 12;285(46):35245-8
references.pmid: 20880840
references.citation: J Exp Med. 1991 Dec 1;174(6):1517-26
references.pmid: 1744583
references.citation: J Biol Chem. 2006 Aug 25;281(34):24336-44
references.pmid: 16803882
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5735-9
references.pmid: 10801981