Restricted accessResearch articleFirst published online 2014-09
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
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.
Get full access to this article
View all access options for this article.
References
1.
KangES, HanD, ParkJ, KwakTK, OhMA, LeeSA, ChoiS, ParkZY, KimY and LeeJW. (2008). O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic β cells. Exp Cell Res, 314:2238–2248.
2.
LoveDC and HanoverJA. (2005). The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci STKE, 2005:re13.
3.
WangS, HuangX, SunD, XinX, PanQ, PengS, LiangZ, LuoC, YangY, et al. (2012). Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates Akt signaling. PLoS One, 7:e37427
4.
HartGW, HousleyMP and SlawsonC. (2007). Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins. Nature, 446:1017–1022.
5.
ZacharaNE and HartGW. (2006). Cell signaling, the essential role of O-GlcNAc!. Biochim Biophys Acta, 1761:599–617.
6.
JeonJH, SuhHN, KimMO and HanHJ. (2013). Glucosamine-induced reduction of integrin β4 and plectin complex stimulates migration and proliferation in mouse embryonic stem cells. Stem Cells Dev, 22:2975–2989.
7.
SoesantoYA, LuoB, JonesD, TaylorR, GabrielsenJS, ParkerG and McClainDA. (2008). Regulation of Akt signaling by O-GlcNAc in euglycemia. Am J Physiol Endocrinol Metab, 295:E974–E980.
8.
KuoM, ZilberfarbV, GangneuxN, ChristeffN and IssadT. (2008). O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene. FEBS Lett, 582:829–834.
9.
RamadossP, Unger-SmithNE, LamFS and HollenbergAN. (2009). STAT3 targets the regulatory regions of gluconeogenic genes in vivo. Mol Endocrinol, 23:827–837.
10.
ConaghanJ, HandysideAH, WinstonRM and LeeseHJ. (1993). Effects of pyruvate and glucose on the development of human preimplantation embryos in vitro. J Reprod Fertil, 99:87–95.
11.
QuinnP. (1995). Enhanced results in mouse and human embryo culture using a modified human tubal fluid medium lacking glucose and phosphate. J Assist Reprod Genet, 12:97–105.
12.
HeiligC, BrosiusF, SiuB, ConcepcionL, MortensenR, HeiligK, ZhuM, WeldonR, WuG and ConnerD. (2003). Implications of glucose transporter protein type 1 (GLUT1)-haplodeficiency in embryonic stem cells for their survival in response to hypoxic stress. Am J Pathol, 163:1873–1885.
13.
ShafiR, IyerSP, ElliesLG, O'DonnellN, MarekKW, ChuiD, HartGW and MarthJD. (2000). The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci U S A, 97:5735–5739.
14.
HaeuslerRA, KaestnerKH and AcciliD. (2010). FoxOs function synergistically to promote glucose production. J Biol Chem, 285:35245–35248.
15.
Ido-KitamuraY, SasakiT, KobayashiM, KimHJ, LeeYS, KikuchiO, Yokota-HashimotoH, IizukaK, AcciliD and KitamuraT. (2012). Hepatic FoxO1 integrates glucose utilization and lipid synthesis through regulation of Chrebp O-glycosylation. PLoS One, 7:e47231
16.
EijkelenboomA and BurgeringBM. (2013). FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol, 14:83–97.
17.
HousleyMP, RodgersJT, UdeshiND, KellyTJ, ShabanowitzJ, HuntDF, PuigserverP and HartGW. (2008). O-GlcNAc regulates FoxO activation in response to glucose. J Biol Chem, 283:16283–16292.
18.
HousleyMP, UdeshiND, RodgersJT, ShabanowitzJ, PuigserverP, HuntDF and HartGW. (2009). A PGC-1α-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J Biol Chem, 284:5148–5157.
19.
PajvaniUB, ShawberCJ, SamuelVT, BirkenfeldAL, ShulmanGI, KitajewskiJ and AcciliD. (2011). Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat Med, 17:961–967.
20.
ZhangX, YalcinS, LeeDF, YehTY, LeeSM, SuJ, MungamuriSK, RimmeleP, KennedyM, et al. (2011). FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol, 13:1092–1099.
21.
KitamuraT, KitamuraYI, FunahashiY, ShawberCJ, CastrillonDH, KolliparaR, DePinhoRA, KitajewskiJ and AcciliD. (2007). A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J Clin Invest, 117:2477–2485.
22.
CollinsQF, XiongY, LupoEGJr., LiuHY and CaoW. (2006). p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. J Biol Chem, 281:24336–24344.
23.
BradfordMM. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem, 72:248–254.
24.
MackmanN, BrandK and EdgingtonTS. (1991). Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor κB binding sites. J Exp Med, 174:1517–1526.
25.
SchleicherED and WeigertC. (2000). Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int Suppl, 77:S13–S18.
26.
SlawsonC, ZacharaNE, VossellerK, CheungWD, LaneMD and HartGW. (2005). Perturbations in O-linked β-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J Biol Chem, 280:32944–32956.
27.
YangYR, SongM, LeeH, JeonY, ChoiEJ, JangHJ, MoonHY, ByunHY, KimEK, et al. (2012). O-GlcNAcase is essential for embryonic development and maintenance of genomic stability. Aging Cell, 11:439–448.
28.
JangH, KimTW, YoonS, ChoiSY, KangTW, KimSY, KwonYW, ChoEJ, and YounHD. (2012). O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell, 11:62–74.
29.
MatsuuraA, ItoM, SakaidaniY, KondoT, MurakamiK, FurukawaK, NadanoD, MatsudaT, and OkajimaT. (2008). O-linked N-acetylglucosamine is present on the extracellular domain of notch receptors. J Biol Chem, 283:35486–35495.
30.
ChampattanachaiV, MarchaseRB, and ChathamJC. (2008). Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein O-GlcNAc and increased mitochondrial Bcl-2. Am J Physiol Cell Physiol, 294:C1509–C1520.
31.
Andrés-BergósJ, TardioL, Larranaga-VeraA, GómezR, Herrero-BeaumontG, and LargoR. (2012). The increase in O-linked N-acetylglucosamine protein modification stimulates chondrogenic differentiation both in vitro and in vivo. J Biol Chem, 287:33615–33628.
32.
EricksonJR, PereiraL, WangL, HanG, FergusonA, DaoK, CopelandRJ, DespaF, HartGW, RipplingerCM, and BersDM. (2013). Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature, 502:372–376.
33.
LiuF, IqbalK, Grundke-IqbalI, HartGW, and GongCX. (2004). O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A, 101:10804–10809.
34.
DuXL, EdelsteinD, DimmelerS, JuQ, SuiC and BrownleeM. (2001). Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest, 108:1341–1348.
35.
DuXL, EdelsteinD, RossettiL, FantusIG, GoldbergH, ZiyadehF, WuJ and BrownleeM. (2000). Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A, 97:12222–12226.
36.
Jafar-NejadH, LeonardiJ and Fernandez-ValdiviaR. (2010). Role of glycans and glycosyltransferases in the regulation of Notch signaling. Glycobiology, 20:931–949.
37.
FortiniME. (2009). Notch signaling: the core pathway and its posttranslational regulation. Dev Cell, 16:633–647.
38.
ShenC, ChenY, LiuH, ZhangK, ZhangT, LinA and JingN. (2008). Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-secretase. J Biol Chem, 283:17721–17730.
39.
KimSK, ParkHJ, HongHS, BaikEJ, JungMW and Mook-JungI. (2006). ERK1/2 is an endogenous negative regulator of the γ-secretase activity. FASEB J, 20:157–159.
40.
LohYH, WuQ, ChewJL, VegaVB, ZhangW, ChenX, BourqueG, GeorgeJ, LeongB, et al. (2006). The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet, 38:431–440.
41.
MedvedevSP, ShevchenkoAI and ZakianSM. (2010). Molecular basis of Mammalian embryonic stem cell pluripotency and self-renewal. Acta Naturae, 2:30–46.
42.
ChewJL, LohYH, ZhangW, ChenX, TamWL, YeapLS, LiP, AngYS, LimB, RobsonP and NgHH. (2005). Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol Cell Biol, 25:6031–6046.
43.
Okumura-NakanishiS, SaitoM, NiwaH and IshikawaF. (2005). Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem, 280:5307–5317.
44.
NatsumeA, KinjoS, YukiK, KatoT, OhnoM, MotomuraK, IwamiK and WakabayashiT. (2011). Glioma-initiating cells and molecular pathology: implications for therapy. Brain Tumor Pathol, 28:1–12.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
