The Increase in O-Linked N-Acetylglucosamine Protein Modification Stimulates Chondrogenic Differentiation Both in Vitro and in Vivo

Andrés-Bergós, J.; Tardío, L.; Larrañaga-Vera, A.; Gómez, Rodolfo; Herrero‐Beaumont, Gabriel; Largo, Raquel

doi:10.1074/jbc.m112.354241

Cited by 82 publications

(92 citation statements)

References 67 publications

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“…Although recent reports show the protein modification of O-GlcNAc using mass spectrometry [28,29], we have not solved the problems of complete structural identification. Therefore, we confirmed the modification of O-GlcNAc using both CTD110.6 and RL2 antibodies (O-GlcNAc-specific antibody recognizing other motif) as well as immunofluorescence staining consistent with previous study [30][31][32][33]. These results provide evidence that O-GlcNAc regulates the activation of major signaling pathways and then manipulates the stem cell functions.…”

Section: Discussionsupporting

confidence: 91%

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

Jeon

Kim

Ryu

et al. 2014

Stem Cells and Development

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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 (g-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.

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Section: Discussionsupporting

confidence: 91%

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

Jeon

Kim

Ryu

et al. 2014

Stem Cells and Development

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“…The timing associated with observed effects of OGA inhibition on ALP expression are in-line with studies in chondrocytes that showed increased ALP transcript levels after 9 days of differentiation in the presence of Thiamet G (27). Similarly, in human MSCs, altered regulation of ALP activity by alanine-substitution at MAPK-regulated Runx2 phosphorylation sites were observed after 6 days (71).…”

Section: Inhibition Of Oga Increases Alp Expression and Activity Insupporting

confidence: 73%

“…As a positive control, BMMSCs were also differentiated in the presence of BMP2/7. Chronic pharmacological inhibition of OGA increased global protein O-GlcNAc levels and induced an expected compensatory increase in OGA transcript and protein expression (27) (Fig. 5A, supplemental Fig.…”

Section: Inhibition Of Oga Increases Alp Expression and Activity Inmentioning

confidence: 99%

“…Previous studies have linked enhanced expression of differentiation markers in chondrocytes and pre-osteoblasts with elevated modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc), and suggested O-GlcNAcylation of Runx2 contributes to osteoblast differentiation (27,28). Cycling of O-GlcNAc modification on protein Ser/Thr residues is essential to mammalian tissue specification, cell survival, and embryonic development (29 -32), and there are numerous examples of O-GlcNAc modification impinging on phosphorylated-mediated signal transduction (33)(34)(35)(36).…”

Section: Runx2mentioning

confidence: 99%

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O-GlcNAc Modification of the runt-Related Transcription Factor 2 (Runx2) Links Osteogenesis and Nutrient Metabolism in Bone Marrow Mesenchymal Stem Cells

Nagel

Ball

2014

Molecular & Cellular Proteomics

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Runx2 [also known as: core binding factor ␣ 1 (CBFA1); acute myeloid leukemia transcription factor 3 (AML3); polyoma enhancer-binding protein 2␣ (PEPB2␣)] is a member of the runt-domain gene family of DNA binding proteins (Runx1, Runx2, and Runx3), which control the expression of numerous genes involved in cell growth, proliferation, and determination of cell lineage (1). Aberrant expression and activity of Runx proteins are implicated in leukemia, metastatic breast cancer, and defects in skeletal development and bone remodeling (2-4). Runx2 is expressed during early embryonic development in mesenchymal and cartilage condensations of the developing bone anlagen, and its transcription, activity, and stability are tightly regulated (5-7). Considered the master regulator of osteoblast differentiation, Runx2 also contributes to chondrocyte maturation (8,9) and, through these cell-types, controls intramembranous and endochondral ossification culminating in the formation of the mineralized skeleton (5, 6, 10). A gain-of-function mutation of Runx2, resulting from duplication of exons 3 to 5, is linked to dysplastic long bone formation, enlarged clavicles, and thickening of the cranial vault (11). Conversely, the rare autosomal dominant disorder, cleidocranial dysplasia, has been traced to multiple loss-of-function mutations within the Cbfa1 gene, and is characterized by defective formation or absence of the clavicle, enlarged fontanelles, and dental abnormalities (9, 12, 13). Mice nullizygous for Runx2 develop a cartilaginous skeletal framework that fails to undergo mineralization caused by the absence of osteoblasts, and these mice die at birth because of respiratory failure (5, 10).

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“…Reducing hyper-O-GlcNAcylation in prostate cancer PC-3ML and liver cancer HepG2 cells suppresses the expression of MMP-2 and MMP-9 (9, 12). Conversely, elevation of O-GlcNAcylation using the OGA inhibitor Thiamet-G or knockdown of OGA enhances the activity of MMP-2 and MMP-9 in chondrocytes and increases the expression of MMP-1, MMP-2, and MMP-3 (12,76). Therefore, hyper-O-GlcNAcylation in tumors may contribute to angiogenesis through up-regulation of VEGF and MMPs.…”

Section: O-glcnac and Cancer Angiogenesismentioning

confidence: 99%

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Vosseller

2014

Journal of Biological Chemistry

177

145

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O-Linked ␤-N-acetylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in cellular signaling. Recent work indicates that increased O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this minireview, we discuss how hyper-O-GlcNAcylation may be linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics. We also discuss potential therapeutic modulation of O-GlcNAc levels in cancer treatment.

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The Increase in O-Linked N-Acetylglucosamine Protein Modification Stimulates Chondrogenic Differentiation Both in Vitro and in Vivo

Cited by 82 publications

References 67 publications

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

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

O-GlcNAc Modification of the runt-Related Transcription Factor 2 (Runx2) Links Osteogenesis and Nutrient Metabolism in Bone Marrow Mesenchymal Stem Cells

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

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