Hexosamines Are Unlikely to Function as a Nutrient-Sensor in 3T3-L1 Adipocytes: A Comparison of UDP-Hexosamine Levels after Increased Glucose Flux and Glucosamine Treatment

Bosch, Remko R.; Pouwels, M.J.M.; Span, Paul N.; Olthaar, André J.; Tack, Cees J.; Hermus, A.R.M.M.; Sweep, Fred C.G.J.

doi:10.1385/endo:23:1:17

Cited by 14 publications

(10 citation statements)

References 27 publications

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“…Perturbation of the HBP causes diabetes in murine models 33 and in 3T3-L1 adipocytes; insulin-stimulated glucose uptake results in 30% increase in the production of UDP-GlcNAc. 34 Of special interest, development of insulin resistance is associated with a fourfold increase in the levels of UDP-GlcNAc in the skeletal muscles, 35 whereas we observed that inhibition of UAP1 expression results in a significant decrease in the levels of UDP-GlcNAc (Figure 2e). High-glucose-induced development of insulin resistance can be prevented by an inhibitor of GFPT1, 33 and it remains to be determined whether UAP1 could be pharmacologically regulated to affect insulin responsiveness.…”

Section: Resultsmentioning

confidence: 70%

UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation

et al. 2014

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Prostate cancer is the second most common cause of cancer-associated deaths in men, and signaling via a transcription factor called androgen receptor (AR) is an important driver of the disease. Consequently, AR target genes are prominent candidates to be specific for prostate cancer and also important for the survival of the cancer cells. Here we assess the levels of all hexosamine biosynthetic pathway (HBP) enzymes in 15 separate clinical gene expression data sets and identify the last enzyme in the pathway, UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), to be highly overexpressed in prostate cancer. We analyzed 3261 prostate cancers on a tissue microarray and found that UAP1 staining correlates negatively with Gleason score (P=0.0039) and positively with high AR expression (P<0.0001). Cells with high UAP1 expression have 10-fold increased levels of the HBP end-product, UDP-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is essential for N-linked glycosylation occurring in the endoplasmic reticulum (ER) and high UAP1 expression associates with resistance against inhibitors of N-linked glycosylation (tunicamycin and 2-deoxyglucose) but not with a general ER stress-inducing agent, the calcium ionophore A23187. Knockdown of UAP1 expression re-sensitized cells towards inhibitors of N-linked glycosylation, as measured by proliferation and activation of ER stress markers. Taken together, we have identified an enzyme, UAP1, which is highly overexpressed in prostate cancer and protects cancer cells from ER stress conferring a growth advantage.

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Section: Resultsmentioning

confidence: 70%

UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation

et al. 2014

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“…OGT is proposed to respond directly to UDP-GlcNAc levels (via mechanisms discussed in the section on Protein Glycosylation), and the responsiveness of the HBP pathway to glucose is thought to be an important component of OGT's cellular biochemistry. The responsiveness of the pathway was challenged, however, on the basis of measurements showing that total cellular UDP-GlcNAc levels vary only twofold in response to a physiologically relevant range of extracellular glucose concentrations (between 1 and 25 mM) (55). These measurements were of total cellular UDP-GlcNAc levels, and it is possible that a larger dynamic range would be observed in the cytosol and/or nucleus.…”

Section: The Hexosamine Biosynthetic Pathwaymentioning

confidence: 99%

The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells?

Levine

Walker

2016

Annu. Rev. Biochem.

169

165

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O-linked N-acetylglucosamine transferase (OGT) is found in all metazoans and plays an important role in development but at the single-cell level is only essential in dividing mammalian cells. Postmitotic mammalian cells and cells of invertebrates such as Caenorhabditis elegans and Drosophila can survive without copies of OGT. Why OGT is required in dividing mammalian cells but not in other cells remains unknown. OGT has multiple biochemical activities. Beyond its well-known role in adding β-O-GlcNAc to serine and threonine residues of nuclear and cytoplasmic proteins, OGT also acts as a protease in the maturation of the cell cycle regulator host cell factor 1 (HCF-1) and serves as an integral member of several protein complexes, many of them linked to gene expression. In this review, we summarize current understanding of the mechanisms underlying OGT's biochemical activities and address whether known functions of OGT could be related to its essential role in dividing mammalian cells.

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“…Intuitively, increased cellular glucose and flux through the HBP would only increase UDP-GlcNAc levels to a specific concentration and no higher. For example, adipocytes exposed to increasing amounts of glucose in the presence of insulin show a 30% increase in UDP-GlcNAc concentration compared to a 365% increase in glucose uptake13. Is this slight increase in UDP-GlcNAc concentration enough to allow O-GlcNAc to act as a nutrient sensor?…”

Section: Nutrient Flux Through the Hexosamine Biosynthetic Pathway (Hbp)mentioning

confidence: 99%

O-GlcNAc signaling: a metabolic link between diabetes and cancer?

Slawson

Copeland

Hart

2010

Trends in Biochemical Sciences

306

246

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O-linked β-N-acetylglucosamine (O-GlcNAc) is a sugar attachment to serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins. In many ways, O-GlcNAcylation is similar to phosphorylation since both post-translational modifications cycle rapidly in response to internal or environmental cues. O-GlcNAcylated proteins are involved in transcription, translation, cytoskeletal assembly, signal transduction, and many other cellular functions. O-GlcNAc signaling is intertwined with cellular metabolism; indeed, the donor sugar for O-GlcNAcylation (UDP-GlcNAc) is synthesized from glucose, glutamine, and UTP via the hexosamine biosynthetic pathway. Emerging research indicates that O-GlcNAc signaling and its crosstalk with phosphorylation are altered in metabolic diseases, such as diabetes and cancer. O-GlcNAc: A metabolic Signaling MoleculeOne of the most pressing medical issues facing industrialized countries is the rapid rise of type 2 diabetes, a metabolic disorder characterized by severely elevated blood glucose and insensitivity to insulin. In the United States alone, 7.8% of the population is diagnosed with diabetes, and up to 57 million Americans have pre-diabetes. The cost for treating type 2 diabetes was $174 billion in 2007, and consumed 32% of Medicare spending (http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf). Furthermore, diabetes is a risk factor for Alzheimer's disease, cardiovascular disease, and cancer, but the underlying mechanisms remain poorly understood 1 . Both diabetes and cancer show cellular alterations in energy metabolism, stress responsiveness, and signaling. Multiple biochemical processes are involved; however, one potential link in all of these diseases is disrupted O-GlcNAc signaling.O-GlcNAc is a post-translational protein modification consisting of a single Nacetylglucosamine moiety attached via an O-β-glycosidic linkage to serine and threonine residues2 -4. O-GlcNAc modified proteins are generally either cytoplasmic or nuclear proteins, and unlike asparagine-linked or mucin-type O-glycosylation, O-GlcNAc is not further processed into a complex oligosaccharide2 , 3. In many ways, O-GlcNAc is similar to protein phosphorylation; for example the sugar can be attached or removed dynamically in response to changes in the cellular environment triggered by stress, hormones, or nutrients [5,6]. Because O-GlcNAc is attached to serine/threonine residues, the sugar is in direct competition with phosphorylation (eg. c-myc7). Furthermore, O-GlcNAcylated or phosphorylated residues can be in close proximity to each other and sterically impair the attachment of the other © 2010 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production proce...

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Hexosamines Are Unlikely to Function as a Nutrient-Sensor in 3T3-L1 Adipocytes: A Comparison of UDP-Hexosamine Levels after Increased Glucose Flux and Glucosamine Treatment

Cited by 14 publications

References 27 publications

UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation

UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation

The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells?

O-GlcNAc signaling: a metabolic link between diabetes and cancer?

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