Insulin signaling controls the expression of
            <i>O</i>
            ‐GlcNAc transferase and its interaction with lipid microdomains

Pérez-Cervera, Yobana; Dehennaut, Vanessa; Gil, Moyira Aquino; Guedri, Katia; Mata, Carlos Josué Solórzano; Stichelen, Stéphanie Olivier-Van; Michalski, Jean‐Claude; Foulquier, François; Lefebvre, Tony

doi:10.1096/fj.12-217984

Cited by 47 publications

(55 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Embryonic lethality and developmental delay observed by genetic deletion of Ogt or Mgea5 demonstrates the critical role of these enzymes in O-GlcNAc cycling (10,11). We (1), along with others (12)(13)(14), have observed alterations in the expression level of OGT and OGA protein along with concomitant protein O-GlcNAc modification in various pathological conditions. We recently reported that the up-regulation of miR-539 could be a mechanism for decreased OGA level in the infarcted mouse heart (15).…”

Section: The Posttranslational O-linked N-acetylglucosamine (O-mentioning

confidence: 87%

E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression

Muthusamy

Hong

Dassanayaka

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Protein O-GlcNAcylation, which is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), has emerged as an important posttranslational modification that may factor in multiple diseases. Until recently, it was assumed that OGT/ OGA protein expression was relatively constant. Several groups, including ours, have shown that OGT and/or OGA expression changes in several pathologic contexts, yet the cis and trans elements that regulate the expression of these enzymes remain essentially unexplored. Here, we used a reporter-based assay to analyze minimal promoters and leveraged in silico modeling to nominate several candidate transcription factor binding sites in both Ogt (i.e. the gene for OGT protein) and Mgea5 (i.e. the gene for OGA protein). We noted multiple E2F binding site consensus sequences in both promoters. We performed chromatin immunoprecipitation in both human and mouse cells and found that E2F1 bound to candidate E2F binding sites in both promoters. In HEK293 cells, we overexpressed E2F1, which significantly reduced OGT and MGEA5 expression. Conversely, E2F1-deficient mouse fibroblasts had increased Ogt and Mgea5 expression. Of the known binding partners for E2F1, we queried whether retinoblastoma 1 (Rb1) might be involved. Rb1-deficient mouse embryonic fibroblasts showed increased levels of Ogt and Mgea5 expression, yet overexpression of E2F1 in the Rb1-deficient cells did not alter Ogt and Mgea5 expression, suggesting that Rb1 is required for E2F1-mediated suppression. In conclusion, this work identifies and validates some of the promoter elements for mouse Ogt and Mgea5 genes. Specifically, E2F1 negatively regulates both Ogt and Mgea5 expression in an Rb1 protein-dependent manner.2 modification occurs in a variety of cellular proteins and is known to be an important metabolic sensor in all metazoans. Alterations in O-GlcNAc levels occur in several diseases, including heart failure, diabetes, cancer, and neurodegenerative disorders (1-5). Evidence suggests that changes in O-GlcNAc levels play a critical role in protein activity, stability, and localization (6 -9). Using the substrate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the enzyme O-GlcNAc transferase (OGT) adds the GlcNAc moiety to serine and threonine residues, whereas O-GlcNAcase (OGA) removes it. Embryonic lethality and developmental delay observed by genetic deletion of Ogt or Mgea5 demonstrates the critical role of these enzymes in O-GlcNAc cycling (10, 11). We (1), along with others (12-14), have observed alterations in the expression level of OGT and OGA protein along with concomitant protein O-GlcNAc modification in various pathological conditions. We recently reported that the up-regulation of miR-539 could be a mechanism for decreased OGA level in the infarcted mouse heart (15). Another study showed that increases in O-GlcNAc levels by pharmacological inhibition of OGA increased OGA expression through the O-GlcNAc modification of RNA polymerase II, whereas OGT levels decreased (13). Thus, changes in OGT/OGA protein e...

show abstract

Section: The Posttranslational O-linked N-acetylglucosamine (O-mentioning

confidence: 87%

E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression

Muthusamy

Hong

Dassanayaka

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Specifically, insulin signalling has been shown to regulate OGT through several distinct mechanisms, including modulation of OGT expression, subcellular localization, and enzymatic activity. In addition to upregulating OGT expression through a PI3K-dependent pathway, insulin stimulation promotes translocation of OGT from the nucleus to the cytoplasm and localization of OGT to lipid rafts in the plasma membrane, where it is activated via tyrosine phosphorylation by the insulin receptor 5, 87, 88 (Fig. 3c).…”

Section: Nutritional and Hormonal Regulationmentioning

confidence: 99%

Protein O-GlcNAcylation: emerging mechanisms and functions

Yang

Qian

2017

Nat Rev Mol Cell Biol

854

869

View full text Add to dashboard Cite

O-GlcNAcylation—the attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to cytoplasmic, nuclear and mitochondrial proteins—is a post-translational modification that regulates fundamental cellular processes in metazoans. A single pair of enzymes—O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA)—controls the dynamic cycling of this post-translational modification in a nutrient- and stress-responsive manner. Recent years have seen remarkable advances in our understanding of O-GlcNAcylation at levels ranging from structural and molecular biology to cell signalling and gene regulation to physiology and disease. Emerging from these recent developments are new mechanisms and functions of O-GlcNAcylation that enable us to begin constructing a unified conceptual framework through which to understand the significance of this modification in cellular and organismal physiology.

show abstract

“…Notably, reduced O-GlcNAcylation of Sp1 down-regulates the transcription of the pro-angiogenic factor VEGF-A (vascular endothelial growth factor A), involved in retinal vascularization [29]. Inhibition of OGT by Ac 4 -5S-GlcNAc provided insights into the role of OGT in the insulin response, showing a concerted role of O-GlcNAc and insulin-dependent signalling cascades on membrane lipid microdomains [30]. The compound has also been used on pancreatic cancer cells suggesting a correlation between hyper-O-GlcNAcylation and apoptosis via the modulation of the NF-κB antiapoptotic transcriptional activity [31].…”

Section: Substrate Analoguesmentioning

confidence: 99%

O-GlcNAc transferase inhibitors: current tools and future challenges

Trapannone

Rafie

Aalten

2016

Biochemical Society Transactions

View full text Add to dashboard Cite

The O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification (O-GlcNAcylation) is the dynamic and reversible attachment of N-acetylglucosamine to serine and threonine residues of nucleocytoplasmic target proteins. It is abundant in metazoa, involving hundreds of proteins linked to a plethora of biological functions with implications in human diseases. The process is catalysed by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) that add and remove sugar moieties respectively. OGT knockout is embryonic lethal in a range of animal models, hampering the study of the biological role of O-GlcNAc and the dissection of catalytic compared with non-catalytic roles of OGT. Therefore, selective and potent chemical tools are necessary to inhibit OGT activity in the context of biological systems. The present review focuses on the available OGT inhibitors and summarizes advantages, limitations and future challenges.

show abstract

Insulin signaling controls the expression of O ‐GlcNAc transferase and its interaction with lipid microdomains

Cited by 47 publications

References 41 publications

E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression

E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression

Protein O-GlcNAcylation: emerging mechanisms and functions

O-GlcNAc transferase inhibitors: current tools and future challenges

Contact Info

Product

Resources

About