High glucose and insulin promote<i>O-</i>GlcNAc modification of proteins, including α-tubulin

Walgren, Jennie; Vincent, Timothy S.; Schey, Kevin L.; Buse, Maria G.

doi:10.1152/ajpendo.00382.2002

Cited by 143 publications

(82 citation statements)

References 64 publications

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“…Increasing O-GlcNAc levels have been associated with increased transcription of HSP40 and HSP70 levels (228), and the latter is a known target for O-GlcNAc modification (199,207). Whereas we found no change in HSP70 expression in cardiomyocytes after glucosamine treatment (21), PUGNAc treatment augmented HSP70 levels in response to oxidative stress (108).…”

Section: Protein O-glcnacylation and Cardiovascular Protectionmentioning

confidence: 49%

ProteinO-GlcNAcylation: a new signaling paradigm for the cardiovascular system

Laczy¹,

Hill²,

Wang³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

141

135

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The posttranslational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide ␤-N-acetylglucosamine (O-GlcNAc) is a highly dynamic and ubiquitous protein modification. Protein O-GlcNAcylation is rapidly emerging as a key regulator of critical biological processes including nuclear transport, translation and transcription, signal transduction, cytoskeletal reorganization, proteasomal degradation, and apoptosis. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are both major hallmarks of diabetes mellitus and diabetes-related cardiovascular complications. Conversely, there is a growing body of data demonstrating that the acute activation of O-GlcNAc levels is an endogenous stress response designed to enhance cell survival. Reports on the effect of altered O-GlcNAc levels on the heart and cardiovascular system have been growing rapidly over the past few years and have implicated a role for O-GlcNAc in contributing to the adverse effects of diabetes on cardiovascular function as well as mediating the response to ischemic injury. Here, we summarize our present understanding of protein O-GlcNAcylation and its effect on the regulation of cardiovascular function. We examine the pathways regulating protein O-GlcNAcylation and discuss, in more detail, our understanding of the role of O-GlcNAc in both mediating the adverse effects of diabetes as well as its role in mediating cellular protective mechanisms in the cardiovascular system. In addition, we also explore the parallels between O-GlcNAc signaling and redox signaling, as an alternative paradigm for understanding the role of O-GlcNAcylation in regulating cell function. hexosamine biosynthesis; protein O-glycosylation; ␤-N-acetylglucosamine transferase; diabetes mellitus POSTTRANSLATIONAL MODIFICATION (PTM) of proteins is a common mechanism for the modulation of protein function, location, and turnover. Although protein phosphorylation is probably the most widely studied form of PTM, there are many other PTMs, including acylation, ubiquitylation, methylation, acetylation, thiolation, nitration, and glycosylation (107). The focus of this review is protein glycosylation, specifically, O-glycosylation of nuclear and cytoplasmic proteins. Classical protein glycosylation occurs in the endoplasmic reticulum and Golgi, leading to the formation of stable and complex elongated oligosaccharide structures via both N-linkage on asparagine and O-linkage on the hydroxy amino acids serine and threonine in addition to hydroxyproline, hydroxylysine, and tyrosine residues of proteins that become secreted or membrane component glycoproteins (189). In contrast, glycosylation of nuclear and cytoplasmic proteins is a rapid and dynamic modification of serine or threonine residues by the O-linked attachment of the monosaccharide ␤-N-acetylglucosamine (OGlcNAc) (97,195); this process is referred to as protein O-GlcNAcylation to contrast it wi...

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Section: Protein O-glcnacylation and Cardiovascular Protectionmentioning

confidence: 49%

ProteinO-GlcNAcylation: a new signaling paradigm for the cardiovascular system

Laczy¹,

Hill²,

Wang³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

141

135

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“…Moreover, increasing HBP pathway flux by glutamine treatment to elevate O-GlcNAc enhances expression of HSF1 and HSP70 in a septic mouse model and in isolated rat cardiomyocytes (32,61). HSP70 and HSP90 are modified by O-GlcNAc (62,63). Additionally, HSP70 displays lectin-like binding activity specifically toward O-GlcNAc (64), and HSP90 inhibition destabilizes OGT and reduces O-GlcNAcylation (65).…”

Section: O-glcnac and Cancer Cell Survivalmentioning

confidence: 99%

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Vosseller

2014

Journal of Biological Chemistry

173

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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“…Hyper-GlcNAcylation of the transcription factors Sp1, FoxO1, and the transcriptional coactivator CRTC2 or TORC2 [transducer of regulated cyclic adenosine monophosphate response element-binding protein (CREB) 2] have all been linked to high glucose-induced expression of gluconeogeneic genes and thus may contribute to glucose toxicity (18,45,46,51,104). Hyperglycemic condition results in increased GlcNAcylation of Sp1 at multiple sites (51,104) and is directly correlated with its DNA-binding and transcriptional activities (53,106) regulating multiple glucose responsive genes associated with diabetes (muscle/fat cell; Fig.…”

Section: Glcnacylation Of Proteins Regulating Glucose-responsive Tranmentioning

confidence: 99%

“…Hyperglycemic condition results in increased GlcNAcylation of Sp1 at multiple sites (51,104) and is directly correlated with its DNA-binding and transcriptional activities (53,106) regulating multiple glucose responsive genes associated with diabetes (muscle/fat cell; Fig. 2) (22).…”

Section: Glcnacylation Of Proteins Regulating Glucose-responsive Tranmentioning

confidence: 99%

Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity

Copeland

Bullen

Hart

2008

American Journal of Physiology-Endocrinology and Metabolism

222

197

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GlcNAcylation is a nutrient/stress-sensitive modification that regulates proteins involved in a wide array of biological processes, including transcription, signaling, and metabolism. GlcNAcylation is involved in the etiology of glucose toxicity and chronic hyperglycemia-induced insulin resistance, a major hallmark of type 2 diabetes. Several reports demonstrate a strong positive correlation between GlcNAcylation and the development of insulin resistance. However, recent studies suggest that inhibiting GlcNAcylation does not prevent hyperglycemia-induced insulin resistance, suggesting that other mechanisms must also be involved. To date, proteomic analyses have identified more than 600 GlcNAcylated proteins in diverse functional classes. However, O-GlcNAc sites have been mapped on only a small percentage (Ͻ15%) of these proteins, most of which were isolated from brain or spinal cord tissue and not from other metabolically relevant tissues. Mapping the sites of GlcNAcylation is not only necessary to elucidate the complex cross-talk between GlcNAcylation and phosphorylation but is also key to the design of site-specific mutational studies and necessary for the generation of site-specific antibodies, both of which will help further decipher O-GlcNAc's functional roles. Recent technical advances in O-GlcNAc site-mapping methods should now finally allow for a much-needed increase in site-specific analyses to address the functional significance of O-GlcNAc in insulin resistance and glucose toxicity as well as other major biological processes.O-linked ␤-N-acetylglucosamine; diabetes; O-linked ␤-N-acetylglucosamine transferase; ␤-N-acetylglucosaminidase; hexosamine biosynthesis THE ADDITION of a single O-linked ␤-N-acetylglucosamine (OGlcNAc) moiety (GlcNAcylation) to the hydroxyl groups of serine and/or threonine residues of target proteins is an inducible, reversible, and dynamic posttranslational modification (PTM). Since its discovery in the early 1980s (44, 97), OGlcNAc has been found to have an abundance and protein distribution similar to phosphorylation, but thus far only about 600 GlcNAcylated proteins have been identified. Unlike traditional glycosylation, the O-GlcNAc modification is nearly exclusively located on cytoplasmic and nuclear proteins and is not elongated into more complex glycan structures, such as those found on extracellular or luminal domains of membrane or secreted glycoproteins. O-GlcNAc is involved in a wide range of biological processes, ranging from cell cycle progression and transcription to signal transduction and metabolism (38,93). Emerging evidence suggests that elevated GlcNAcylation of proteins contributes to glucose toxicity and is strongly associated with hyperglycemia-induced insulin resistance, two major hallmarks of type 2 diabetes (see recent review in Ref. 19). This review will provide a critical evaluation of three broad areas and experimental approaches used to support O-GlcNAc's putative roles in the pathogenesis of diabetes: 1) regulation of hexosamine biosynthetic pathwa...

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High glucose and insulin promoteO-GlcNAc modification of proteins, including α-tubulin

Cited by 143 publications

References 64 publications

ProteinO-GlcNAcylation: a new signaling paradigm for the cardiovascular system

ProteinO-GlcNAcylation: a new signaling paradigm for the cardiovascular system

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity

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