X marks the spot: Does it matter that O-GlcNAc Transferase is an X-linked gene?

Stichelen, Stéphanie Olivier-Van; Abramowitz, Lara K.; Hanover, John A.

doi:10.1016/j.bbrc.2014.06.068

Cited by 25 publications

(22 citation statements)

References 87 publications

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“…Whereas females have two X chromosomes, males have an X and Y chromosome. In mammals, this process for dosage compensation is called X-inactivation, and is defined by silencing of one of the two female X-chromosomes [26]. During early embryogenesis, X-chromosome inactivation occurs differently for extra-embryonic vs. embryonic tissues.…”

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

“…During early embryogenesis, X-chromosome inactivation occurs differently for extra-embryonic vs. embryonic tissues. In the extra-embryonic tissues, the paternally inherited X-chromosome (Xp) is silenced (imprinted X-inactivation, iXCI) [26]. Within the inner cell mass (ICM), from which the embryo is derived, cells undergo random X-inactivation (rXCI), e.g.…”

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

“…Within the inner cell mass (ICM), from which the embryo is derived, cells undergo random X-inactivation (rXCI), e.g. half the cells silence the Xp and the other half silence the maternally inherited X-chromosome (Xm) [26]. Interestingly, the O- GlcNAc transferase gene is localized on the X-chromosome close to the X-inactivation center (XIC) (Reviewed in [26]).…”

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

“…half the cells silence the Xp and the other half silence the maternally inherited X-chromosome (Xm) [26]. Interestingly, the O- GlcNAc transferase gene is localized on the X-chromosome close to the X-inactivation center (XIC) (Reviewed in [26]). Because Ogt is an X-linked nutrient sensor whose dosage is important for human health and disease, silencing of extra- Ogt alleles seems critical for normal female development.…”

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

“…Because Ogt is an X-linked nutrient sensor whose dosage is important for human health and disease, silencing of extra- Ogt alleles seems critical for normal female development. Indeed, heterozygous Ogt knockout (KO) female is embryonic lethal when the mutant allele is maternally inherited, whereas paternal inheritance is viable (Reviewed in [26]). In fact, in the female placenta, Ogt is only expressed by the maternal allele [27].…”

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

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You are what you eat

Stichelen

Hanover

2015

Current Opinion in Clinical Nutrition and Metabolic Care

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Purpose of review The O-linked N-acetylglucosamine (O-GlcNAc) modification is both responsive to nutrient availability and capable of altering intracellular cellular signaling. We summarize data defining a role for O-GlcNAcylation in metabolic homeostasis and epigenetic regulation of development in the intrauterine environment. Recent Findings O-GlcNAc Transferase (OGT) catalyzes nutrient-driven O-GlcNAc addition and is subject to random X-inactivation. OGT plays key roles in growth factor signaling, stem cell biology, epigenetics, and possibly imprinting. The O-GlcNAcase, which removes O-GlcNAc is subject to tight regulation by higher order chromatin structure. O-GlcNAc cycling plays an important role in the intrauterine environment where OGT expression is an important biomarker of placental stress. Summary Regulation of O-GlcNAc cycling by X-inactivation, epigenetic regulation, and nutrient-driven processes make it an ideal candidate for a nutrient-dependent epigenetic regulator of human disease. In addition, O-GlcNAc cycling influences chromatin modifiers critical to the regulation and timing of normal development including the polycomb repression complex (PRC2) and the TET proteins mediating DNA methyl cytosine demethylation. The pathway also impacts the Hypothalamic-Pituitary-Adrenal Axis critical to intrauterine programming influencing disease susceptibility in later life.

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Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

Section: Dosage Of Ogt Is Regulated By Imprinted X-inactivationmentioning

confidence: 99%

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You are what you eat

Stichelen

Hanover

2015

Current Opinion in Clinical Nutrition and Metabolic Care

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Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

Zachara

2018

FEBS Letters

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Almost 100 years after the first descriptions of proteins conjugated to carbohydrates (mucins), several studies suggested that glycoproteins were not restricted to the serum, extracellular matrix, cell surface, or endomembrane system. In the 1980’s, key data emerged demonstrating that intracellular proteins were modified by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc). Subsequently, this modification was identified on thousands of proteins that regulate cellular processes as diverse as protein aggregation, localization, post-translational modifications, activity, and interactions. In this Review, we will highlight critical discoveries that shaped our understanding of the molecular events underpinning the impact of O-GlcNAc on protein function, the role that O-GlcNAc plays in maintaining cellular homeostasis, and our understanding of the mechanisms that regulate O-GlcNAc-cycling.

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O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle

Hanover¹,

Chen

Bond³

2018

J Bioenerg Biomembr

122

123

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Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes. O-GlcNAcylation can thereby alter epigenetics, transcription, signaling, proteostasis, and bioenergetics, key 'hallmarks of cancer'. In this review, we summarize accumulating evidence that many cancer hallmarks are linked to dysregulation of O-GlcNAc cycling on cancer-relevant targets. We argue that onconutrient and oncometabolite-fueled elevation increases HBP flux and triggers O-GlcNAcylation of key regulatory enzymes in glycolysis, Kreb's cycle, pentose-phosphate pathway, and the HBP itself. The resulting rerouting of glucose metabolites leads to elevated O-GlcNAcylation of oncogenes and tumor suppressors further escalating elevation in HBP flux creating a 'vicious cycle'. Downstream, elevated O-GlcNAcylation alters DNA repair and cellular stress pathways which influence oncogenesis. The elevated steady-state levels of O-GlcNAcylated targets found in many cancers may also provide these cells with a selective advantage for sustained growth, enhanced metastatic potential, and immune evasion in the tumor microenvironment.

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X marks the spot: Does it matter that O-GlcNAc Transferase is an X-linked gene?

Cited by 25 publications

References 87 publications

You are what you eat

You are what you eat

Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle

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