The expression of sialyltransferases is regulated by the bioavailability and biosynthesis of sialic acids

Bork, Kaya; Weidemann, Wenke; Berneck, Beatrice; Kuchta, Magdalena; Bennmann, Dorit; Thate, Annett; Huber, Otmar; Gnanapragassam, Vinayaga S.; Horstkorte, Rüdiger

doi:10.1016/j.gep.2017.03.003

Cited by 18 publications

(16 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, these compounds supply butyrate to a cell upon esterase processing [ 70 , 73 ]; this SCFA can act as an histone deacetylase (HDAC) inhibitor and alter gene expression epigentically [ 43 ]. Second, the transcript levels of sialyltransferases can be regulated by the bioavailability and biosynthesis of sialic acid [ 74 ], which is dramatically affected by analog supplementation [ 38 , 39 ]. We found, however, that the transcript levels of SAMG genes was only minimally affected by analog supplementation with only minor differences observed between control and analog-treated cells in the heat map representations ( Fig 3 ).…”

Section: Resultsmentioning

confidence: 99%

Integration of genetic and metabolic features related to sialic acid metabolism distinguishes human breast cell subtypes

et al. 2018

View full text Add to dashboard Cite

In this report we use ‘high-flux’ tributanoyl-modified N-acetylmannosamine (ManNAc) analogs with natural N-acetyl as well as non-natural azido- and alkyne N-acyl groups (specifically, 1,3,4-O-Bu3ManNAc, 1,3,4-O-Bu3ManNAz, and 1,3,4-O-Bu3ManNAl respectively) to probe intracellular sialic acid metabolism in the near-normal MCF10A human breast cell line in comparison with earlier stage T-47D and more advanced stage MDA-MB-231 breast cancer lines. An integrated view of sialic acid metabolism was gained by measuring intracellular sialic acid production in tandem with transcriptional profiling of genes linked to sialic acid metabolism. The transcriptional profiling showed several differences between the three lines in the absence of ManNAc analog supplementation that helps explain the different sialoglycan profiles naturally associated with cancer. Only minor changes in mRNA transcript levels occurred upon exposure to the compounds confirming that metabolic flux alone can be a key determinant of sialoglycoconjugate display in breast cancer cells; this result complements the well-established role of genetic control (e.g., the transcription of STs) of sialylation abnormalities ubiquitously associated with cancer. A notable result was that the different cell lines produced significantly different levels of sialic acid upon exogenous ManNAc supplementation, indicating that feedback inhibition of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE)—generally regarded as the ‘gatekeeper’ enzyme for titering flux into sialic acid biosynthesis—is not the only regulatory mechanism that limits production of this sugar. A notable aspect of our metabolic glycoengineering approach is its ability to discriminate cell subtype based on intracellular metabolism by illuminating otherwise hidden cell type-specific features. We believe that this strategy combined with multi-dimensional analysis of sialic acid metabolism will ultimately provide novel insights into breast cancer subtypes and provide a foundation for new methods of diagnosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Integration of genetic and metabolic features related to sialic acid metabolism distinguishes human breast cell subtypes

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The pathway is regulated by cytoplasmic CMP-sialic acid that feedback-inhibits UDP-GlcNAc 2-epimerase activity by binding to its allosteric site [51,52]. Either Neu5Ac or CMP-sialic acid levels are believed to induce the transcription of sialyltransferases in the nucleus [53].…”

Section: Sialic Acid Biosynthesis Pathwaymentioning

confidence: 99%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

View full text Add to dashboard Cite

GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic Brimmed^vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.

show abstract

“…Notably, in spite of the mutation in Gne, the sialic acid enzymatic gene set, upstream and downstream of the GNE molecule, is not substantially altered in this experimental system. It has been reported that sialic acid availability in stem cells regulates the transcription of sialyltransferases [43] : absolute lack of sialic acid did upregulate sialyltransferases in Gne KO stem cells. Although hyposialylation has been reported in the sick mice kidney [27], we see only a slight upregulation of 3 among the 20 known sialyltransferases.…”

Section: Discussionmentioning

confidence: 89%

“…One possible explanation could be that the kidney disease in these mice affects the glomeruli, which function as a filtration barrier. Podocytes are the most differentiated cell type in the glomeruli and are crucial for the maintenance of the barrier integrity [43]. Recently, podocytes have been defined as contractile units which assist the glomeruli filtration function.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Hallmark Muscle Genes Protects GneM743T/M743T Mutated Knock-In Mice From Kidney and Muscle Phenotype

Benyamini

Kling

Yakovlev

et al. 2020

JND

View full text Add to dashboard Cite

Background: Mutations in GNE cause a recessive, adult onset myopathy characterized by slowly progressive distal and proximal muscle weakness. Knock-in mice carrying the most frequent mutation in GNE myopathy patients, Gne M743T/M743T , usually die few days after birth from severe renal failure, with no muscle phenotype. However, a spontaneous sub-colony remains healthy throughout a normal lifespan without any kidney or muscle pathology. Objective: We attempted to decipher the molecular mechanisms behind these phenotypic differences and to determine the mechanisms preventing the kidney and muscles from disease. Methods: We analyzed the transcriptome and proteome of kidneys and muscles of sick and healthy Gne M743T/M743T mice. Results: The sick Gne M743T/M743T kidney was characterized by up-regulation of extra-cellular matrix degradation related processes and by down-regulation of oxidative phosphorylation and respiratory electron chain pathway, that was also observed in the asymptomatic muscles. Surprisingly, the healthy kidneys of the Gne M743T/M743T mice were characterized by up-regulation of hallmark muscle genes. In addition the asymptomatic muscles of the sick Gne M743T/M743T mice showed upregulation of transcription and translation processes. Conclusions: Overexpression of muscle physiology genes in healthy Gne M743T/M743T mice seems to define the protecting mechanism in these mice. Furthermore, the strong involvement of muscle related genes in kidney may bridge the apparent phenotypic gap between GNE myopathy and the knock-in Gne M743T/M743T mouse model and provide new directions in the study of GNE function in health and disease.

show abstract

The expression of sialyltransferases is regulated by the bioavailability and biosynthesis of sialic acids

Cited by 18 publications

References 11 publications

Integration of genetic and metabolic features related to sialic acid metabolism distinguishes human breast cell subtypes

Integration of genetic and metabolic features related to sialic acid metabolism distinguishes human breast cell subtypes

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

Upregulation of Hallmark Muscle Genes Protects GneM743T/M743T Mutated Knock-In Mice From Kidney and Muscle Phenotype

Contact Info

Product

Resources

About