Mannose Inhibits Hyaluronan Synthesis by Down-regulation of the Cellular Pool of UDP-N-acetylhexosamines

Jokela, Tiina; Jauhiainen, Marjo; Auriola, Seppo; Kauhanen, Miia; Tiihonen, Riikka; Tammi, Markku; Tammi, Raija

doi:10.1074/jbc.m706001200

Cited by 61 publications

(61 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Raising cellular UDP-GlcUA content stimulates hyaluronan synthesis, whereas a low concentration of UDP-GlcUA can limit the synthesis (12,17). We have shown that the same applies to UDP-GlcNAc: limiting or increasing its content stimulates and inhibits, respectively, the synthesis of hyaluronan (18).…”

mentioning

confidence: 73%

“…2C). Notably, although mannose increased the content of UDPGlcUA, this could not prevent the decreased synthesis of hyaluronan caused by UDP-HexNAc depletion because equimolar amounts of each substrate are needed (18).…”

Section: Resultsmentioning

confidence: 99%

“…Mannose and Glucosamine Regulate the Content of UDP-sugars-In epidermal keratinocytes, the cellular UDPHexNAc content responds rapidly to changes in culture conditions (18). Therefore, the medium was changed 22 h prior to the experiments to allow stabilization of the basal UDP-HexNAc content.…”

Section: Resultsmentioning

confidence: 99%

“…cDNA was prepared using 1 g of total RNA as a template for 1 h at 37°C with 100 pmol of oligo(dT) 18 , where ⌬⌬Ct is ⌬Ct stimulus Ϫ ⌬Ct solvent , ⌬Ct is Ct gene of interest Ϫ Ct RPLP0 , and Ct is the cycle at which the threshold is crossed. The gene-specific primers for the genes analyzed are shown in supplemental Table S1.…”

Section: Methodsmentioning

confidence: 99%

“…ELISA for Hyaluronan-Media from the cultures were assayed for the concentration of hyaluronan using a sandwichtype ELISA as described previously (13,18).…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Cellular Content of UDP-N-acetylhexosamines Controls Hyaluronan Synthase 2 Expression and Correlates with O-Linked N-Acetylglucosamine Modification of Transcription Factors YY1 and SP1

Jokela

Makkonen

Oikari

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Hyaluronan, a high molecular mass polysaccharide on the vertebrate cell surface and extracellular matrix, is produced at the plasma membrane by hyaluronan synthases using UDP-GlcNAc and UDP-GlcUA as substrates. The availability of these UDP-sugar substrates can limit the synthesis rate of hyaluronan. In this study, we show that the cellular level of UDP-HexNAc also controls hyaluronan synthesis by modulating the expression of HAS2 (hyaluronan synthase 2). Hyaluronan, a non-sulfated glycosaminoglycan present on the vertebrate cell surface and extracellular matrix, is involved in cellular functions, including migration, proliferation, adhesion, and various signaling systems, by its unique physicochemical properties and interactions with specific cell surface receptors (1). Hyaluronan is synthesized by HAS1-3, integral plasma membrane proteins that use cytosolic UDP-GlcNAc and UDPGlcUA as substrates to produce the long linear hyaluronan chains. During its synthesis, the growing hyaluronan chain runs through a pore in the plasma membrane into the extracellular matrix (2).Changes in hyaluronan production have been associated mostly with the expression level of HAS genes (3-6), especially in keratinocytes (7-13). Of the three genes, particularly HAS2 is subject to regulation by growth factors, cytokines, and hormones (4,14,15). In keratinocyte cultures, EGF, keratinocyte growth factor, TNF␣, and retinoic acid induce, whereas TGF␤ inhibits, HAS2 expression (8, 10, 13, 16). Accordingly, the HAS2 promoter has been shown to contain functional response elements (REs) 3 for different transcription factors, including retinoid acid receptor, NF-B, CREB1 (cAMP response elementbinding protein 1), and SP1 (specificity protein 1) (7,11,16).Besides by the protein expression of hyaluronan synthase (HAS) enzymes, hyaluronan synthesis is also controlled by the availability of the hyaluronan precursors, the substrates of HAS. Raising cellular UDP-GlcUA content stimulates hyaluronan synthesis, whereas a low concentration of UDP-GlcUA can limit the synthesis (12, 17). We have shown that the same applies to UDP-GlcNAc: limiting or increasing its content stimulates and inhibits, respectively, the synthesis of hyaluronan (18).The cellular content of UDP-GlcNAc makes an interesting connection between hyaluronan synthesis and cellular energy metabolism. UDP-GlcNAc is a product of the hexosamine synthesis pathway, into which 2-5% of the cellular influx of glucose is shunted (19). The rate-limiting step in hexosamine synthesis from glucose to UDP-GlcNAc is considered to be the GFAT1 (glutamine:fructose-6-phosphate amidotransferase 1) and GFAT2 isoenzymes (20). The flux of glucose through the hexosamine pathway serves as a cellular sensor of glucose availability, and it regulates the expression of a number of genes 3 The abbreviations used are: RE, response element; HAS, hyaluronan synthase; CBP, cAMP response element-binding protein-binding protein; PCAF, p300/CBP-associated factor.

show abstract

mentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…ELISA for Hyaluronan-Media from the cultures were assayed for the concentration of hyaluronan using a sandwichtype ELISA as described previously (13,18).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Cellular Content of UDP-N-acetylhexosamines Controls Hyaluronan Synthase 2 Expression and Correlates with O-Linked N-Acetylglucosamine Modification of Transcription Factors YY1 and SP1

Jokela

Makkonen

Oikari

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

The role of hyperglycemia‐evoked intracellular hyaluronan accumulation and its activity on the autophagic and endoplasmic reticulum stress pathways

Wang

Hascall

2023

Proteoglycan Research

View full text Add to dashboard Cite

Mesangial expansion is a hallmark of diabetic nephropathy (DN) that reduces the area for filtration and leads eventually to sclerosis and renal failure. A phenotypic activation and transient proliferation of the glomerular mesangial cells and a subsequent prominent glomerular infiltration of monocytes and macrophages appear to have a key role in the induction of mesangial matrix expansion, hypercellularity, and the onset of proteinuria. The molecular mechanisms underlying glomerular infiltration and activation by monocytes in DN are still unclear. Our previous studies indicate that aberrant intracellular synthesis of hyaluronan (HA) by hyperglycemic dividing mesangial cells is the central mechanism involved. These studies demonstrated that mesangial cells that divided in hyperglycemia activated synthesis of HA in intracellular compartments and induced endoplasmic reticulum (ER) stress/autophagy to secrete and form a monocyte adhesive extracellular HA matrix. This recruits inflammatory cells and establishes a chronic inflammatory fibrosis process that leads to sclerosis and renal failure. Our perspectives for the role of intracellular HA synthesis, ER stress, and autophagy in diabetic nephropathy are described.

show abstract

Hydrocortisone effect on hyaluronate synthesis in a self-assembled human dermal equivalent

Deshpande

Papp

Schaffer

et al. 2013

J Tissue Eng Regen Med

View full text Add to dashboard Cite

Human dermal matrix is a 'self-assembled' dermal equivalent containing large amounts of the glycosaminoglycan hyaluronic acid (hyaluronate, hyaluronan, HA). We sought to investigate the actions of the hormone hydrocortisone on hyaluronate synthesis in the human dermal matrix. To this end, human dermal fibroblasts were cultured under serum-free conditions, and in the absence of a three-dimensional matrix, in the presence of varying amounts of hydrocortisone. The resultant human dermal matrices were characterized. We report that low concentrations of hydrocortisone enhance hyaluronate synthesis in the human dermal equivalent and higher concentrations cause inhibition of hyaluronate synthesis. Other glycosaminoglycan (chondroitin sulphate) synthesis is not affected by changing hydrocortisone concentrations up to 500× (200 µg/ml) of the base value. In order to gain preliminary insight into the molecular mechanism of hyaluronate inhibition, a differential gene array analysis was conducted of human dermal matrix grown in the presence of 200 µg/ml hydrocortisone and in a physiological concentration (0.4 µg/ml, normal conditions). The results of these experiments demonstrate the differential expression of 43 genes in the 500× (200 µg/ml) hydrocortisone construct as compared to the construct grown under normal conditions (0.4 µg/ml hydrocortisone). These preliminary experiments suggest that hydrocortisone at higher concentrations may exert its inhibitory effect on hyaluronate synthesis early in the glycolytic pathway, leading to HA biosynthesis by downregulation of phosphoglucomutase and glucose phosphate isomerase, possibly leading to depletion of the cellular pool of UDP-sugar precursors necessary for HA synthesis. Copyright © 2013 John Wiley & Sons, Ltd.

show abstract

Mannose Inhibits Hyaluronan Synthesis by Down-regulation of the Cellular Pool of UDP-N-acetylhexosamines

Cited by 61 publications

References 54 publications

Cellular Content of UDP-N-acetylhexosamines Controls Hyaluronan Synthase 2 Expression and Correlates with O-Linked N-Acetylglucosamine Modification of Transcription Factors YY1 and SP1

Cellular Content of UDP-N-acetylhexosamines Controls Hyaluronan Synthase 2 Expression and Correlates with O-Linked N-Acetylglucosamine Modification of Transcription Factors YY1 and SP1

The role of hyperglycemia‐evoked intracellular hyaluronan accumulation and its activity on the autophagic and endoplasmic reticulum stress pathways

Hydrocortisone effect on hyaluronate synthesis in a self-assembled human dermal equivalent

Contact Info

Product

Resources

About