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*
| Autor: | Katri M. Makkonen, Raija Tammi, Sanna Oikari, Elina Koli, Gerald W. Hart, Markku Tammi, Tiina A. Jokela, Riikka Kärnä, Carsten Carlberg |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Keratinocytes
endocrine system Time Factors Sp1 Transcription Factor medicine.medical_treatment Nitrogenous Group Transferases Glycobiology and Extracellular Matrices Biology Hyaluronan Synthase 2 Response Elements Biochemistry Gene Expression Regulation Enzymologic Uridine Diphosphate Acetylglucosamine chemistry.chemical_compound Hyaluronic acid Gene expression medicine Humans Gene Silencing RNA Messenger Glucuronosyltransferase Hyaluronic Acid RNA Small Interfering Molecular Biology Transcription factor YY1 Transcription Factor Glutamine amidotransferase Regulation of gene expression Sp1 transcription factor Growth factor Computational Biology Cell Biology carbohydrates (lipids) chemistry Hyaluronan Synthases Mannose Protein Binding |
| Popis: | 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). Increasing UDP-HexNAc in HaCaT keratinocytes by adding glucosamine down-regulated HAS2 gene expression, whereas a decrease in UDP-HexNAc, realized by mannose treatment or siRNA for GFAT1 (glutamine:fructose-6-phosphate amidotransferase 1), enhanced expression of the gene. Tracing the UDP-HexNAc-initiated signal to the HAS2 promoter revealed no change in the binding of STAT3, NF-κB, and cAMP response element-binding protein, shown previously to mediate growth factor and cytokine signals on HAS2 expression. Instead, altered binding of SP1 and YY1 to the promoter correlated with cellular UDP-HexNAc content and inhibition of HAS2 expression. siRNA silencing of YY1 and SP1 confirmed their inhibitory effects on HAS2 expression. Reduced and increased levels of O-GlcNAc-modified SP1 and YY1 proteins were associated with stimulation or inhibition of HAS2 expression, respectively. Our data are consistent with the hypothesis that, by regulating the level of protein O-GlcNAc modifications, cellular UDP-HexNAc content controls HAS2 transcription and decreases the effects on hyaluronan synthesis that would result from cellular fluctuations of this substrate. |
| Databáze: | OpenAIRE |
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