Specific Protein-1 Is a Universal Regulator of UDP-glucose Dehydrogenase Expression

Bontemps, Yannick; Vuillermoz, Boris; Antonicelli, Frank; Perreau, Corinne; Danan, Jean‐Louis; Maquart, François‐Xavier; Wegrowski, Yanusz

doi:10.1074/jbc.m209366200

Cited by 37 publications

(18 citation statements)

References 57 publications

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“…Fragments 4, 5, and 6 uniformly lack the first 547 bp surrounding and immediately upstream from the transcriptional start site and exhibit substantially lower luciferase activity than does Fragment 3. That finding suggests this span of sequence contains crucial basal promoter elements, consistent with the report of Bontemps et al (15) …”

Section: Divergent Expression Of Ugdh Protein and Mrna In Orbitalsupporting

confidence: 82%

“…The structure of the UGDH gene promoter has been examined previously (14,15). Two transcriptional start sites were mapped to 165 and 325 bp upstream from the AUG initiation codon, in good agreement with the lengths of the two UGDH mRNAs (14,44).…”

Section: Discussionmentioning

confidence: 67%

“…Involvement of Sp1 in UGDH Gene Promoter Activity-Sp1 plays a critical role in UGDH gene expression in HepG2, MRC5, and HeLa cells (14,15,38). The UGDH gene promoter region spanning Ϫ899 to ϩ71 nt (Fragments 2, 3, 7, and 8) contains 6 recognizable Sp1 sites.…”

Section: Divergent Expression Of Ugdh Protein and Mrna In Orbitalmentioning

confidence: 99%

“…Basal UGDH promoter activity in HepG2 and HeLa cells requires Sp1 binding to a GC-rich region located at Ϫ548 nt of this promoter (14). Furthermore, Sp1 binding sites within the first 500 bp of the UGDH promoter are responsible for the up-and down-regulation of this gene caused by TGF-␤ and hypoxia, respectively (15). The absence of either TATA or CAAT sequences in this promoter suggests the potential for Sp1 serving as a particularly important determinant of promoter activity and in defining the transcriptional start site (16).…”

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confidence: 99%

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Divergent Sp1 Protein Levels May Underlie Differential Expression of UDP-Glucose Dehydrogenase by Fibroblasts

Tsui

Fernando

Chen

et al. 2011

Journal of Biological Chemistry

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UDP-glucose dehydrogenase (UGDH) catalyzes the formation of UDP-glucuronate. Glucuronate represents an integral component of the glycosaminoglycan, hyaluronan, which accumulates in orbital Graves disease. Here we report that orbital fibroblasts express higher levels of UGDH than do those from skin. This is a consequence of greater UGDH gene promoter activity and more abundant steady-state UGDH mRNA. Six Sp1 sites located in the proximal 550 bp of the UGDH gene promoter appear to determine basal promoter activity, as does a previously unrecognized 49-bp sequence spanning ؊1436 nucleotides (nt) and ؊1388 nt that negatively affects activity. Nuclear Sp1 protein is more abundant in orbital fibroblasts, and its binding to specific sites on DNA is greater than that in dermal fibroblasts. Mutating each of these Sp1 sites in a UGDH gene promoter fragment, extending from ؊1387 to ؉71 nt and fused to a luciferase reporter, results in divergent activities when transfected in orbital and dermal fibroblasts. Reducing Sp1 attenuated UGDH gene promoter activity, lowered steady-state UGDH mRNA levels, and reduced UGDH enzyme activity. Targeting Sp1 and UGDH with specific siRNAs also lowered hyaluronan synthase-1 (HAS-1) and HAS-2 levels and reduced hyaluronan accumulation in orbital fibroblasts. These findings suggest that orbital fibroblasts express high levels of UGDH in an anatomic-specific manner, apparently the result of greater constitutive Sp1. These high UGDH levels may underlie susceptibility of the orbit to localized overproduction of hyaluronan in Graves disease.

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Section: Divergent Expression Of Ugdh Protein and Mrna In Orbitalsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 67%

Section: Divergent Expression Of Ugdh Protein and Mrna In Orbitalmentioning

confidence: 99%

mentioning

confidence: 99%

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Divergent Sp1 Protein Levels May Underlie Differential Expression of UDP-Glucose Dehydrogenase by Fibroblasts

Tsui

Fernando

Chen

et al. 2011

Journal of Biological Chemistry

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“…collagens such as Col11a2 (19) and Col24a1 (20), proteoglycan core proteins such as biglycan (21,22), decorin (23), glypican-3 (24) or murine glypican-4 (25). Binding sites for Sp1 and AP-1 are also involved in the transcriptional regulation of other enzymes participating in glycosaminoglycan biosynthesis, like UDP-glucose dehydrogenase (26,27). Because XT-I catalyzes the initial step in GAG biosynthesis (3-5) and a similar regulation of genes involved in the same biosynthetic pathway is very probable, an important participation of members of the Sp1 and AP-1 protein family in the regulation of the XYLT1 expression is very likely.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of the Human Xylosyltransferase I Gene Promoter Region

Müller

Prante

Kleesiek

et al. 2009

Journal of Biological Chemistry

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Human xylosyltransferase I catalyzes the initial and rate-limiting step in the biosynthesis of glycosaminoglycans and proteoglycans. Furthermore, this enzyme has been shown to play a major role in the physiological development of bone and cartilage as well as in pathophysiological processes such as systemic sclerosis, dilated cardiomyopathy, or fibrosis. Here, we report for the first time the identification and characterization of the XYLT1 gene promoter region and important transcription factors involved in its regulation. Members of the activator protein 1 (AP-1) and specificity protein 1 (Sp1) family of transcription factors are necessary for the transcriptional regulation of the XYLT1 gene, which was proven by curcumin, tanshinone IIA, mithramycin A, and short interference RNA treatment. A stepwise 5 and 3 deletion of the predicted GCrich promoter region, which lacks a TATA and/or CAAT box, revealed that a 531-bp core promoter element is able to drive the transcription on a basal level. A binding site for transcription factors of the AP-1 family, which is essential for full promoter activity, was identified by site-directed mutagenesis located 730 bp 5 of the translation initiation site. The ability of this site to bind members of the AP-1 family was further verified by electrophoretic mobility shift assays. A promoter element containing this binding site was able to drive the transcription to about 79-fold above control in SW1353 chondrosarcoma cells. Our findings provide a first insight into the regulation of the XYLT1 gene and may contribute to understanding the processes taking place during extracellular matrix formation and remodeling in health and disease.

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UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

et al. 2022

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Metabolic rewiring is one of the indispensable drivers of epithelial–mesenchymal transition (EMT) involved in breast cancer metastasis. In this study, we explored the metabolic changes during spontaneous EMT in three separately established breast EMT cell models using a proteomic approach supported by metabolomic analysis. We identified common proteomic changes, including the expression of CDH1, CDH2, VIM, LGALS1, SERPINE1, PKP3, ATP2A2, JUP, MTCH2, RPL26L1 and PLOD2. Consistently altered metabolic enzymes included the following: FDFT1, SORD, TSTA3 and UDP‐glucose dehydrogenase (UGDH). Of these, UGDH was most prominently altered and has previously been associated with breast cancer patient survival. siRNA‐mediated knock‐down of UGDH resulted in delayed cell proliferation and dampened invasive potential of mesenchymal cells and downregulated expression of the EMT transcription factor SNAI1. Metabolomic analysis revealed that siRNA‐mediated knock‐down of UGDH decreased intracellular glycerophosphocholine (GPC), whereas levels of acetylaspartate (NAA) increased. Finally, our data suggested that platelet‐derived growth factor receptor beta (PDGFRB) signalling was activated in mesenchymal cells. siRNA‐mediated knock‐down of PDGFRB downregulated UGDH expression, potentially via NFkB‐p65. Our results support an unexplored relationship between UGDH and GPC, both of which have previously been independently associated with breast cancer progression.

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Specific Protein-1 Is a Universal Regulator of UDP-glucose Dehydrogenase Expression

Abstract: UDP-glucose dehydrogenase (UGDH) is

Cited by 37 publications

References 57 publications

Divergent Sp1 Protein Levels May Underlie Differential Expression of UDP-Glucose Dehydrogenase by Fibroblasts

Divergent Sp1 Protein Levels May Underlie Differential Expression of UDP-Glucose Dehydrogenase by Fibroblasts

Identification and Characterization of the Human Xylosyltransferase I Gene Promoter Region

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

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