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Sökning: WFRF:(Fransson Lars Åke)

  • Resultat 1-10 av 48
  • [1]2345Nästa
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1.
  • Lofgren, Kajsa, et al. (författare)
  • Involvement of glypican-1 autoprocessing in scrapie infection
  • 2008
  • Ingår i: European Journal of Neuroscience. - : Wiley-Blackwell. - 1460-9568. ; 28:5, s. 964-972
  • Tidskriftsartikel (refereegranskat)abstract
    • The copper-binding cellular prion protein (PrPC) and the heparan sulphate (HS)-containing proteoglycan glypican-1 (Gpc-1) can both be attached to lipid rafts via their glycosylphosphatidylinositol anchors, and copper ions stimulate their cointernalization from the cell surface to endosomes. The prion protein controls cointernalization and delivers copper necessary for S-nitrosylation of conserved cysteines in the Gpc-1 core protein. Later, during recycling through endosomal compartments, nitric oxide can be released from the S-nitroso groups and catalyses deaminative degradation and release of the HS substituents. Here, by using confocal immunofluorescence microscopy, we show that normal PrPC and Gpc-1 colocalize inside GT1-1 cells. However, in scrapie-infected cells (ScGT1-1), Gpc-1 protein remained at the cell surface separate from the cellular prion protein. Scrapie infection stimulated Gpc-1 autoprocessing and the generated HS degradation products colocalized with intracellular aggregates of the disease-related scrapie prion protein isoform (PrPSc). Coimmunoprecipitation experiments demonstrated an association between Gpc-1 and PrPC in uninfected cells, and between HS degradation products and PrPSc in infected cells. Silencing of Gpc-1 expression or prevention of Gpc-1 autoprocessing elevated the levels of intracellular PrPSc aggregates in infected cells. These results suggest a role for Gpc-1 autoprocessing in the clearance of PrPSc from infected cells.
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2.
  • Cöster, Lars, et al. (författare)
  • Structure of proteoheparan sulfates from fibroblasts. Confluent and proliferating fibroblasts produce at least three types of proteoheparan sulfates with functionally different core proteins
  • 1986
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 1083-351X. ; 261:26, s. 12079-12088
  • Tidskriftsartikel (refereegranskat)abstract
    • [3H]Leucine- and [35S]sulfate-labeled proteoheparan sulfates were isolated from postconfluent or proliferating cultures of human skin fibroblasts. Cell layers were solubilized by Triton X-100, and transferrin-binding macromolecules were isolated by affinity chromatography. Proteoglycans with no affinity for transferrin were purified by using ion-exchange and gel permeation chromatography. Postconfluent cells synthesize a proteoheparan sulfate of Mr 350,000 (as determined by gel permeation chromatography) which has affinity for transferrin as well as for octyl-Sepharose. Its core protein (Mr 180,000) consists of two disulfide-bonded polypeptides of Mr 90,000. This species was not detected in cultures of proliferating cells. Proliferating and confluent cells also synthesize other forms of proteoheparan sulfates (Mr 200,000-400,000) which have no affinity for transferrin. However, most of them have affinity for octyl-Sepharose. The core protein of proteoheparan sulfates made by proliferating cells has Mr 50,000. A smaller form (Mr 250,000) of this proteoglycan was solubilized by Triton X-100, whereas a larger form (Mr 400,000) remained associated with the pericellular matrix. A third type of proteoheparan sulfate (Mr 200,000) without affinity for transferrin nor octyl-Sepharose was associated with postconfluent cell layers but not with proliferating ones. Its core protein has Mr 35,000. Heparan sulfate oligosaccharides (Mr 6,000 or higher) were found in proliferating cells but not in postconfluent ones.
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3.
  • Fransson, Lars-Åke, et al. (författare)
  • Oligosaccharide mapping of proteoglycan-bound and xyloside-initiated dermatan sulfate from fibroblasts
  • 1991
  • Ingår i: Glycoconjugate Journal. - : Springer. - 1573-4986. ; 8:2, s. 108-115
  • Tidskriftsartikel (refereegranskat)abstract
    • The copolymeric structure of dermatan sulfate chains synthesized by skin fibroblasts has been examined. Chains initiated onto exogeneous p-nitrophenyl-beta-D-xylopyranoside or attached to protein in a large proteoglycan, PG-L, and two small proteoglycans, PG-S1 and PG-S2, have been compared by using high resolution electrophoresis and gel chromatography of oligosaccharides generated by specific enzymatic or chemical degradations. The results confirm that chains attached to PG-L are glucuronate-rich, whereas novel findings indicate that chains attached to either of the two PG-S variants yield closely similar oligosaccharide maps, have approximately equal glucuronate and iduronate content and contain over 90% 4-sulfated disaccharide repeating units. Dermatan sulfate chains built onto xyloside at concentrations of 50 microM and below have a copolymeric structure similar to that of chains from the two PG-S variants. These findings indicate that the polymer-modifying machinery can generate chains with extended iduronate-containing repeats also when the xylose primer is not linked to core protein.
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4.
  • Jönsson, Mats, et al. (författare)
  • Initiation of the decorin glycosaminoglycan chain in the endoplasmic reticulum-Golgi intermediate compartment
  • 2003
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 1083-351X. ; 278:24, s. 21415-21420
  • Tidskriftsartikel (refereegranskat)abstract
    • We have transiently expressed decorin with a C- terminal KDEL endoplasmic reticulum retention signal peptide in COS- 7 cells to study initiation of galactosaminoglycan synthesis in the endoplasmic reticulum- Golgi intermediate compartment. All decorin- KDEL molecules were substituted with N- linked oligosaccharides sensitive to endoglycosidase H, indicating that the core protein was located proximal to the medial- Golgi. O-Linked glycosylation was only initiated in a minor fraction of the molecules. The O- linked saccharides were characterized by gel filtration after stepwise degradations using chondroitin ABC/ AC-I lyases, beta1 - 3- glycuronidase, beta-galactosidase, and alkaline phosphatase. The major O- linked saccharide was the linkage region pentasaccharide GalNAcbeta1-4GlcUAbeta1-3Galbeta1-3Galbeta1-4-Xyl- 2- phosphate, demonstrating initiation of chondroitin synthesis in the endoplasmic reticulum- Golgi intermediate compartment. In the presence of brefeldin A, partial elongation of a chondroitin chain took place, indicating retrieval of polymerases but not of sulfotransferases.
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5.
  • Aili, Ulrika, et al. (författare)
  • Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.
  • 2010
  • Ingår i: Cancer Research. - : American Association for Cancer Research Inc.. - 1538-7445. ; 70:9, s. 3771-3779
  • Tidskriftsartikel (refereegranskat)abstract
    • Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy.
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6.
  • Belting, Mattias, et al. (författare)
  • Glypican-1 is a vehicle for polyamine uptake in mammalian cells. A pivotal role for nitrosothiol-derived nitric oxide.
  • 2003
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 1083-351X. ; 278:47, s. 47181-47189
  • Tidskriftsartikel (refereegranskat)abstract
    • Polyamines (putrescine, spermidine, and spermine) are essential for growth and survival of all cells. When polyamine biosynthesis is inhibited, there is up-regulation of import. The mammalian polyamine transport system is unknown. We have previously shown that the heparan sulfate (HS) side chains of recycling glypican-1 (Gpc-1) can sequester spermine, that intracellular polyamine depletion increases the number of NO-sensitive N-unsubstituted glucosamines in HS, and that NO-dependent cleavage of HS at these sites is required for spermine uptake. The NO is derived from S-nitroso groups in the Gpc-1 protein. Using RNA interference technology as well as biochemical and microscopic techniques applied to both normal and uptake-deficient cells, we demonstrate that inhibition of Gpc-1 expression abrogates spermine uptake and intracellular delivery. In unperturbed cells, spermine and recycling Gpc-1 carrying HS chains rich in N-unsubstituted glucosamines were co-localized. By exposing cells to ascorbate, we induced release of NO from the S-nitroso groups, resulting in HS degradation and unloading of the sequestered polyamines as well as nuclear targeting of the deglycanated Gpc-1 protein. Polyamine uptake-deficient cells appear to have a defect in the NO release mechanism. We have managed to restore spermine uptake partially in these cells by providing spermine NONOate and ascorbate. The former bound to the HS chains of recycling Gpc-1 and S-nitrosylated the core protein. Ascorbate released NO, which degraded HS and liberated the bound spermine. Recycling HS proteoglycans of the glypican-type may be plasma membrane carriers for cargo taken up by caveolar endocytosis.
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10.
  • Belting, Mattias, et al. (författare)
  • Tumor attenuation by combined heparan sulfate and polyamine depletion.
  • 2002
  • Ingår i: Proceedings of the National Academy of Sciences. - : National Acad Sciences. - 1091-6490. ; 99:1, s. 371-376
  • Tidskriftsartikel (refereegranskat)abstract
    • Cells depend on polyamines for growth and their depletion represents a strategy for the treatment of cancer. Polyamines assemble de novo through a pathway sensitive to the inhibitor, alpha-difluoromethylornithine (DFMO). However, the presence of cell-surface heparan sulfate proteoglycans may provide a salvage pathway for uptake of circulating polyamines, thereby sparing cells from the cytostatic effect of DFMO. Here we show that genetic or pharmacologic manipulation of proteoglycan synthesis in the presence of DFMO inhibits cell proliferation in vitro and in vivo. In cell culture, mutant cells lacking heparan sulfate were more sensitive to the growth inhibitory effects of DFMO than wild-type cells or mutant cells transfected with the cDNA for the missing biosynthetic enzyme. Moreover, extracellular polyamines did not restore growth of mutant cells, but completely reversed the inhibitory effect of DFMO in wild-type cells. In a mouse model of experimental metastasis, DFMO provided in the water supply also dramatically diminished seeding and growth of tumor foci in the lungs by heparan sulfate-deficient mutant cells compared with the controls. Wild-type cells also formed tumors less efficiently in mice fed both DFMO and a xylose-based inhibitor of heparan sulfate proteoglycan assembly. The effect seemed to be specific for heparan sulfate, because a different xyloside known to affect only chondroitin sulfate did not inhibit tumor growth. Hence, combined inhibition of heparan sulfate assembly and polyamine synthesis may represent an additional strategy for cancer therapy.
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