81 research outputs found
Identification of bloodâprotein carriers of the CA 19â9 antigen and characterization of prevalence in pancreatic diseases
The current best serum marker for pancreatic cancer, CA 19â9, detects a carbohydrate antigen on multiple protein carriers. Better knowledge of the protein carriers of the CA 19â9 antigen in various disease states may lead to improved diagnostic tests. To identify proteins that carry the CA 19â9 antigen, we immunoprecipitated the CA 19â9 antigen from pooled sera and identified the associated proteins using MS. Among the highâconfidence identifications, we confirmed the presence of the CA 19â9 antigen on Apolipoprotein Bâ100 by antibody arrays and Western blot and on kininogen, ARVCF, and Apolipoprotein E by antibody arrays. We characterized the frequency and levels of the CA 19â9 antigen on the four proteins across various patient groups (pancreatic cancer, pancreatitis, and healthy controls) using antibody arrays. Nearly, 10â25% of the subjects showed elevations of the antigen on each protein, but the elevations were not associated with disease state or total CA 19â9 levels. These results contribute to our knowledge of the carrier proteins of an important functional glycan and the rate at which the glycan is displayed. This work also demonstrates a strategy for using the complementary methods of MS and antibody microarrays to identify protein carriers of glycans and assess the diagnostic value of measuring glycans on individual proteins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87153/1/pmic_201000827_sm_SupplInfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/87153/2/3665_ftp.pd
Analysis of the proximal promoter of the human colon-specific B4GALNT2 (Sda synthase) gene: B4GALNT2 is transcriptionally regulated by ETS1
13siopenBackground: The Sda antigen and corresponding biosynthetic enzyme B4GALNT2 are primarily expressed in normal colonic mucosa and are down-regulated to a variable degree in colon cancer tissues. Although their expression profile is well studied, little is known about the underlying regulatory mechanisms. Methods: To clarify the molecular basis of Sda expression in the human gastrointestinal tract, we investigated the transcriptional regulation of the human B4GALNT2 gene. The proximal promoter region was delineated using luciferase assays and essential trans-acting factors were identified through transient overexpression and silencing of several transcription factors. Results: A short cis-regulatory region restricted to the â72 to +12 area upstream of the B4GALNT2 short-type transcript variant contained the essential promoter activity that drives the expression of the human B4GALNT2 regardless of the cell type. We further showed that B4GALNT2 transcriptional activation mostly requires ETS1 and to a lesser extent SP1. Conclusions: Results presented herein are expected to provide clues to better understand B4GALNT2 regulatory mechanisms.openWavelet-Vermuse C.; Groux-Degroote S.; Vicogne D.; Cogez V.; Venturi G.; Trinchera M.; Brysbaert G.; Krzewinski-Recchi M.-A.; Bachir E.H.; Schulz C.; Vincent A.; Van Seuningen I.; Harduin-Lepers A.Wavelet-Vermuse, C.; Groux-Degroote, S.; Vicogne, D.; Cogez, V.; Venturi, G.; Trinchera, M.; Brysbaert, G.; Krzewinski-Recchi, M. -A.; Bachir, E. H.; Schulz, C.; Vincent, A.; Van Seuningen, I.; Harduin-Lepers, A
Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors
Alterations in sphingosine kinase activity change the degradation rates of Rhodopsin and the transient receptor potential (TRP) channel by lysosomes and can result in retinal degeneration
Cancer-Associated Glycosphingolipids as Tumor Markers and Targets for Cancer Immunotherapy
Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on adoptive cellular therapy with T cells engineered to express chimeric antigen receptors
Gangliosphingolipids:Structure and Biological Roles
International audienc
Gangliosides: The Double-Edge Sword of Neuro-Ectodermal Derived Tumors
International audienc
Les mécanismes de régulation de la glycosylation
La glycosylation est lâune des modifications essentielles des protĂ©ines et des lipides. Elle sâeffectue principalement dans le rĂ©ticulum endoplasmique et lâappareil de Golgi et fait appel Ă une machinerie molĂ©culaire spĂ©cifique, associant plusieurs centaines de glycosyltransfĂ©rases, de glycosidases, de transporteurs et de protĂ©ines rĂ©gulatrices. Des modifications de la glycosylation sont retrouvĂ©es dans certaines maladies, notamment dans les cancers. Ces altĂ©rations peuvent affecter toutes les formes de glycosylation rĂ©ticulaires et/ou golgiennes, et conduire Ă des dysfonctionnements du mĂ©tabolisme cellulaire. Dans cette revue, nous prĂ©sentons lâĂ©tat actuel des connaissances des mĂ©canismes de la glycosylation. Nous illustrerons, au travers dâexemples reprĂ©sentatifs, comment lâaltĂ©ration de certains de ces mĂ©canismes de rĂ©gulation peut affecter les diffĂ©rentes formes de glycosylation des protĂ©ines et des lipides et participer au dĂ©veloppement des cancers
Role of GD3 Synthase ST8Sia I in Cancers
GD3 synthase controls the biosynthesis of complex gangliosides, bearing two or more sialic acid residues. Disialylated gangliosides GD3 and GD2 are tumor-associated carbohydrate antigens (TACA) in neuroâectoderm-derived cancers, and are directly involved in cell malignant properties, i.e., migration, invasion, stemness, and epithelialâmesenchymal transition. Since GD3 and GD2 levels are directly linked to GD3 synthase expression and activity, targeting GD3 synthase appears to be a promising strategy through which to interfere with ganglioside-associated malignant properties. We review here the current knowledge on GD3 synthase expression and regulation in cancers, and the consequences of complex ganglioside expression on cancer cell signaling and properties, highlighting the relationships between GD3 synthase expression and epithelialâmesenchymal transition and stemness. Different strategies were used to modulate GD3 synthase expression in cancer cells in vitro and in animal models, such as inhibitors or siRNA/lncRNA, which efficiently reduced cancer cell malignant properties and the proportion of GD2 positive cancer stem cells, which are associated with high metastatic properties, resistance to therapy, and cancer relapse. These data show the relevance of targeting GD3 synthase in association with conventional therapies, to decrease the number of cancer stem cells in tumors
Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer
Glycosylation is one of the most important modifications of proteins and lipids, and cell surface glycoconjugates are thought to play important roles in a variety of biological functions including cell-cell and cell-substrate interactions, bacterial adhesion, cell immunogenicity and cell signaling. Alterations of glycosylation are observed in number of diseases such as cancer and chronic inflammation. In that context, pro-inflammatory cytokines have been shown to modulate cell surface glycosylation by regulating the expression of glycosyltransferases involved in the biosynthesis of carbohydrate chains. These changes in cell surface glycosylation are also known to regulate cell signaling and could contribute to disease pathogenesis. This review summarizes our current knowledge of the glycosylation changes induced by pro-inflammatory cytokines, with a particular focus on cancer and cystic fibrosis, and their consequences on cell interactions and signaling
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