Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we reported the development of sugar-assisted ligation (SAL), a novel peptide ligation method for the synthesis of glycopeptides. After screening a large number of glycoprotein sequences in a glycoprotein database, it became evident that a large proportion (approximately 53%) of O-glycosylation sites contain amino acid residues that will not undergo SAL reactions. To overcome these inherent limitations and broaden the scope of the method we report here the development of an extended SAL method. Glycopeptides containing up to six amino acid extensions N-terminal to the glycosylated residue were shown to facilitate ligation reactions with peptide thioesters, and these products were isolated in good yields. Kinetic analysis was used to show that as glycopeptides were extended by further amino acid residues, ligation reactions became slower. This finding was rationalized by molecular dynamics simulations using AMBER9. These studies suggested a general trend whereby the proximal distance between the reactive sites of the thioester intermediate (the N-terminal amine and the carbonyl carbon of the thioester) increased as glycopeptides were extended, thus slowing down the ligation rate. Each of the extended SAL methods showed broad tolerance to a number of different amino acid combinations at the ligation junction. Re-evaluation of the glycoprotein database suggested that 95% of the O-linked glycosylation sites can now be utilized to facilitate SAL or extended SAL reactions. As such, this method represents an extremely valuable tool for the synthesis of naturally occurring glycopeptides and glycoproteins. To demonstrate the applicability of the method, extended SAL was successfully implemented in the synthesis of the starting unit of the cancer-associated MUC1 glycoprotein.
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PMID:Extended sugar-assisted glycopeptide ligations: development, scope, and applications. 1793 27

The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5' end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms ofMUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5' exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, over-representation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well.
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PMID:Genetic regulation of MUC1 alternative splicing in human tissues. 1923 35

Adhesion of circulating tumor cells to the blood vessel endothelium is a critical step in cancer metastasis. We show in this study that galectin-3, the concentration of which is greatly increased in the circulation of cancer patients, increases cancer cell adhesion to macrovascular and microvascular endothelial cells under static and flow conditions, increases transendothelial invasion, and decreases the latency of experimental metastasis in athymic mice. These effects of galectin-3 are shown to be a consequence of its interaction with cancer-associated MUC1, which breaks the "protective shield" of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 and ligand(s) for E-selectin. Thus, the interaction in the bloodstream of cancer patients between circulating galectin-3 and cancer cells expressing MUC1 bearing the galectin-3 ligand TF (Galbeta1,3GalNAc-) promotes metastasis. This provides insight into the molecular regulation of metastasis and has important implications for the development of novel therapeutic strategies for prevention of metastasis.
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PMID:Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. 1969 Jan 36

Altered glycosylation on the surfaces or secreted proteins of tumor cells is common in pancreatic cancer and is thought to promote cancer progression, but the factors leading to the changes in carbohydrate structures are incompletely understood. We hypothesized that pro-inflammatory conditions can lead to alterations in cancer-associated glycans on mucins produced by pancreatic-cancer cells. With the use of a novel antibody-glycan microarray method, we measured the effects of pro-inflammatory stimuli (oxidative stress and treatment with the cytokines IFNgamma, IL-1alpha, and TNFalpha) on the expression and glycosylation of the mucins MUC1, MUC5AC, and MUC16 in multiple pancreatic cancer cell lines. Mucin glycosylation was significantly affected in specific cell lines, particularly in structures involving terminal galactose or N-acetylgalactosamine. In addition, the responses of the cell lines grouped according to the expression of cell-surface markers that are associated with tumorigenicity, as cell lines bearing minimal surface markers, showed evidence of increased O-glycan extension and decreased presentation of terminal beta1,4-linked galactose, opposite to cell lines bearing multiple markers. These results suggest mechanisms whereby inflammation might influence tumor behavior in a cell-type specific manner through modulating the presentation of cancer-associated glycans.
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PMID:Mucin glycosylation is altered by pro-inflammatory signaling in pancreatic-cancer cells. 1971 13

Autoantibodies to cancer antigens hold promise as biomarkers for early detection of cancer. Proteins that are aberrantly processed in cancer cells are likely to present autoantibody targets. The extracellular mucin MUC1 is overexpressed and aberrantly glycosylated in many cancers; thus, we evaluated whether autoantibodies generated to aberrant O-glycoforms of MUC1 might serve as sensitive diagnostic biomarkers for cancer. Using an antibody-based glycoprofiling ELISA assay, we documented that aberrant truncated glycoforms were not detected in sera of cancer patients. An O-glycopeptide microarray was developed that detected IgG antibodies to aberrant O-glycopeptide epitopes in patients vaccinated with a keyhole limpet hemocyanin-conjugated truncated MUC1 peptide. We detected cancer-associated IgG autoantibodies in sera from breast, ovarian, and prostate cancer patients against different aberrent O-glycopeptide epitopes derived from MUC1. These autoantibodies represent a previously unaddressed source of sensitive biomarkers for early detection of cancer. The methods we have developed for chemoenzymatic synthesis of O-glycopeptides on microarrays may allow for broader mining of the entire cancer O-glycopeptidome.
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PMID:Cancer biomarkers defined by autoantibody signatures to aberrant O-glycopeptide epitopes. 2012 78

Chimeras of poly(n-isopropyl acrylamide) and immunogenic peptides from the cancer-associated glycoprotein MUC1 were synthesised using a combination of solid-phase peptide synthesis, RAFT polymerisation and copper-catalysed alkyne-azide cycloaddition reactions.
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PMID:Polymer-peptide chimeras for the multivalent display of immunogenic peptides. 2023 1

MUC1 is a cell-surface, epithelial glycoprotein that forms an essential protective barrier of cells and serves to modulate intercellular communication. During cancer progression, the dysregulation of glycosyltransferases, which serve to elongate cell-surface glycans, leads to aberrant gIycosylation patterns on this glycoprotein. This results in the presentation of well-characterized, tumor-associated carbohydrate antigens (TACAs) which represent important biomarkers for a range of epithelial cancers. The synthesis of well-defined, multivalent MUC1 glycopeptide constructs bearing TACAs therefore represents a viable opportunity for the development of cancer vaccine candidates. We report herein the synthesis of a glycopeptide thioester, comprising the full eicosapeptide variable number tandem repeat (VNTR) region of MUC1, which was prepared bearing multiple copies of the cancer-associated TN antigen. The glycopeptide thioester was prepared on the solid-phase using two different methods on 2-chlorotrityl chloride and sulfamylbutyryl resins. The solid-phase assembly on 2-chlorotrityl chloride resin, followed by thioesterification in solution, afforded the desired thioester in 4% yield over 41 linear steps. Likewise, the glycopeptide thioester was successfully prepared on sulfamylbutyryl resin using an activation and thiol-release strategy in a 9% isolated yield. The resulting peptide thioester was successfully ligated to a deprotected MUC1 glycopeptide using the direct aminolysis ligation to afford a 5.8 kDa, 40 amino acid MUC1 glycopeptide bearing 10 copies of the T(N) antigen. This work represents an important step toward the immunological evaluation of multivalent MUC1 constructs.
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PMID:Synthesis of MUC1 glycopeptide thioesters and ligation via direct aminolysis. 2056 42

Chronic inflammation plays an important role in the initiation and progression of various human diseases including benign prostatic hyperplasia or prostate cancer. Here we show that the proinflammatory cytokine interleukin-6 (IL-6) has prosurvival effects and chronically activates the Jak2/STAT3 signalling pathway in a model of benign prostatic hyperplasia (BPH-1). We demonstrate that the antiinflammatory cytokine transforming growth factor-beta1 (TGF-beta1), which also permanently activates its canonical signalling pathway through SMAD proteins in BPH-1 cells, modifies the effects of IL-6 on cell proliferation. Importantly, TGF-beta1 inhibits IL-6 signal transduction by decreasing the phosphorylation levels of STAT3. This effect is associated with decreased expression of Jak2 at both mRNA and protein levels. Moreover, we showed that TGF-beta1 inhibits IL-6-induced expression of the cancer-associated gene MUC1. These observations demonstrated a novel interaction between TGF-beta1 and IL-6 signalling and suggested another mechanism of how defects in TGF-beta signalling, frequently associated with prostate pathologies, can contribute to the disruption of tissue homeostasis.
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PMID:TGF-beta1 suppresses IL-6-induced STAT3 activation through regulation of Jak2 expression in prostate epithelial cells. 2060 12

Cancer-associated autoantibodies hold promise as sensitive biomarkers for early detection of cancer. Aberrant post-translational variants of proteins are likely to induce autoantibodies, and changes in O-linked glycosylation represent one of the most important cancer-associated post-translational modifications (PTMs). Short aberrant O-glycans on proteins may introduce novel glycopeptide epitopes that can elicit autoantibodies because of lack of tolerance. Technical barriers, however, have hampered detection of such glycopeptide-specific autoantibodies. Here, we have constructed an expanded glycopeptide array displaying a comprehensive library of glycopeptides and glycoproteins derived from a panel of human mucins (MUC1, MUC2, MUC4, MUC5AC, MUC6 and MUC7) known to have altered glycosylation and expression in cancer. Seromic profiling of patients with colorectal cancer identified cancer-associated autoantibodies to a set of aberrant glycopeptides derived from MUC1 and MUC4. The cumulative sensitivity of the array analysis was 79% with a specificity of 92%. The most prevalent of the identified autoantibody targets were validated as authentic cancer immunogens by showing expression of the epitopes in cancer using novel monoclonal antibodies. Our study provides evidence for the value of glycopeptides and other PTM-peptide arrays in diagnostic measures.
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PMID:Seromic profiling of colorectal cancer patients with novel glycopeptide microarray. 2181 98

Sialyl-Tn is a simple mucin-type carbohydrate antigen aberrantly expressed in gastrointestinal adenocarcinomas and in the precursor lesion intestinal metaplasia. Sialyl-Tn tumour expression is an independent indicator of poor prognosis. We have previously shown in vitro that ST6GalNAc-I and ST6GalNAc-II sialyltransferases can synthesize sialyl-Tn. The aim of the present study was to establish whether ST6GalNAc-I is the major enzyme responsible for the expression of sialyl-Tn. We used a model of CHO-ldlD cells producing only MUC1-Tn glycoform and showed that ST6GalNAc-I is the key-enzyme leading to sialyl-Tn biosynthesis. We developed novel monoclonal antibodies specific for ST6GalNAc-I and evaluated its expression in gastrointestinal tissues. ST6GalNAc-I was detected in normal colon mucosa co-localized with O-acetylated sialyl-Tn. Expression was largely unaltered in colorectal adenocarcinomas. In contrast, we found that ST6GalNAc-I is weakly expressed in normal gastric mucosa, but over-expressed in intestinal metaplasia, co-localized with sialyl-Tn. In gastric carcinomas ST6GalNAc-I was also associated with sialyl-Tn, but with heterogeneous staining and partial co-localization. Our results showed ST6GalNAc-I as the major enzyme controlling the expression of cancer-associated sialyl-Tn antigen in gastrointestinal tissues.
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PMID:ST6GalNAc-I controls expression of sialyl-Tn antigen in gastrointestinal tissues. 2162 48


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