Focus on Molecules: human mucin MUC16.
Ontology highlight
ABSTRACT:
SUBMITTER: Perez BH
PROVIDER: S-EPMC2586928 | biostudies-literature | 2008 Nov
REPOSITORIES: biostudies-literature
Publications
Focus on Molecules: human mucin MUC16.
Perez Beatriz H BH Gipson Ilene K IK
Experimental eye research 20080103 5
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Project description:Lacritin targets its coreceptor 'syndecan-1' in lacritin-dependent production of the important dry eye mucin 'MUC16'. Real-time PCR analysis suggests that this effect is post-transcriptional. In contrast, serum stimulation of MUC16 by these cells is transcriptionally dependent. Our goal is to determine whether this regulation is global to other heavily O-glycosylated proteins, and if so, if it is dependent on transcription of a Golgi glycosyltransferases. If not, the mechanism might be microRNA dependent. Among other glycogenes, expression of heparanases, sulfotransferases and epimerase are also of interest. Heparanase is required for lacritin binding to its co-receptor syndecan-1 and this binding site may require a sulfated iduronic acid. In request 1705, we recently asked core D whether they could generate this sulfate iduronic acid-containing glycan (iduronic acid (2-O-sulfated)-N-acetylglucosamine-glucuronic acid-N-acetylglucosamine-[glucuronic acid-N-acetylglucosamine]5-glucuronic acid-galactose-galactose-SERINE) to test as a competitive inhibitor in binding studies. Our experiment is to compare Glyco-gene expression by human corneal epithelial cells in response to cell communication glycoprotein 'lacritin' versus negative control deletion construct 'C-25 lacritin' and versus positive control serum.
2011-09-05 | E-GEOD-31930 | biostudies-arrayexpress
Project description:Lacritin targets its coreceptor 'syndecan-1' in lacritin-dependent production of the important dry eye mucin 'MUC16'. Real-time PCR analysis suggests that this effect is post-transcriptional. In contrast, serum stimulation of MUC16 by these cells is transcriptionally dependent. Our goal is to determine whether this regulation is global to other heavily O-glycosylated proteins, and if so, if it is dependent on transcription of a Golgi glycosyltransferases. If not, the mechanism might be microRNA dependent.
2011-09-06 | GSE31930 | GEO
Project description:Transmembrane mucins are highly O-glycosylated glycoproteins that coat the apical glycocalyx on mucosal surfaces and represent the first line of cellular defense against infection and injury. Relatively low levels of N-glycans are found on transmembrane mucins, and their structure and function remain poorly characterized. We previously reported that carbohydrate-dependent interactions of transmembrane mucins with galectin-3 contribute to maintenance of the epithelial barrier at the ocular surface. Now, using MALDI-TOF mass spectrometry, we report that transmembrane mucin N-glycans in differentiated human corneal epithelial cells contain primarily complex-type structures with N-acetyllactosamine, a preferred galectin ligand. In N-glycosylation inhibition experiments, we find that treatment with tunicamycin and siRNA-mediated knockdown of the Golgi N-acetylglucosaminyltransferase I gene (MGAT1) induce partial loss of both total and cell-surface levels of the largest mucin, MUC16, and a concomitant reduction in glycocalyx barrier function. Moreover, we identified a distinct role for N-glycans in promoting MUC16's binding affinity toward galectin-3 and in causing retention of the lectin on the epithelial cell surface. Taken together, these studies define a role for N-linked oligosaccharides in supporting the stability and function of transmembrane mucins on mucosal surfaces.
| S-EPMC5491790 | biostudies-literature
Project description:The majority of bacterial infections occur across wet-surfaced mucosal epithelia, including those that cover the eye, respiratory tract, gastrointestinal tract and genitourinary tract. The apical surface of all these mucosal epithelia is covered by a heavily glycosylated glycocalyx, a major component of which are membrane-associated mucins (MAMs). MAMs form a barrier that serves as one of the first lines of defense against invading bacteria. While opportunistic bacteria rely on pre-existing defects or wounds to gain entry to epithelia, non opportunistic bacteria, especially the epidemic disease-causing ones, gain access to epithelial cells without evidence of predisposing injury. The molecular mechanisms employed by these non opportunistic pathogens to breach the MAM barrier remain unknown. To test the hypothesis that disease-causing non opportunistic bacteria gain access to the epithelium by removal of MAMs, corneal, conjunctival, and tracheobronchial epithelial cells, cultured to differentiate to express the MAMs, MUCs 1, 4, and 16, were exposed to a non encapsulated, non typeable strain of Streptococcus pneumoniae (SP168), which causes epidemic conjunctivitis. The ability of strain SP168 to induce MAM ectodomain release from epithelia was compared to that of other strains of S. pneumoniae, as well as the opportunistic pathogen Staphylococcus aureus. The experiments reported herein demonstrate that the epidemic disease-causing S. pneumoniae species secretes a metalloproteinase, ZmpC, which selectively induces ectodomain shedding of the MAM MUC16. Furthermore, ZmpC-induced removal of MUC16 from the epithelium leads to loss of the glycocalyx barrier function and enhanced internalization of the bacterium. These data suggest that removal of MAMs by bacterial enzymes may be an important virulence mechanism employed by disease-causing non opportunistic bacteria to gain access to epithelial cells to cause infection.
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Project description:The CA125 assay detects circulating MUC16 and is one of the most widely used cancer biomarkers for the follow-up of ovarian cancer. We previously demonstrated that detection of aberrant cancer-associated glycoforms of MUC16 as well as MUC1 in circulation could improve the yield of these serum assays. Our aim was to refine ovarian cancer biomarkers by detection of aberrant glycoforms (Tn, STn, and T) of MUC16 and MUC1 in ovarian cancer tissue using Proximity Ligation Assays (PLA). We studied two series of serous ovarian tumours, a pilot series of 66 ovarian tumours (27 cystadenomas, 16 borderline tumours and 23 adenocarcinomas) from Centro Hospitalar S. João, Porto and a validation series of 89 ovarian tumours (17 cystadenomas, 25 borderline tumours and 47 adenocarcinomas) from the Portuguese Institute of Oncology Francisco Gentil, Lisbon. PLA reactions for MUC16/Tn, MUC16/STn, MUC1/Tn and MUC1/STn were negative in benign lesions but often positive in borderline and malignant lesions, in both series. An even better yield was obtained based on positivity for any of the four glyco-mucin profiles, further increasing sensitivity to 72% and 83% in the two series, respectively, with 100% specificity. The strategy is designated glyco-mucin profiling and provides strong support for development of PLA-based serum assays for early diagnosis.
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