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)

The human MUC1 gene codes for the core protein of a mucin which is expressed by glandular epithelia and the carcinomas which develop from these tissues. The core protein is aberrantly glycosylated in cancers, and some antibodies show specificity in their reactions with the cancer-associated mucin, which also contains epitopes recognized by T-cells from breast and pancreatic cancer patients. For evaluating the potential use of mucin-reactive antibodies and mucin-based immunogens in cancer patients, a mouse model, expressing the MUC1 gene product PEM (polymorphic epithelial mucin) as a self antigen, would be extremely useful. To this end, we have developed transgenic mouse strains expressing the human MUC1 gene product in a tissue-specific manner. The TG4 mouse strain was established using a 40-kilobase fragment containing 4.5 kilobases of 5' and 27 kilobases of 3' flanking sequence. The TG18 strain was developed using a 10.6-kilobase SacII fragment from the 40-kilobase fragment; this fragment contained 1.6 kilobases of 5' sequence and 1.9 kilobases of 3' flanking sequence. Both strains showed tissue specificity of expression of the MUC1 gene, which was very similar to the profile of expression seen in human tissues. The antibody SM-3 is directed to a core protein epitope, which is selectively exposed in breast cancers and which shows a more restricted distribution on normal human tissues. It was established that the distribution of the SM-3 epitope of PEM in the tissues of the transgenic mice is similar to that seen in humans. The transgenic mouse strains described here should form the basis for the development of a preclinical model for the evaluation of PEM-based antigens and of antibodies directed to PEM in cancer therapy.
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PMID:Tissue-specific expression of a human polymorphic epithelial mucin (MUC1) in transgenic mice. 137 33

Pancreatic and mammary cancer cells are reported to have different oligosaccharides on the same apomucin, the MUCI gene product. A better understanding of the tissue specificity of these sugar structures may help in identifying the source of mucins when they are found in the sera. Serum levels of 3 pancreatic-cancer-associated carbohydrate epitopes identified by monoclonal antibodies (MAbs) SPan-1, 19-9 and DU-PAN-2, were compared to those of CA15-3 in a variety of malignant conditions. CA15-3 identifies both carbohydrate and peptide determinants associated with the MUC1 apomucin in breast tissues. SPan-1 antigen was elevated in a high percentage of patients with pancreatic, gastric and colorectal cancer but in only a few of the patients with malignancies of non-GI origin such as breast, ovary and lung. The 19-9 and DU-PAN-2 antigens had a similar pattern of much greater sensitivity for pancreatic cancer than for these non-gastrointestinal cancers. The levels of these 3 markers showed significant correlations in pancreatic cancer. In contrast, CA15-3 was elevated in a large number of patients with breast, lung, ovarian and pancreatic cancers. There was no correlation of CA15-3 with the 3 other markers in pancreatic cancer. SPan-1 and DF3/115D8 antigens in blood have different mobilities in SDS-PAGE and buoyant densities. Moreover, SPan-1 and DF3 antigenic determinants are localized in different regions of the same normal and malignant pancreas and breast tissues. Thus the SPan-1 determinant can be dissociated from the breast peptide and/or carbohydrate determinants.
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PMID:Differences in expression of SPan-1 and CA15-3 antigens in blood and tissues. 142 28

Although mucins have been studied at the biochemical and biophysical level for some time, attempts to define their structures in detail were only partially successful because of their size and complexity. The advent of monoclonal antibodies reactive with these molecules introduced a new approach to structural studies by defining antigenic epitopes, by allowing purification of the mucin molecules by affinity chromatography, and by providing a means to clone genes coding for the core proteins. By their profile of reactivity with the normal and cancer-associated mucin in a particular tissue, the antibodies also defined a difference in the mucin derived from the two sources. It is now clear that this difference lies in the carbohydrate side chains, as the core proteins are identical. Because the mucins are tumor-associated antigens and the cancer mucins can express epitopes that are relatively tumor specific, this family of molecules is now being intensively studied. There is also considerable interest in elucidating the normal function of the mucin and in determining whether, through an altered structure, this function is subverted in malignancy. In the next few years we should expect that the structure of other mucins will be defined in the same detail as the product of the MUC1 gene. We should also expect to see the continued application of mucin-reactive antibodies in the clinic and the investigation of mucins as agents for immunotherapy of some cancers. As to the function(s) of these molecules, perhaps we will learn enough in the future to make a critical reappraisal of the name.
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PMID:Structure and biology of a carcinoma-associated mucin, MUC1. 189 26

As a result of aberrant glycosylation, cancer-associated mucins expose to the immune system certain carbohydrate, peptide, and possibly glycopeptide epitopes that are not exposed on the normal mucins. This provides the basis for our development of synthetic carbohydrate, peptide, and glycopeptide-based ASI agents corresponding to the cancer-associated mucin epitopes. Our studies on ASI formulations based on carbohydrate structures such as TF and STn have demonstrated their ability to induce immune response relevant to the native epitopes on the cancer cells in animal models and in cancer patients. Further, such immune responses were able to mediate cancer rejection in an animal model. Similar studies on peptide epitopes of a cancer-associated mucin, MUC1, have also shown the ability of the synthetic antigen to induce anticancer immune responses in an animal model. Ongoing studies on the carbohydrate and peptide epitopes would allow us to define the most important target structures on cancer-associated mucins that can selectively stimulate cancer-specific immune responses. Our long-term goal is to develop multiepitopic glycopeptide ASI formulations capable of stimulating strong CMI responses against common carcinomas.
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PMID:Development of active specific immunotherapeutic agents based on cancer-associated mucins. 755 Dec 53

Many of the cancer-associated antigens recently have been identified as mucin antigens. However, there are no detailed studies describing the expression of carbohydrates and core proteins of mucin antigens in ovarian tumors. In this study we examined the expression of carbohydrate antigens, which are associated with the earliest steps in mucin glycosylation (Tn and sialosyl-Tn), and the expression of the mucin core protein antigens associated with the MUC1 gene product (mammary-type apomucin) and the MUC2 gene product (intestinal-type apomucin) in 123 ovarian epithelial (mucinous and serous) tumors. In normal ovarian tissues neither Tn, sialosyl-Tn, nor intestinal-MRP antigens (MUC2 gene product) were expressed, except for positive sialosyl-Tn staining of stromal capillaries, while the MUC1 gene product, DF3 antigen, was expressed in the cell apex of the germinal coelomic epithelium when it had plump, slightly elongated, or pseudostratified nuclei. In the benign adenomas Tn and sialosyl-Tn antigens were detected in a small number of mucinous adenomas and rarely in serous adenomas. In contrast, expression of both Tn and sialosyl-Tn antigens was observed in all the adenocarcinomas and in a considerable number of borderline malignancies. DF3 antigen was expressed in many benign serous tumors but not so frequently in benign mucinous tumors; however, it was frequently expressed in the adenocarcinomas and borderline malignancies of both mucinous and serous types. Intestinal-MRP antigen expression increased with the transition of the mucinous tumors from a benign to malignant state, although it was never detected in the serous tumors. Coexpression of DF3 and intestinal-MRP antigens was seen in borderline malignancies and carcinomas of the mucinous tumors. In conclusion, simultaneous expression of Tn and sialosyl-Tn antigens is a highly effective tumor marker in both mucinous and serous tumors of the ovary. Coexpression of DF3 and intestinal-MRP antigens may indicate the malignant potential of ovarian mucinous tumors.
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PMID:Immunohistochemical study of mucin carbohydrates and core proteins in human ovarian tumors. 816 69

A highly immunogenic peptide motif within the tandem repeat domain of MUC1 mucin is assumed to be exposed during development of breast cancer due to altered O-glycosylation. To elucidate the structural aspects of these changes, we have isolated and analysed the integrated or secretory MUC1 glycoforms from carcinoma cell lines or solid tumors and from human milk. The buoyant densities measured in CsCl gradients for MUC1 glycoforms from cancer cells revealed heterogeneity of the physicochemical species and a significant reduction of their carbohydrate contents compared to MUC1 from skim milk. Immunoreactivity patterns of MUC1 glycoforms from tumor or T47D cells exhibited a lack of fucosylated Lewis blood-group-related antigens and the appearance of core-type antigen sialyl(NeuGl)-TF, Gal beta 1-3(NeuGl alpha 2-6)GalNAc. Structural chemistry of MUC1 oligosaccharides demonstrated that the cancer-associated glycoforms carry mainly sialylated trisaccharides NeuAc alpha 2-3Gal Beta 1-3GalNAc or NeuAc alpha 2-6(Gal beta l-3)GalNAc, exhibit a concomitant decrease in the ratio of GlcNAc/GalNAc, a reduction or disappearance of L-fucose, and a partial substitution of N-acetylneuraminic acid by the N-glycolylated variant. On comparison to the secretory MUC1 in human milk, the glycoforms on human milk fat globule membranes showed apparently identical patterns of O-linked oligosaccharides with a preponderance of neutral polylactosamino-glycans. During serum-free cultivation of T47D cells over 4 weeks, the expression of secretory MUC1 glycoforms was inconsistent based on the decreasing contents of sialic acid and on the concomitant increase of immunodetectable TF antigen.
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PMID:MUC1 glycoforms in breast cancer--cell line T47D as a model for carcinoma-associated alterations of 0-glycosylation. 861 81

The M344 tumor-associated antigen, expressed in 70% of superficial bladder tumors, is a sialylated carbohydrate present on a high molecular mass thiol-reducible secreted mucin, which we named MAUB for mucin antigen of the urinary bladder. Herein we studied the relationship between MAUB and other known mucins in the MGH-U3 bladder cancer line where MAUB expression is modulated by culture conditions. Northern blots, immunoradiometric assays, and Western blots showed that only MUC1 and MUC2 are expressed in this MAUB-positive cell line. MUC1 differs from MAUB by its molecular mass and its non-oligomeric nature, while MUC2 has similar molecular mass and response to culture conditions. However, in double determinant immunoradiometric assays, MAUB and MUC2 did not cross-react. Moreover, confocal microscopy showed different subcellular localization of the two antigens. Treatment of MGH-U3 cells with MUC2 antisense oligodeoxynucleotides resulted in decreased expression of MUC2 and increased expression of MAUB, ruling out the possibility that monoclonal antibody M344 recognizes a different glycosylated form of MUC2. In addition, we identified a tumor specimen expressing MAUB but no MUC2 antigen or mRNA. Together, these results suggest that there is expression of at least three mucins in MGH-U3 cells and that MAUB is a cancer-associated mucin distinct from those identified so far.
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PMID:MAUB is a new mucin antigen associated with bladder cancer. 863 21

The cancer-associated epitope defined by the monoclonal antibody (MAb) 9H8 was shown to be closely related to the T antigen (Thomsen-Friedenreich antigen) by its sensitivity to 0-glycanase treatment of a mucin glycopeptide known to express this epitope. The reactivity with this glycopeptide increased upon neuraminiclase treatment, and among several MAbs tested for ability to block binding of the 9H8 antibody, the one specific for the T antigen was the most efficient. Out of 41 serum samples from breast-cancer patients, 11 showed elevated levels of the 9H8 epitope, and several sera also showed elevated levels of the cancer-associated carbohydrate epitopes sialyl-Lewis a and sialyl-Lewis x. By the use of antibodies specific for the MUC1 apoprotein (Ma552 and HMFG-2) it could be shown that these epitopes were attached to the MUC1 apoprotein in at least 4 of the cases. By combining antibodies specific to 9H8, sialyl-Lewis a and sialyl-Lewis x in catcher and tracer positions in several types of immunofluorometric assays, it was shown that the 9H8 epitope was rarely co-expressed with sialyl-Lewis a or sialyl-Lewis x epitopes an the same molecule, though all were expressed on MUC1 mucins. In fact, they can be considered as mutually exclusive epitopes, suggesting that these sera contained different populations of MUC1 mucins distinguishable by different sets of oligosaccharides. The existence of mutually exclusive carbohydrate epitopes on different MUC1 mucins in one and the same patient should be taken into account when designing immunoassays exploiting MUC1-reactive antibodies.
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PMID:Distinct sub-populations of carcinoma-associated MUC1 mucins as detected by the monoclonal antibody 9H8 and antibodies against the sialyl-Lewis a and sialyl-Lewis x epitopes in the circulation of breast-cancer patients. 864 22

A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Underglycosylation exposes tandem repeat peptide sequences on cancer-associated MUC1 mucin that are normally cryptic. High levels of MUC1 mucin are correlated with a poor prognosis and immunosuppression in adenocarcinoma patients. In this report we show that cancer-associated MUC1 mucin, affinity-purified from ascites fluids of cancer patients, and synthetic tandem repeats of MUC1 mucin core peptide can suppress human T-cell proliferative responses. This MUC1 mucin-induced suppression of T-cell responses can be reversed by the addition of exogenous IL-2 or anti-CD28 monoclonal antibody. These results are consistent with other studies showing that lymphocytes present in the vicinity of tumor cells are anergic and can be reactivated with exogenous interleukin-2. Overcoming MUC1 mucin-induced immunosuppression with IL-2 combined with active specific immunotherapy might be an effective immunotherapeutic strategy against human adenocarcinomas.
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PMID:Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. 977 24

The membrane-bound MUC1 mucin is expressed in normal mucosas and the aberrant expression of its under-glycosylated forms has been reported in carcinomas from different sites. Several studies have provided conflicting evidence regarding the relationship between MUC1 expression and outcome in cancer patients. In this study, we investigated the immunohistochemical expression of MUC1 epitopes, using 2 monoclonal antibodies (MAbs): HMFG1, which reacts with the fully glycosylated MUC1, was studied in 73 gastric carcinomas; and SM3, which recognises an under-glycosylated form of MUC1, was studied in 180 cases. HMFG1 stained the antrum foveolar cells and the body glands of normal gastric mucosa, whereas SM3 reactivity was restricted to the perinuclear region of some foveolar cells. Type I intestinal metaplasia exhibited down-regulation of MUC1 expression using both MAbs. Every gastric carcinoma was stained with HMFG1 and 80% with SM3. High levels of expression of HMFG1 were associated with lymphatic invasion, nodal metastatization, and advanced pTNM staging. The expression of SM3 was associated with the histologic (solid) type of carcinoma, expanding growth pattern, wall penetration, lymphatic invasion and age of the patients. Despite a trend for a poor outcome in patients with tumours (over)expressing MUC1 mucin, the survival of the patients evaluated by univariate and multivariate analysis was not significantly associated with the levels of expression of HMFG1 or with the expression of the SM3 epitope. We conclude that (a) MUC1 expression, namely of the SM3 cancer-associated epitope, is significantly associated with several aspects of gastric cancer development and progression; and (b) MUC1 expression should not be used as a prognostic marker in patients with gastric carcinoma.
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PMID:Expression of fully and under-glycosylated forms of MUC1 mucin in gastric carcinoma. 969 34


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