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)

A low-molecular-weight acceptor of galactosyltransferase activity was detected in sera and effusions of patients with extensive maligant disease. This substance was purified to homogeneity from both human serum and effusion by using sequential charcoal/Celite and DEAE-cellulose column chromatography. The purified acceptor was shown to act as substrate for both purified normal and cancer-associated human galactosyltransferase (EC 2.4.1.22) isoenzymes, but had a higher affinity for the cancer-associated isoenzyme (Km = 20 microM) than for the normal isoenzyme (Km = 500 microM). The substrate was found to be a glycopeptide with mol.wt. approx. 3600 determined by polyacrylamide-gel chromatography. Carbohyydate analysis demonstrated only the presence of glucosamine and mannose. Amino acid analysis revealed that the peptide moiety consisted of eight different amino acids, including two residues of asparagine and one residue of serine, but no threonine. These structural data suggest that the acceptor is a fraction of an asparagine-glucosamine type of glycoprotein.
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PMID:Detection, purification and characterization of a human cancer-associated galactosyltransferase acceptor. 8 90

NMR and ESR spectroscopies have been used to examine the plasma protease inhibitor pregnancy zone protein (PZP) and its complex with chymotrypsin. The 1H NMR spectrum of PZP shows relatively few sharp resonances, which, by analogy with human alpha 2-macroglobulin, probably arise from the proteolytically sensitive bait region. Upon reaction with chymotrypsin to form a 1:1 protease.PZP tetramer complex, there is a large increase in the intensity of sharp resonances due to an increase in mobility of these residues. 35Cl NMR has been used to follow binding of zinc and manganese to apo-PZP. Zinc binding causes a linear broadening of the bulk Cl-, consistent with access of Cl- to PZP-bound zinc. Since zinc in the two highest affinity sites in human alpha 2-macroglobulin causes no broadening of Cl-, it is concluded that these zinc sites are absent from PZP. The mobility of chymotrypsin in the PZP.chymotrypsin complex was examined by covalently attaching a nitroxide spin label at the serine residue in the active site of the enzyme and examining the appearance of the ESR spectrum. The chymotrypsin is rigidly held by the PZP to which it is covalently bound. In an analogous experiment performed previously on alpha 2-macroglobulin, chymotrypsin, bound in the presence of methylamine and therefore largely noncovalently bound, was found to be free to rotate inside the cage formed by the protease inhibitor.
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PMID:NMR and ESR studies on human pregnancy zone protein. Comparison with human alpha 2-macroglobulin. 169 19

Two monoclonal antibodies, MLS 102, which recognizes cancer-associated mucin antigens, and MLS 103, which recognizes normal mucin, were used to isolate, by immunoaffinity chromatography, the corresponding antigens from cell lysates and spent medium of a human colorectal carcinoma cell line, LS 180. The MLS 102 antigen contained serine, threonine, and proline as major amino acids. The carbohydrate chains of the MLS 102 antigen were composed of O-linked NeuAc alpha 2----6GalNAc (56%), N-acetylgalactosamine (25%), and longer oligosaccharide chains. The MLS 103 antigen differed from the MLS 102 antigen in both amino acid and carbohydrate composition. Most O-linked oligosaccharides of the MLS 103 antigen were longer than the disaccharide found in the MLS 102 antigen. Immunostaining of LS 180 cells using MLS 102 and MLS 103 revealed that the cells are heterogeneous with respect to the expression of the antigens.
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PMID:Characterization of mucin antigens recognized by monoclonal antibodies raised against human colon cancer cells. 198 95

Mucins synthesized in colonic cancer are known to be different from those in the normal colon; however, the biochemical differences between these mucins have not been defined. We have purified mucins from samples of nonneoplastic (normal) human colon and colon cancer and found that the carbohydrate content of the cancer-associated mucins is 48% of that in the normal colon, including significant reductions in galactose, N-acetylglucosamine, N-acetylgalactosamine, and fucose. By subjecting the mucins to alkaline degradation, we determined that there are 19% fewer oligosaccharide chains per milligram of cancer-associated colonic mucin than there are in mucins from normal colons. We also found a reduction in mean oligosaccharide chain length in cancer-associated mucin (5.83 carbohydrate residues per chain) compared with those derived from normal colons (10.2 residues). Total and individual amino acid contents were greater in cancer-associated mucins, with the exception of three amino acids (threonine, serine, and proline), two of which represent the O-linked glycosylation sites for glycoproteins. Thus, mucins are aberrantly glycosylated in colon cancer, both in terms of the number and mean chain length of the oligosaccharide moiety. Because of their relative abundance in colonic tissue, mucins appear to be useful molecular species in the study of the derangements in protein glycosylation that occur during neoplasia.
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PMID:The carbohydrate composition of mucin in colonic cancer. 232 10

Mucin glycoproteins are major secretory products of the colon and contain O-linked oligosaccharides synthesized on a polypeptide backbone. The initial step in the synthesis of O-linked oligosaccharides is the addition of N-acetylgalactosamine to serine or threonine residues forming the Tn antigen. This substance can then receive additional carbohydrate residues such as sialic acid to form sialosyl-Tn antigen, or galactose to form T antigen. In the colon, the T antigen is an oncodevelopmental cancer-associated antigen but little is known about Tn and sialosyl-Tn expression. The present comparative immunohistochemical study was performed to analyze the expression of these antigens in fetal, normal adult, and malignant colorectal tissues with an aim toward elucidating whether Tn and sialosyl-Tn are also oncodevelopmental colon cancer-associated antigens and to gain insight into the earliest steps of mucin glycosylation in colonocytes. We used three reagents to detect Tn antigen (two monoclonal antibodies ETn1.01 and CU-1, and one lectin Vicia villosa), two reagents to detect sialosyl-Tn (monoclonal antibodies TKH2 and B72.3) and one to detect T antigen (monoclonal antibody AH9-16). Except for occasional reactivity with VVA and CU-1, cells of normal colonic mucosa did not express Tn, sialosyl-Tn, or T antigens. However, in the transitional mucosa immediately adjacent to cancer, all three antigens were expressed (ranging from 35 to 67% of cases depending upon the reagent). In colon cancers, the percentage of cases expressing each antigen were as follows: Tn 72-81%, sialosyl-Tn 93-96%, and T 71%. Unlike T antigen, which was preferentially expressed by moderately well- and well-differentiated adenocarcinomas, both Tn and sialosyl-Tn antigens were expressed by most histological subsets of colon cancers, including poorly differentiated adenocarcinomas and mucinous (colloid and signet ring cell type) carcinomas. The majority of cancers expressed both Tn and sialosyl-Tn, usually in association with T antigen. Only one cancer lacked all three antigens. Fetal colonic mucosal cells expressed all three antigens, particularly in goblet cell mucin. These results indicate that like T antigen, Tn and sialosyl-Tn are oncodevelopmental cancer-associated antigens in the colon. Moreover, Tn and sialosyl-Tn antigens appear to be useful markers of poorly differentiated adenocarcinomas and mucinous carcinomas: two histological subsets that often fail to express other cancer-associated antigens and that are often associated with a poor clinical outcome.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. 290 46

Mucin has been purified from nude mouse xenografts of SW1990 human pancreatic cancer cells. The mucin was eluted at the void volume of Sepharose CL-4B and was of density greater than 1.3 in CsCl gradients. The isolated mucin had a high content of threonine, serine, and proline, with 31% of the amino acid residues O-glycosylated. The average oligosaccharide composition was NeuAc1.8Fuc0.7Gal2.0GlcNAc1.7GalNAc1.4. Polyclonal rabbit antibodies prepared against the purified mucin recognized primarily mucin polypeptide, and there was extensive immunological cross-reaction between SW1990 pancreatic cancer mucin and LS174T colon cancer mucin. However, using carbohydrate-specific monoclonal antibodies, the two mucins were found to differ. SW1990 mucin had more Lewis, sialyl Lewis, and sialyl Lewis activity, while the colon cancer mucin had more sialyl T antigen. Since pancreatic mucins, whether from normal pancreas or pancreatic cancer, have not previously been well characterized, the availability of SW1990 pancreatic cancer mucin may be useful as a model for studying the expressing of organ-specific or cancer-associated antigens.
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PMID:Pancreatic cancer mucin from xenografts of SW1990 cells: isolation, characterization, and comparison to colon cancer mucin. 322 46

Previous studies from this laboratory have demonstrated that arylsulfatase B (ASB) is phosphorylated by a protein kinase, which is the first finding of phosphorylation in lysosomal hydrolases. The present study was undertaken to characterize the sites of phosphorylation in ASB from transplanted human lung cancer and from normal human tissues, and to identify type of tumor protein kinase responsible for the phosphorylation of ASB. When ASB purified from liver and placenta was phosphorylated in vitro by a cAMP-dependent protein kinase, it gave a single tryptic phosphopeptide (X) and phosphothreonine. On the other hand, the tumor ASB which had been phosphorylated in vivo demonstrated two phosphopeptides X and Y. Since the tumor ASB had been shown to be phosphorylated both at threonine and serine residues, phosphorylation at threonine residue of peptide X, which is phosphorylated by a cAMP-dependent protein kinase, will be cancer-associated. Through photoaffinity labeling with a labeled cAMP analogue to detect regulatory subunits of cAMP-dependent protein kinase subtypes, it was found that the cAMP-dependent protein kinase in the transplanted lung tumor was largely type II which can be ascribed to the appearance of highly phosphorylated ASB in the tumor.
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PMID:Protein phosphorylation of human lysosomal arylsulfatase B from normal and cancer tissues. 338 98

It is proposed that cells store calcium in the hydrogen belt of their membranes, on the cytoplasmic side, with the Ca2+ ion captive in cages formed by the phosphate and carbonyl oxygens of two acidic phospholipid molecules; for instance, phosphatidylinositol and phosphatidylserine. Evidence for the existence of such Ca-cages is adduced from the properties of the [Ca(phosphatidate)2] complex. Cytoplasmic Ca2+ concentration, approx. 10(-7) M, corresponds to the calcium cage dissociation constant. The high stability of the cages is the result of multiple hydrogen bonds between inositol and serine, or inositol and inositol. Phosphorylation of the inositol in position 4 and 5 opens the calcium cage by breaking the inter-headgroup hydrogen bonds and by introducing electrostatic and steric hindrance. This allows the escape of Ca2+ into the cytosol. The mono in equilibrium with di in equilibrium with triphosphoinositide shuttle serves as a regulator of Ca2+ concentration in the cytoplasm: phosphorylation of the lipids will raise, dephosphorylation lower the level of free Ca2+. The inositide shuttle may be linked to a stimulus-induced inositide cycle in which inositol triphosphate is generated, and to Ca(phosphatidate)2 cross-membrane transport.
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PMID:Hypothesis: control of intracellular calcium level. 394 95

The effect of cancer-associated galactosyltransferase acceptor (CAGA) on incorporation of a variety of macromolecular precursors has been studied in transformed and nontransformed cells. Incorporation of [3H]-mannose, [3H]-galactose, and [3H]-glucosamine into acid precipitable material after one-hour pulse was inhibited more than 70% within four hours after exposure to CAGA in polyoma-transformed BHK cells and within eight hours after exposure in chick embryo fibroblasts infected with a temperature-sensitive RSV mutant (Ts68) grown at the permissive temperature (CEF-RSV 37 degrees C). Initial short-term rate of uptake (less than one minute) and total long-term uptake (one hour) of the labelled carbohydrates (acid-soluble and acid-insoluble material) was inhibited less than 15% over this period. Incorporation of 14C-leucine, 3H-serine, 3H-uridine, and 3H-thymidine into acid-precipitable material was also inhibited greater than 85% in transformed cells, but more than 12-hour exposure to CAGA was required before maximal inhibition was detected. Uptake of these labelled precursors was inhibited less than 20% up to eight hours after exposure to CAGA. In nontransformed cells (BHK and CEF) incorporation of labelled monosaccharides as well as protein and nucleic acid precursors into acid-precipitable material was reduced less than 25% up to 12 hours following exposure to CAGA. Infected CEF grown at the nonpermissive temperature (CEF-RSV 41 degrees C) were affected to an extent similar to other nontransformed cells. These data suggest that the specific action of CAGA on transformed cells may be due to inhibition of glycoconjugate synthesis.
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PMID:Inhibition of carbohydrate incorporation in transformed cells by a cancer-associated galactosyltransferase acceptor (CAGA). 640 58

Several investigators have shown that the expression of the sialyl-Tn (STn) epitope on cancer associated mucins is associated with a poor prognosis in several human cancers suggesting that STn may have functional significance in metastasis. We postulate that antibodies against the STn-epitope can inhibit metastasis. We generated a synthetic "mimic", NANA alpha (2-->6)GalNAc alpha-O-Crotyl (STn-crotyl), of the natural O-linked epitope on mucins, NANA alpha (2-->6)GalNAc alpha-O-Serine (STn-serine). STn-crotyl was conjugated to the carrier protein KLH through the crotyl linker arm and a "vaccine" containing STn-KLH plus Detox adjuvant was formulated. The immunogenicity of the vaccine was evaluated in BALB/c mice and in metastatic breast cancer patients. The specificity and titres of IgG antibodies were evaluated by ELISA on ovine submaxillary mucin (OSM) solid phases. OSM is a convenient source of repeating, natural O-linked STn-serine structures. Mice immunized three times with as little as 0.25 microgram of STn-KLH produced a median IgG titre of over 1:5000 on solid phase OSM. Anti-OSM IgG monoclonal antibodies generated from these mice were completely inhibited in their binding to solid phase OSM equally well by STn-serine and STn-crotyl synthetic haptens but not by several other closely related synthetic haptens. Breast cancer patients immunized 2-8 times with 25 or 100 micrograms of the same vaccine produced median peak IgG titres 1:1280 measured on STn-HSA and 1:80 on OSM. Once again, hapten inhibition experiments with the human sera demonstrated the specificities of the IgG antibodies for STn-crotyl and STn-serine, but not against several other related synthetic haptens. We found little or no evidence that the artificial linker arm (crotyl linker) contributed significantly to either the titre or affinity of the antibodies generated in either mice or human breast cancer patients. This suggests that the antibodies recognized the cancer-associated disaccharide NANA alpha (2-->6)GalNAc. Evidence of a clinical response was noted in several of the immunized breast cancer patients with other patients showing prolonged disease stability.
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PMID:Specificity of the IgG response in mice and human breast cancer patients following immunization against synthetic sialyl-Tn, an epitope with possible functional significance in metastasis. 752 78


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