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 WD40 repeat protein WDR5 specifically associates with the K4-methylated histone H3 in human cells. To investigate the structural basis for this specific recognition, we have determined the structure of WDR5 in complex with a dimethylated H3-K4 peptide at 1.9 A resolution. Unlike the chromodomain that recognizes the methylated H3-K4 through a hydrophobic cage, the specificity of WDR5 for methylated H3-K4 is conferred by the nonconventional hydrogen bonds between the two zeta-methyl groups of the dimethylated Lys4 and the carboxylate oxygen of Glu322 in WDR5. The three amino acids Ala-Arg-Thr preceding Lys4 form most of the specific contacts with WDR5, with Ala1 forming intermolecular hydrogen bonds and salt bridges, and the side chain of Arg2 inserting into the central channel of WDR5. Both structural and biochemical studies presented here suggest another mode of recognition for the methylated histone tail.
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PMID:Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. 1660 Aug 77

In the middle of the last century, there was a spectacular progress in the discovery, characterization and synthesis of neuropeptides. This was only possible because increasingly sophisticated analytical and isolation technology was becoming available. The pituitary lobes have become a real treasure house for the detection of different peptides, but also other glands and organs in the gastrointestinal (GI) and central nervous system (CNS) tracts have contained an ever growing list of regulatory peptides with sometimes unknown functionality. The main burning issues were to elucidate their role in physiology and, case by case and based on their structure, whether it was possible to design useful drugs for human therapy. Both issues were and are still being dealt with, and the history of somatostatin and somatostatin analogs is a good example of how such issues are being tackled successfully. In 1973, Brazeau and Guillemin's search at the Salk Institute for a GHRH in extracts of thousands of sheep hypothalami was crowned by a surprise, the discovery of a GHRH antagonist, a 14-amino acid Cystin bridge-containing peptide which they called somatostatin. This neuropetide appeared to be widely distributed in animal and human organs in the periphery and CNS, suggesting its potential regulatory functions, yet a thorough characterization of its properties due to its extremely short half-life was not possible. More insight could only be feasible with the synthesis of stable and potent analogs, a program that soon started in different research centers around the world. After having elucidated the 3-dimensional structure, the enzymatic degradation pattern and minimal chain length for biological activity of the natural hormone, the synthesis of a large number of analogs was started as early as 1974. The approach of the Sandoz team was to start with a hexapeptide lead structure Cys-Phe-DTrp-Lys-Thr-Cys and, by systematic elongation of the N and C terminals, in 1980 they managed to characterize the most stable and active analog with the following structure: H-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-OI-Octreotide. It was more potent in inhibiting GH in vivo compared to the native hormone. It demonstrated sufficient stability in vivo and, therefore, it was selected for clinical studies. In 1988, the first registration was obtained for treating acromegaly and carcinoid tumors. Since then, different depot preparations have been made available. Other analogs with similar structures have been also synthesized and are commercially available. The so-called targeting approach takes advantage of the presence of somatostatin receptors on different tumors. By coupling octreotide structural elements to so-called cage molecules complexing B or Y emitting isotopes, also the detection of somatostatin receptor containing tumors could be visualized and treated. The use of different somatostatin derivatives found its way since then both in basic research and in human therapy, and it is still opening new and exciting prospects.
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PMID:The history of somatostatin analogs. 1662 37

The cell membrane mucin MUC1 is over-expressed and aberrantly glycosylated in many cancers, and cancer-associated MUC1 glycoforms represent potential targets for immunodiagnostic and therapeutic measures. We have recently shown that MUC1 with GalNAcalpha1-O-Ser/Thr (Tn) and NeuAcalpha2-6GalNAcalpha1-O-Ser/Thr (STn) O-glycosylation is a cancer-specific glycoform, and that Tn/STn-MUC1 glycopeptide-based vaccines can override tolerance in human MUC1 transgenic mice and induce humoral immunity with high specificity for MUC1 cancer-specific glycoforms (Sorensen AL, Reis CA, Tarp MA, Mandel U, Ramachandran K, Sankaranarayanan V, Schwientek T, Graham R, Taylor-Papadimitriou J, Hollingsworth MA, et al. 2006. Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance. Glycobiology. 16:96-107). In order to further characterize the immune response to Tn/STn-MUC1 glycoforms, we generated monoclonal antibodies with specificity similar to the polyclonal antibody response found in transgenic mice. In the present study, we define the immunodominant epitope on Tn/STn-MUC1 glycopeptides to the region including the amino acids GSTA of the MUC1 20-amino acid tandem repeat (HGVTSAPDTRPAPGSTAPPA). Most other MUC1 antibodies are directed to the PDTR region, although patients with antibodies to the GSTA region have been identified. A panel of other MUC1 glycoform-specific monoclonal antibodies was included for comparison. The study demonstrates that the GSTA region of the MUC1 tandem repeat contains a highly immunodominant epitope when presented with immature short O-glycans. The cancer-specific expression of this glycopeptide epitope makes it a prime candidate for immunodiagnostic and therapeutic measures.
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PMID:Identification of a novel cancer-specific immunodominant glycopeptide epitope in the MUC1 tandem repeat. 1705 May 88

The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme family that regulates numerous signaling pathways. Biallelic mutations of the structural PP2A Abeta subunit occur in several types of human tumors; however, the functional consequences of these cancer-associated PP2A Abeta mutations in cell transformation remain undefined. Here we show that suppression of PP2A Abeta expression permits immortalized human cells to achieve a tumorigenic state. Cancer-associated Abeta mutants fail to reverse tumorigenic phenotype induced by PP2A Abeta suppression, indicating that these mutants function as null alleles. Wild-type PP2A Abeta but not cancer-derived Abeta mutants form a complex with the small GTPase RalA. PP2A Abeta-containing complexes dephosphorylate RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. These observations identify PP2A Abeta as a tumor suppressor gene that transforms immortalized human cells by regulating the function of RalA.
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PMID:The tumor suppressor PP2A Abeta regulates the RalA GTPase. 1754 Jan 76

Protein glycosylation is an important post-translational modification underlying host-parasite interactions, which may determine the outcome of infection. Although Mesocestoides vogae represents an important model for investigating the various aspects of cestode biology, virtually no information is available about the structure and synthesis of glycans in this parasite. In this work, focused on the initiation pathway of mucin-type O-glycosylation in M. vogae, we characterized O-glycoproteins bearing the simple mucin-type cancer-associated Tn and sialyl-Tn antigens, and the expression and activity of ppGalNAc-T, the key enzyme responsible for the first step of mucin-type O-glycosylation. Using immunohistochemistry, Tn and sialyl-Tn antigens were detected mainly in the tegument (microtriches) and in parenchymal cells. Tn expression was also observed in lateral nerve cords. Both Tn and sialyl-Tn antigens were detected in in vitro cultured parasites. Based on their electrophoretic mobility, Tn- and sialyl-Tn-bearing glycoproteins from M. vogae were separated into several components of 22 to 60 kDa. The observation that Tn and sialyl-Tn glycoproteins remained in the 0.6N perchloric acid-soluble fraction suggested that they could be good candidates for characterizing mucin-type glycosylation in this parasite. O-glycoproteins were purified and initially characterized using a proteomic approach. Immunohistochemical analysis of the tissue distribution of ppGalNAc-T revealed that this enzyme is expressed in the sub-tegumental region and in the parenchyma of the parasite. In M. vogae cultured in vitro, ppGalNAc-T was mainly detected in the suckers. Using a panel of 8 acceptor substrate synthetic peptides, we found that M. vogae ppGalNAc-T preferentially glycosylate threonine residues, the best substrates being peptides derived from human mucin MUC1 and from Trypanosoma cruzi mucin. These results suggest that M. vogae might represent a useful model to study O-glycosylation, and provide new research avenues for future studies on the glycopathobiology of helminth parasites.
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PMID:Mucin-type O-glycosylation in Mesocestoides vogae (syn. corti). 1789 82

Seven separate experiments were conducted with Hy-Line W-36 hens to determine the ideal ratio of Arg, Ile, Met, Met+Cys, Thr, Trp, and Val relative to Lys for maximal egg mass. The experiments were conducted simultaneously and were each designed as a randomized complete block design with 60 experimental units (each consisting of 1 cage with 2 hens) and 5 dietary treatments. The 35 assay diets were made from a common basal diet (2,987 kcal/kg of ME; 12.3% CP; 4.06% Ca, 0.47% nonphytate P), formulated using corn, soybean meal, and meat and bone meal. The true digestible amino acid contents in the basal diet were determined using the precision-fed assay with adult cecectomized roosters. Crystalline L-Arg (free base), L-Ile, L-Lys.HCl, DL-Met, L-Thr, L-Trp, and L-Val (considered 100% true digestible) were added to the basal diet at the expense of cornstarch to make the respective assayed amino acid first limiting and to yield 5 graded inclusions of the assayed amino acid. Hens were fed the assay diets from 26 to 34 wk of age, with the first 2 wk considered a depletion period. Egg production was recorded daily and egg weight was determined weekly on eggs collected over 48 h; egg mass was calculated as egg production x egg weight. The requirement for each amino acid was determined using the broken-line regression method. Consumption of Arg did not affect egg mass, thus a requirement could not be determined. The true digestible amino acid requirements used to calculate the ideal amino acid ratio for maximum egg mass were 426 mg/d of Ile, 538 mg/d of Lys, 253 mg/d of Met, 506 mg/d of Met+Cys, 414 mg/d of Thr, 120 mg/d of Trp, and 501 mg/d of Val. The ideal amino acid ratio for maximum egg mass was Ile 79%, Met 47%, Met+Cys 94%, Thr 77%, Trp 22%, and Val 93% on a true digestible basis relative to Lys. The ideal Met and Met+Cys ratios were verified in an ensuing identical experiment with 52- to 58-wk-old hens.
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PMID:Ideal ratios of isoleucine, methionine, methionine plus cystine, threonine, tryptophan, and valine relative to lysine for white leghorn-type laying hens of twenty-eight to thirty-four weeks of age. 1833 97

Regular consumption of mesalazine has been associated with a reduced risk of colorectal cancer (CRC) in patients with inflammatory bowel disease. The molecular mechanisms underlying the antineoplastic effect of 5-aminosalicylic acid remain, however, poorly characterized. In this study, we examined whether mesalazine affects cell cycle progression and analyzed specific checkpoint pathways in experimental models of CRC. Mesalazine inhibited the growth of HCT-116 and HT-29 cells, two CRC cell lines that express either a wild-type or mutated p53. Cell cycle analysis revealed that mesalazine induced cells to accumulate in S phase. This effect was associated with a sustained phosphorylation of the cyclin-dependent kinase (CDK)2 at threonine 14 and tyrosine 15 residues, an event that inactivates the CDK2-cyclin complex and blocks S-G(2) phase cell cycle transition. Consistently, mesalazine reduced the protein content of CDC25A, a phosphatase that regulates CDK2 phosphorylation status. Analysis of upstream kinases that negatively control CDC25A expression showed that mesalazine enhanced the activation of CHK1 and CHK2. However, silencing of CHK1 and CHK2 did not prevent the mesalazine-induced CDC25A protein downregulation. In contrast, CDC25A protein ubiquitination and degradation and accumulation of cells in S phase following mesalazine exposure were reverted by proteasome inhibitors. Notably, mesalazine also inhibited CDC25A in human CRC explants. Finally, we showed that mesalazine downregulated CDC25A in CT26, a murine CRC cell line, and prevented the formation of CT26-derived tumors in mice. Data show that mesalazine negatively regulates CDC25A protein expression, thus delaying CRC cell progression.
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PMID:Mesalazine negatively regulates CDC25A protein expression and promotes accumulation of colon cancer cells in S phase. 1849 57

Tn-antigen (alpha-N-acetyl-galactosamine(GalNAc)-Ser/Thr) is a cancer-associated carbohydrate antigen expressed in various epithelial and hematological cancers, and although a number of anti-Tn IgG and IgM antibodies have been generated, they have not been fully validated for cancer immunotherapy. In this study, we generated a novel murine anti-Tn IgG1 monoclonal antibody, KM3413, by immunization of mucins purified from a culture supernatant of LS180: a human colon cancer cell line. The binding of KM3413 was detected against consecutive Tn-antigens (Tn3 and Tn2), but not against monovalent antigens (Tn1). The affinity (K(D)) of KM3413 was determined to be about 10(-7) M with BIAcore. Cross-reactivity against type-A blood antigen, which shares a sugar residue, alpha-linked GalNAc, with Tn-antigen, was not detected. Next, we generated mouse-human chimeric IgG1 of KM3413 (cKM3413) and evaluated its anti-tumor activities against Jurkat: a human T-lymphoid leukemia cell line. In vitro assay revealed that cKM3413 induced antibody-dependent cellular cytotoxicity (ADCC) and direct killing activity with cross-link antibody. Furthermore, treatment of cKM3413 (1 or 10 mg/kg) showed significantly better survival of Jurkat-inoculated C.B-17/lcr-scid Jcl mice compared with controls using PBS treatment (p<0.001). These results suggest that humanized antibody against clustered Tn-antigens is a promising therapeutic antibody against Tn-positive cancers.
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PMID:Mouse-human chimeric anti-Tn IgG1 induced anti-tumor activity against Jurkat cells in vitro and in vivo. 1875 69

The influence of the form of phytic acid on the regulation of mucin and endogenous losses of amino acids, nitrogen and energy in chickens was investigated. Forty-eight 10-week-old male broilers were grouped by weight into eight blocks of six cages with one bird per cage. Birds received by intubation six dextrose-based combinations of phytic acid and phytase arranged in a 3 x 2 factorial consisting of phytic acid form (no phytic acid, 1.0 g free phytic acid or 1.3 g magnesium-potassium phytate) and phytase (0 or 1000 units). Each bird received the assigned combination added to 25 g dextrose at each of the two feedings on the first day of experimentation. All excreta were collected continuously for 54 h following feeding and frozen until analysed. Frozen excreta were thawed, pooled for each bird, lyophilised, ground, and analysed for DM, energy, nitrogen, amino acids, mucin, and sialic and uric acids. Chickens fed either magnesium-potassium phytate or free phytic acid showed increased (P < 0.05) loss of crude mucin and sialic acid. The amount of crude mucin lost was significantly greater (P < 0.05) with magnesium-potassium phytate than with free phytic acid treatment. Both phytic acid treatments also increased (P < 0.05) endogenous loss of threonine, proline and serine. In conclusion, the form of phytic acid fed to chickens affects the extent of mucin and endogenous amino acid losses from the gastrointestinal tract.
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PMID:Phytic acid increases mucin and endogenous amino acid losses from the gastrointestinal tract of chickens. 1876 81

The objective of this study was to determine the inevitable endogenous amino acid (AA) loss at the terminal ileum of broilers that were fed diets with 2 different fiber levels using a regression approach. The design of the study was a randomized complete block employing a factorial arrangement of treatments with 3 CP levels (50, 90, and 130 g/kg) and 2 fiber levels. The fiber level was adjusted by inclusion of cellulose at the expense of cornstarch. The AA pattern of the CP was the same in all diets. Titanium dioxide was used as indigestible marker. Six cages of 8 birds were allocated to each diet. The experimental diets were offered for ad libitum consumption for 3 d, starting on 21 d of age. Digesta were sampled on a cage basis from the distal two-thirds of the intestine section between Meckel's diverticulum and 2 cm anterior to the ileo-ceca-colonic junction. Inevitable endogenous CP and AA losses were determined by extrapolating the linear regressions between intake and prececal flow toward zero intake. The inevitable losses of CP and AA, expressed in relation to DM intake, were significantly increased by increased cellulose inclusion in the diet. Amino acids with the greatest loss were Glu, Asp, and Thr, whereas Met was the AA with the lowest loss. The ranking of the concentrations of AA of inevitable CP loss was very similar between the 2 fiber levels. This ranking also was similar in comparison to published values for the endogenous AA losses in broilers. It was concluded that the fiber level in the diet can affect the amount of AA inevitably lost at the terminal ileum and that all AA are affected to a similar extent. The results suggest that there is no effect of enhanced fiber level in the diet on AA composition of prececal endogenous CP loss in broilers. These findings can be considered in modeling the AA requirements of broilers.
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PMID:Effect of inclusion of cellulose in the diet on the inevitable endogenous amino acid losses in the ileum of broiler chicken. 1943 31


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