Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD46 (membrane cofactor protein) is a human cell surface glycoprotein with cofactor activity for factor I-mediated cleavage of complement components C3b and C4b. The CD46 protein from normal lymphocytes resolves on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as two major bands of 66 and 56 kDa. CD46 cDNA encodes four extracellular short consensus repeat domains, a Ser/Thr/Pro (STP)-rich region, a transmembrane region and a cytoplasmic tail. We now show that exquisite control of mRNA splicing is responsible for the heterogeneous expression of CD46 isoforms. Differential splicing of 5 exons generates at least 14 CD46 mRNA variants whose expression is stringently regulated by allelic, tissue-specific and malignancy-related factors, as: (a) leukemic cells and Epstein-Barr virus-transformed B cells preferentially incorporate the first of three STP exons (exon 7) into mRNA, and produce a larger CD46 isoform of 74 kDa, (b) an allelic difference in the proportion of 66- and 56-kDa CD46 isoforms on lymphocytes corresponds to the preferential inclusion or exclusion of the second STP exon (exon 8), (c) the third STP exon (exon 9) is specifically deleted in some placentae, (d) spermatozoa delete both exons 12 and 13, encoding a shorter transmembrane region and a unique cytoplasmic tail and (e) all tissues tested differentially splice exon 13, resulting in two alternative cytoplasmic tails. The distribution of the 14 alternatively spliced RNA transcripts correlated with the presence of protein isoforms of the predicted size, indicating that alternative splicing leads to heterogeneity of CD46 glycoproteins.
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PMID:Tissue-specific and allelic expression of the complement regulator CD46 is controlled by alternative splicing. 160 Oct 37

The HER2 protooncogene encodes a growth factor receptor-like transmembrane protein tyrosine kinase (p185HER2) whose ligand remains to be fully characterized. The overexpression of p185HER2 is implicated in aggressive forms of breast and ovarian cancers. The role of p185HER2 in aggressive malignancy, as well as its cell surface localization, makes it an attractive target for therapeutic monoclonal antibodies. In this report we have studied the modulation of p185HER2 function with 2 monoclonal antibodies, termed 4D5 and 6E9, which bind the extracellular domain of p185HER2. 4D5 inhibited proliferation of p185HER2 overexpressing SK-BR-3 human breast carcinoma cells (ED50 of approximately 1 nM) but did not inhibit proliferation of cultured human breast carcinoma MCF7 cells, low expressors of p185HER2. Monoclonal antibody 6E9 does not inhibit the growth of either cell line. Antibody binding studies revealed 2 populations of p185HER2 molecules on SK-BR-3 cells: one of high abundance (approximately 2 x 10(6) sites/cell) recognized by 4D5 (Kd approximately 6 nM) and the other of low abundance (2 x 10(4) sites/cell) recognized by 6E9 (Kd approximately 0.1 nM). 4D5, in an agonistic manner, downregulated SK-BR-3 cell surface p185HER2, was internalized, and stimulated p185HER2 phosphorylation in intact cells. Phosphoamino acid analysis of p185HER2 derived from SK-BR-3 cells incubated with the 4D5 monoclonal antibody demonstrated increased tyrosine, serine and threonine phosphorylation. 4D5, on short term (5 min) exposure to SK-BR-3 cells, stimulated inositol lipid hydrolysis as evidenced by increased intracellular levels of inositol polyphosphates (InsP) and sn-1,2-diacylglycerol (sn-1,2-DAG). On longer (24 h) exposure to the cells, the antibody appeared to downregulate this signalling pathway since the intracellular levels of InsP and sn-1,2-DAG decreased by 30 to 40%. 6E9 did not inhibit SK-BR-3 cell proliferation, downregulate surface p185HER2, stimulate receptor phosphorylation, or stimulate the second messenger pathway. Despite these agonistic properties, 4D5 was an inhibitor of SK-BR-3 cell proliferation at all concentrations tested (0.7 to 70 pM). The data suggest that 4D5 is a partial or weak agonist and thus may inhibit cell proliferation by mimicking ligand-like receptor downregulation.
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PMID:Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. 168 87

Staurosporine is a potent microbial inhibitor of a number of protein kinases, including protein kinase C, cyclic AMP-dependent kinase, and the tyrosine kinase pp60src. We have used staurosporine to investigate the role of phosphorylation in the regulation of the epidermal growth factor (EGF) receptor in both human epidermal carcinoma A431 cells and mouse Swiss 3T3 fibroblasts. We report here that staurosporine treatment causes enhancement in high affinity EGF binding and a decrease in the phosphorylation state of the unstimulated receptor at a number of residues, including threonine 669. Staurosporine also antagonizes the inhibition of high affinity EGF binding and the increase in phosphorylation state of the unstimulated EGF receptor by phorbol esters and the calcium ionophore A23187. Staurosporine is an effective inhibitor of the EGF-stimulated receptor tyrosine kinase in vitro and thus does not enhance EGF stimulation of EGF receptor autophosphorylation in vivo. These results suggest that phosphorylation plays a major role in the regulation of the high affinity binding state of the EGF receptor in both unstimulated and mitogenically activated cells.
Cancer Res 1990 Feb 01
PMID:Regulation of the epidermal growth factor receptor by growth-modulating agents: effects of staurosporine, a protein kinase inhibitor. 168 32

Human granulocyte colony-stimulating factor (G-CSF) rapidly loses the biological activity and the receptor binding capacity following radioiodination. We have made a mutein of human G-CSF, KW-2228, in which Thr-1, Leu-3, Gly-4, Pro-5, and Cys-17 were respectively substituted with Ala, Thr, Tyr, Arg, and Ser; showed more potent G-CSF activity; and retained full biological activity and receptor binding capacity at least 2 weeks of radioiodination. G-CSF is an effective growth factor for the blasts of myeloid leukemia. Radioiodinated KW-2228 was prepared using solid-phase glucose oxidase-lactoperoxidase. Human leukemia cell lines and the blast cells from leukemia patients were examined for binding. High affinity binding sites were identified on myeloid cell lines and on the blasts obtained from acute myeloid leukemia patients. Scatchard analysis showed that a single binding site for G-CSF was observed (361-1688 receptors/cell; Kd 128-1400 pM). In contrast, specific binding of 125I-KW-2228 was not demonstrated on lymphoblastic cell lines or the blast cells of acute lymphoid leukemia or lymphoma. This difference was reflected in the effectiveness of G-CSF to stimulate colony formation in acute myeloid leukemia blasts, while G-CSF did not stimulate colony formation of the blast cells from acute lymphoid leukemia.
Cancer Res 1990 Mar 15
PMID:Receptor binding of human granulocyte colony-stimulating factor to the blast cells of myeloid leukemia. 168 9

A murine anti-(human gastric carcinoma) monoclonal antibody, GL-013 (IgG1), which reacts with a high-molecular-mass glycoprotein from colorectal tumour tissue [Yang and Price (1989) Anticancer Res 9: 1707], was examined for reactivity against a panel of purified and partially purified antigens associated with tumours of the gastrointestinal tract. These included carcinoembryonic antigen (CEA), normal cross-reacting antigen, Y-hapten glycoproteins, and perchloric acid extracts and glycolipid preparations from colorectal tumours. While the GL-013 antibody failed to bind to these antigens, it was found to react strongly with synthetic peptides with sequences based upon that reported for the protein core of a human gastrointestinal mucin [Barnd et al. (1989) Proc Natl Acad Sci USA 86: 7159; Gum et al. (1989) J Biol Chem 264: 6480]. In control tests, a series of other anti-(colorectal tumour) antibodies (IgG1 and IgG3), with broad reactivity towards gastrointestinal carcinomas, as well as an anti-CEA antibody, (IgG1) failed to react with the synthetic peptides. It is concluded that the anti-(gastric carcinoma) monoclonal antibody GL-013 binds to a threonine-rich peptide epitope expressed within the protein core of gastrointestinal mucins.
Cancer Immunol Immunother 1991
PMID:Reactivity of an anti-(human gastric carcinoma) monoclonal antibody with core-related peptides of gastrointestinal mucin. 170 22

Two mucin-type glycoproteins detected by the monoclonal antibody C50, which reacts with the carcinoma-associated sialyl-Lewis a and sialyl-lactotetraose epitopes, were found in secreted and solubilized materials from the colon carcinoma cell line COLO 205. The larger glycoprotein (H-CanAg; heavy cancer antigen) was predominantly found in extracts of cells grown in vitro or as nude mice xenografts whereas the smaller species (L-CanAg; light cancer antigen) was the major component in spent culture medium and serum from grafted mice. Using detergent in the extraction buffer doubled the yield of H-CanAg, suggesting that this glycoprotein is membrane bound whereas the yield of L-CanAg was relatively unaffected. The two glycoproteins were purified from xenograft extracts and spent culture medium using perchloric acid precipitation, monoclonal antibody affinity purification, ion exchange chromatography, and gel filtration. Both glycoproteins were unaffected by reduction and alkylation in guanidine HCl. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, relative molecular masses were estimated to be 600-800 kDa for H-CanAg and 150-300 kDa for L-CanAg. Carbohydrate analysis revealed that the CanAg glycoproteins were highly glycosylated (81-89% carbohydrate by weight), carrying carbohydrate chains with average lengths of 13-18 sugars which were rich in fucose and sialic acid (2-3 residues/chain for each sugar). L-CanAg isolated from spent medium was glycosylated to a higher degree than its counterpart from xenograft extract. Immunochemical studies of the intact glycoproteins showed that both H-CanAg and L-CanAg expressed the monoclonal antibody-defined, sialic acid-containing carbohydrate epitopes CA203 and CA242 as well as the Lewis a blood group antigen whereas only H-CanAg appeared to carry the sialyl-Lewis x epitope. The amino acid compositions were typical of mucins, containing high amounts of serine, threonine (more than 25% together), and proline (11-18%). Significant differences in amino acid composition between H-CanAg and L-CanAg were found. A rabbit antiserum against the cytoplasmic C-terminal part of the MUC1 gene product, core protein of the carcinoma-associated polymorphic epithelial mucin (PEM) and DU-PAN-2, reacted with H-CanAg. After deglycosylation with trifluoromethanesulfonic acid, H-CanAg but not L-CanAg was recognized by the monoclonal antibodies SM-3 and HMFG-2, directed to the tandem repeat of the PEM apoprotein. However, these antibodies which react with PEM from mammary carcinomas without prior deglycosylation were unable to recognize intact H-CanAg, probably as a consequence of a more extensive glycosylation of this glycoprotein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Purification and characterization of a membrane-bound and a secreted mucin-type glycoprotein carrying the carcinoma-associated sialyl-Lea epitope on distinct core proteins. 171 81

Mucins are large molecular weight glycoproteins characterized by carbohydrate sugars attached via 'O-glycosidic' linkages to serine or threonine. Mucins are synthesized by a variety of epithelial tissues as membrane-bound or secreted proteins, encoded by several distinct mucin genes. Numerous alterations of mucin-associated carbohydrates can be detected in neoplastic epithelial tissues and on circulating mucins in patients with adenocarcinomas. The expression of various sialyosylated-carbohydrate epitopes may correlate with poor prognosis and enhanced metastatic disease in colorectal adenocarcinomas. Mucin-associated carbohydrate and peptide antigens are currently being investigated for their role in cancer diagnosis, monitoring for progression or metastases, immunotherapy and immunosuppression.
Semin Cancer Biol 1991 Dec
PMID:Carbohydrate antigens on cancer-associated mucin-like molecules. 172 30

The serine/threonine O-linked carbohydrates GalNAc alpha and Gal beta 1-3GalNAc alpha, referred to as Tn and T antigens, respectively, appear to be more prevalent in some human carcinomas than in surrounding tissues. Tn/T antigens may represent incomplete synthesis of O-linked oligosaccharides, due to decreased activity of specific glycosyltransferases, or alternatively, increased glycosidases activity in tumors which may expose these internal O-linked oligosaccharide sequences. To explore these possibilities, we measured UDP-Gal:GalNAc alpha-R beta 1-3 galactosyltransferase (beta 3Gal-T) and Gal beta 1-3GalNAc alpha-R beta 1-3 galactosidase in a series of human breast tumors. In addition, glycoproteins extracted from the tumors were separated by SDS-PAGE and stained with the lectins HPA (GalNAc alpha-R reactive) and PNA (Gal beta-3GalNAc alpha-R reactive). The relative levels of HPA- to PNA-reactive glycoproteins in the carcinomas correlated inversely with beta 3Gal-T activities. The results suggest that Tn antigen expression in human breast carcinoma is due in part to low beta 3Gal-T activity, a situation similar to that observed previously in haematopoietic cells of individuals with a condition called Tn syndrome.
Cancer Biochem Biophys 1991 Nov
PMID:Tn antigen and UDP-Gal:GalNAc alpha-R beta 1-3Galactosyltransferase expression in human breast carcinoma. 184 11

Inherited susceptibility to a wide variety of neoplasias (Li-Fraumeni syndrome), has been shown in studies of one cancer-prone family, to have an intriguing association with an aberrant c-raf-1 gene and inheritance of a radioresistant phenotype in their non-cancerous skin fibroblasts. This association together with observations that DNA topoisomerases, when defective, can introduce errors into DNA and that these enzymes are perturbed in vitro by serine/threonine kinases similar to raf encoded proteins, prompted investigation of DNA topoisomerase activity of the family's fibroblasts. Since radioresistance was transferred to murine cells (NIH-3T3) when the aberrant c-raf-1 gene from this family was transfected, we also examined transformants containing this and other oncogenes. V-raf/c-myc and EJ-ras transformants were examined, the former because the family's skin fibroblasts also have 3-8-fold elevated myc expression (not apparently relevant to radioresistance) and the latter because ras, like raf, conveys radioresistance. The family members' fibroblasts and the three transfected murine lines, showed a similar perturbation of a spermidine and ATP-dependent DNA catenation activity (typical of DNA topoisomerase II). There was a significant positive correlation (r = 0.93; P = 0.0026) between the degree of activation of topoisomerase II and one measure of radioresistance (the Dq value). Relaxation of DNA supercoiling (topoisomerase I activity and other DNA nicking enzymes) was not abnormal. Cytotoxicity assays and evaluation of the influence of topoisomerase II inhibitors on DNA/protein complex formation, corroborated the existence of a qualitative topoisomerase II defect in the family's cells and transfectants. Although the contention that the qualitative topoisomerase II abnormalities observed here may be associated with malfunction is highly speculative, these findings may be relevant to the mechanism of oncogenesis, not only in this family, but with raf and ras type oncogenes.
Br J Cancer 1991 Jan
PMID:Aberrant DNA topoisomerase II activity, radioresistance and inherited susceptibility to cancer. 184 52

Sequential amino acid concentrations were determined in the liver of mice infested with a highly malignant strain of Ehrlich ascites tumour cells. The liver concentrations of a certain group of amino acids showed changes consistent with those previously reported for plasma, ascitic liquid and tumour cells during tumour growth. Shortly after tumour transplantation a significant decrease of the essential amino acids methionine, threonine, valine, isoleucine + phenylalanine, leucine, lysine and histidine, was detected. Some non-essential amino acids, mainly the gluconeogenic substrates alanine and serine, showed a strong reduction in hepatic concentrations during the first days; these amino acids remained significantly lower than controls until animal death. Interestingly, hepatic glutamine increased at days 1 and 2 after inoculation, and proline showed a sustained increase from the seventh day onwards, reaching a value double the control at the end of animal life.
Cancer Lett 1991 Jul 04
PMID:Mouse liver free amino acids during the development of Ehrlich ascites tumour. 185 97


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