Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A monoclonal antibody, 16B-13, derived from the immunization of BALB/c mice with a lung tumor line, immunoprecipitates a common tumor-associated molecule with an apparent mol. wt of 37,000 from lactoperoxidase-iodinated lung carcinoma, colon carcinoma, gastric carcinoma, brest carcinoma, melanoma and lymphoma cells, but not from normal fibroblasts. Analysis by two-dimensional gel electrophoresis of the cell surface-labeled 16B-13 antigen from a colorectal and a melanoma cell line reveals four components with similar mol. wts but with different isoelectric points. The antigen purified from a colorectal carcinoma cell line by immunoaffinity chromatography was shown to be a 37,000 mol. wt polypeptide similar to that obtained by the lactoperoxidase-labeling procedure. However, the purified antigen from the melanoma cell line shows the presence of a 65,000 mol. wt polypeptide and the loss of the 37,000 mol. wt component as detected by Coomassie blue staining and immunoprecipitation.
Mol Immunol 1983 Dec
PMID:Identification and isolation of a common tumor-associated molecule using monoclonal antibody. 665 79

Total mRNA from human colon carcinoma cell line HT-29 treated with either 5-fluorouracil or 5-fluorouridine was assessed in vitro in a reticulocyte lysate translation system. Under conditions of known drug-induced cell lethality, fluoropyrimidine-modified mRNA did not show major quantitative or qualitative changes in translational activity. These results suggest that drug-modified mRNA is probably not associated with the cytotoxicity manifested by these drugs.
Mol Pharmacol 1983 Mar
PMID:In vitro translation of messenger RNA following exposure of human colon carcinoma cells in culture to 5-fluorouracil and 5-fluorouridine. 683 5

The effect of 9-deazaadenosine (c9Ado) on cell lethality and the synthesis of nucleic acids was investigated in human colon carcinoma cell line HT-29. c9Ado produced a rapid threshold-exponential reduction in colony formation as measured by a soft agar clonogenic assay. This effect was evident after either a 2- or 24-hr exposure interval, and was produced over a very narrow concentration range of drug. Following 2 hr of drug exposure at concentrations producing a 1- to 3-log reduction in cell viability, DNA and RNA syntheses were inhibited 20% and protein synthesis was inhibited 35-50%. The latter effect became quite pronounced in comparison to nucleic acid synthesis 4 hr after drug treatment. Long treatment intervals (24 hr) with concentrations of c9Ado producing similar effects on cell viability resulted in 15-35% inhibition of RNA synthesis, 80-85% inhibition of DNA synthesis, and 60-70% inhibition of protein synthesis. None of these metabolic effects could be accounted for by changes in ribonucleoside triphosphate levels despite the considerable formation of c9ATP. Measurements of the incorporation of [3H] c9Ado into total cellular nucleic acids indicated that the labeling of RNA was 40-80% greater than that of DNA. Polysomal poly(A)RNA contained 300% more [3H]c9Ado than non-poly(A)RNA after 2 hr of drug exposure and 50% more [3H]c9Ado following 24 hr of treatment. There was no evidence of DNA strand breakage by incorporated c9Ado. Analysis of nascent protein synthesis in drug-treated cells revealed that this process was inhibited in concert with polysome breakdown. These results suggest that the rapidity by which cell lethality is produced by c9Ado may be related to inhibition of translation via its incorporation into RNA.
Mol Pharmacol 1983 Sep
PMID:9-Deazaadenosine. Cytocidal activity and effects on nucleic acids and protein synthesis in human colon carcinoma cells in culture. 688 72

The cytokinetic and biochemical effects of 5-fluorouracil and 5-fluorouridine were examined in a human colon carcinoma cell line (HT-29) in culture. Logarithmically growing cells were approximately 100 times more sensitive to the lethal effects of 5-fluorouridine than 5-fluorouracil as measured by colony formation in soft agar medium. A 2-hr exposure of cells to 10(-3) M 5-fluorouracil or 10(-5) M 5-fluorouridine produced a 2-log reduction in colony formation, a 31--33% inhibition of [14C]deoxyguanosine incorporation into DNA, and 30--40% inhibition of [3H]adenosine incorporation into total RNA. Increasing the duration of drug exposure to 24 hr produced a proportional reduction in the drug concentration required to produce similar biochemical and cytocidal effects. However, cell lethality produced by either drug did not correlate quantitatively with inhibition of DNA or RNA synthesis. Examination of nuclear rRNA and 4 S RNA synthesis by agarose gel electrophoresis following 2-hr and 24-hr exposure to 5-fluorouracil or 5-fluorouridine indicated that processing of rRNA was not impaired, rRNA synthesis was inhibited by 10--40%, and 4 S RNA synthesis was unaffected. In contrast to these results, measurements of the incorporation fo [3H]5-fluorouracil or [3H]5-fluorouridine into nuclear RNA showed that a significant correspondence existed between the amount of drug incorporated into nuclear RNA and cell lethality. These results indicate that the primary determinant of cell lethality in HT-29 cells is the degree of fluoropyrimidine substitution in nuclear RNA and not inhibition of either DNA or RNA synthesis.
Mol Pharmacol 1982 Mar
PMID:Association of cell lethality with incorporation of 5-fluorouracil and 5-fluorouridine into nuclear RNA in human colon carcinoma cells in culture. 709 47

We previously showed that there is a structure-function relationship among reserpine and yohimbine analogues in their ability to inhibit the function of P-glycoprotein (P-gp) and reverse multidrug resistance (MDR). Because some P-gp inhibitors (e.g., verapamil and nifedipine) can increase mdr1 and P-gp expression in human colon carcinoma cell lines, we used our reserpine/yohimbine analogues to determine whether there was a structural requirement for this induction. We found that 10 microM reserpine increased both mdr1 and P-gp expression by 4-10-fold in 48 hr in a human colon carcinoma cell line that expresses moderate levels of mdr1 (LS180-Ad50) but not in several other cell lines that expressed no mdr1. The reserpine/yohimbine analogues rescinnamine, trimethoxybenzoylyohimbine, and LY191401 (compound G), all of which contain the three structural elements used to describe the MDR pharmacophore, also increased both mdr1 and P-gp expression significantly. Despite some exceptions, we found that there was a good association between the ability of these analogues to induce mdr1 and P-gp expression and their ability to reverse vinblastine and doxorubicin resistance, revealing a structure-function relationship for this phenomenon. The increased P-gp expressed by these cells appeared to be functional, as determined by flow cytometric detection of rhodamine 123 retention. The increased expression was suppressed by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, an RNA synthesis inhibitor, whereas the protein synthesis inhibitor cycloheximide enhanced the expression several-fold, suggesting that induction of mdr1 by these analogues is regulated at both the transcriptional and post-transcriptional levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Pharmacol 1995 Oct
PMID:A structure-function relationship among reserpine and yohimbine analogues in their ability to increase expression of mdr1 and P-glycoprotein in a human colon carcinoma cell line. 747 94

A uniquely developed series of totally human monoclonal antibodies (mAbs) were examined for their complement fixing properties in comparison to human myeloma preparations and to commercially available human polyclonal immunoglobulins. C3b and C4b deposition was measured using a kinetic ELISA technique. When the IgG myeloma proteins were tested for classical pathway activation, our findings were similar to those previously described, where IgG1 and IgG3 were more potent activators of the classical pathway than IgG2 and IgG4. However, those same studies determined that IgG2 was the best activator of the alternative pathway followed by IgG1 and IgG3 while IgG4 does not activate complement via either pathway. In our studies of alternative pathway activation, the IgG2 myeloma exhibited strong activation of the alternative pathway, but, at levels lower than the other three IgG subtypes. Using this test system, we examined the complement activating potential of four totally human mAbs that were constructed from the peripheral blood lymphocytes of a colon carcinoma patient in long term remission. We found that our uniquely constructed totally human IgG2 mAbs (A3, E1, F6 and F8) were able to activate complement by both the classical and alternative pathways to varying degrees. In addition, we found that the complement activating ability of the human mAbs was greater than that of the human IgG2 myeloma immunoglobulins or normal human IgG2 preparations. This study represents the first report of complement activation by totally human mAbs and confirms more recent findings which indicate that levels of complement activation by human IgG immunoglobulins cannot be predicted based solely on their subclass identity.
Mol Immunol 1995 Sep
PMID:Activation of human complement by totally human monoclonal antibodies. 747 1

Clones of cells tumorigenic or nontumorigenic in nude mice have been previously isolated from the SW613-S human colon carcinoma cell line. We have already reported that tumorigenic cells overexpress the cytokeratin 18 (K18) gene in comparison with nontumorigenic cells and that this difference is mainly due to a transcriptional regulation. We now report that a 2,532-bp cloned human K18 gene promoter drives the differential expression of a reporter gene in a transient assay. A 62-bp minimal K18 promoter (TATA box and initiation site) has a low but differential activity. Analysis of deletion and substitution mutants as well as hybrid SV40-K18 promoters and reconstructed K18 promoters indicated that an important element for the activity of the K18 promoter is a high-affinity binding site for transcription factor Sp1 located just upstream of the TATA box. This Sp1 binding element, as well as the intron 1 enhancer element, stimulates the basal activity of the minimal promoter through mechanisms that maintain the differential activity. Gel shift assays and the use of an anti-Sp1 antibody have shown that both tumorigenic and nontumorigenic SW613-S cells contain three factors able to bind to the Sp1 binding element site and that one of them is Sp1. A hybrid GAL4-Sp1 protein transactivated to comparable extents in tumorigenic and nontumorigenic cells a reconstructed K18 promoter containing GAL4 binding sites and therefore without altering its differential behavior. These results indicate that the Sp1 transcription factor is involved in the overexpression of the K18 gene in tumorigenic SW613-S cells through its interaction with a component of the basal transcription machinery.
Mol Cell Biol 1995 May
PMID:An Sp1 binding site and the minimal promoter contribute to overexpression of the cytokeratin 18 gene in tumorigenic clones relative to that in nontumorigenic clones of a human carcinoma cell line. 753 48

Cells selected for overexpression of the integrin alpha 5 beta 1 show decreased proliferation and loss of the transformed phenotype. We provide evidence that de novo expression of the integrin alpha 5 beta 1 in HT29 colon carcinoma cells results in the growth arrest of these cells as characterized by reduced DNA synthesis and cellular proliferation in vitro. In fact, expression of integrin alpha 5 beta 1 on these cells induces the transcription of growth arrest specific gene 1 (gas-1), a gene product known to induce cellular quiescence, but blocks transcription of the immediate early genes c-fos, c-jun, and jun B. In vivo, the alpha 5 beta 1 transfectants display dramatically reduced tumorigenicity as well as a highly differentiated phenotype when compared with their pSVneo-transfected counterparts. Surprisingly, ligation of alpha 5 beta 1 on these cells by cell attachment to a fibronectin substrate not only reverses the growth inhibition and gas-1 gene induction but activates immediate early gene transcription. These findings demonstrate that integrin alpha 5 beta 1 expression in the absence of attachment to fibronectin activates a signaling pathway leading to decreased cellular proliferation and that ligation of this receptor with fibronectin reverses this signal, thereby contributing to the proliferation of transformed cells.
Mol Biol Cell 1995 Jun
PMID:Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin. 757 91

The integrin alpha v beta 6 was initially identified from primary cultures of airway epithelial cells. This integrin is expressed in bronchiolar and alveolar epithelium during development and in settings of injury and/or inflammation and mediates attachment of epithelial cells to fibronectin and tenascin. Like other integrins, this receptor localizes to structures called focal contacts in cells plated on appropriate ligands. In the present study, we produced a mutant beta 6 cDNA (beta 6m) containing a single substitution of Asp140 with Ala and transfected mutant (or wild-type) beta 6 cDNA into the human colon carcinoma cell line SW480. In parallel, we used cDNAs truncated just proximal to the transmembrane domain to generate secreted forms of mutant alpha v beta 6 in Chinese hamster ovary (CHO) cells. The mutant beta 6, like the wild type, formed heterodimers with human alpha v that were expressed on the cell surface of SW480 cells and secreted by CHO cells. Secreted alpha v beta 6 containing this point mutation did not bind to fibronectin-Sepharose. Furthermore, in contrast to wild-type beta 6, the mutant form did not allow SW480 cells to bind to fibronectin in the presence of beta 1-blocking antibody and did not localize to focal contacts. Our results confirm that the Asp140 of beta 6, like the corresponding residues in beta 1 (Asp130) and beta 3 (Asp119), is critical for interactions of alpha v beta 6 with ligand, and also suggest that ligand binding to alpha v beta 6 is necessary for localization of this receptor to focal contacts.
Am J Respir Cell Mol Biol 1995 Aug
PMID:A point mutation in the integrin beta 6 subunit abolishes both alpha v beta 6 binding to fibronectin and receptor localization to focal contacts. 762 92

The tyrosine kinase substrate p120cas (CAS), which is structurally similar to the cell adhesion proteins beta-catenin and plakoglobin, was recently shown to associate with the E-cadherin-catenin cell adhesion complex. beta-catenin, plakoglobin, and CAS all have an Arm domain that consists of 10 to 13 repeats of a 42-amino-acid motif originally described in the Drosophila Armadillo protein. To determine if the association of CAS with the cadherin cell adhesion machinery is similar to that of beta-catenin and plakoglobin, we examined the CAS-cadherin-catenin interactions in a number of cell lines and in the yeast two-hybrid system. In the prostate carcinoma cell line PC3, CAS associated normally with cadherin complexes despite the specific absence of alpha-catenin in these cells. However, in the colon carcinoma cell line SW480, which has negligible E-cadherin expression, CAS did not associate with beta-catenin, plakoglobin, or alpha-catenin, suggesting that E-cadherin is the protein which bridges CAS to the rest of the complex. In addition, CAS did not associate with the adenomatous polyposis coli (APC) tumor suppressor protein in any of the cell lines analyzed. Interestingly, expression of the various CAS isoforms was quite heterogeneous in these tumor cell lines, and in the colon carcinoma cell line HCT116, which expresses normal levels of E-cadherin and the catenins, the CAS1 isoforms were completely absent. By using the yeast two-hybrid system, we confirmed the direct interaction between CAS and E-cadherin and determined that CAS Arm repeats 1 to 10 are necessary and sufficient for this interaction. Hence, like beta-catenin and plakoglobin, CAS interacts directly with E-cadherin in vivo; however, unlike beta-catenin and plakoglobin, CAS does not interact with APC or alpha-catenin.
Mol Cell Biol 1995 Sep
PMID:The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin. 765 99


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