Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addition of pentoxifylline to lymphocytes caused a dose-dependent decrease in PHA-induced interleukin-2 receptor (IL-2R) expression. Expression of IL-2R protein and mRNA were inhibited by 60% at a concentration of 1 mM. Pentoxifylline also inhibited release of IL-2R into the medium by 85%. Treatment with recombinant IL-2 (50 U/ml) did not abrogate the effect of pentoxifylline. In addition to inhibition of IL-2R expression, pentoxifylline also decreased the expression of transferrin receptors and class I MHC antigens. Pentoxifylline also inhibited cell proliferation. However, aphidicolin, an inhibitor of DNA polymerase alpha inhibited cell proliferation to the same extent as pentoxifylline, but had no effect on IL-2R expression, indicating that inhibition of cell proliferation does not necessarily lead to inhibition of IL-2R expression. The inhibitory effect on IL-2R expression was also noted with other methylxanthines, theophylline and isobutylmethylxanthine, and with dbcAMP and forskolin. The inhibitory activity of pentoxifylline was prevented by W-13, a calmodulin antagonist, but not by HA-1004, a cyclic AMP-dependent protein kinase inhibitor. This suggests that pentoxifylline might act in part through a Ca2+/calmodulin-dependent mechanism. Pentoxifylline and other methylxanthines may prove useful in delineating the biochemical pathways involved in induction and expression of cell surface receptors.
 ...
PMID:Pentoxifylline and other methyl xanthines inhibit interleukin-2 receptor expression in human lymphocytes. 170 25

To compare the time course of in vitro expression of various proliferation-associated markers including Ki-67 antigen, transferrin receptors (TfR), and DNA polymerase alpha, six human tumour cell lines of different histological origin were studied under defined conditions. Proliferation markers were demonstrated by peroxidase/anti-peroxidase staining using specific monoclonal antibodies, and their expression was compared to results obtained from [3H]-thymidine incorporation assays and cell counting. Expression of all proliferation markers began to increase during the lag phase, and occurred earlier than elevations of [3H]dT incorporation and cell numbers were recorded. Maximum expression was observed before cell growth reached plateau phase. The time courses of expression of DNA polymerase and Ki-67 were almost identical. The closest correlation of [3H]dT incorporation with time course of expression of proliferation-associated markers was observed, when intranuclear staining of DNA polymerase was analysed. TfR were expressed earlier than the polymerase and Ki-67. Since TfR were also found at remarkable levels in resting cells, they seem less proliferation-specific than Ki-67 and DNA polymerase. While in rapidly growing cell lines more than 95% of the cells expressed Ki-67, TfR, and more than 75% DNA polymerase in cell nuclei, a malignant melanoma and a pleural mesothelioma line displayed fewer than 35% of cells stained for DNA polymerase in cell nuclei during log phase. Determination of growth fractions by monoclonal antibodies may thus contribute to the prediction of chemoresistance by identifying quiescent cells that are not sensitive to S-phase-specific drugs.
 ...
PMID:Expression of the proliferation-associated Ki-67 antigen of transferrin receptors and of DNA polymerase alpha in human tumour lines: implications for in vitro chemoresistance. 173 31

Epstein-Barr virus (EBV)-transformed tamarin (Saguinus oedipus) cells (B95-8) were selected for growth in medium with reduced serum and then transferred to serum-free medium which consisted of RPMI 1640 supplemented with insulin, transferrin, and selenium. Serum-free cells in continuous passage for 1 year had a morphology, growth rate, and culture density which approached those of B95-8 cells grown with serum. The cells expressed virus-induced antigens, including the EBV-associated DNA polymerase. Cells exposed to EBV-inducing agents, n-butyric acid and phorbol 12-myristate-13-acetate, produced transforming virus with titers comparable to those of cultures grown with serum. These findings demonstrate that serum is neither required for the growth of B95-8 cells nor necessary for induction or full expression of the EBV lytic phase in these cells.
 ...
PMID:Growth of B95-8 cells and expression of Epstein-Barr virus lytic phase in serum-free medium. 282 33

Two-stage synthesis of double-stranded DNA was performed using purified rat transferrin mRNA as a template, reverse transcriptase and DNA polymerase I. Double-stranded transcripts of transferrin mRNA were cloned as recombinant plasmid derivatives of pBR322. The insert length in these plasmids varied from 150 to 1500 bp. Clones carrying transferrin mRNA sequences were identified using colony hybridization and Southern blot hybridization with 32P-cDNA probe. Nick-translated DNAs from transformed clones hybridized with a single component of rat liver polysomal RNA that corresponded to transferrin mRNA in its molecular weight (0.86 MD). In hybridization selection cell-free translation test cloned plasmid DNAs hybridized specifically with rat liver poly(A) +RNA that programmed the cell-free synthesis of a polypeptide identical to pretransferrin in antigenic properties and molecular weight.
 ...
PMID:[Cloning of double-stranded DNA--a transcript of rat transferrin mRNA]. 620 Jul 63

The ubiquitous trace metal zinc has been discovered since a long time as an intrinsic element in all biological systems. However, its role other than structural or catalytic in enzymes is poorly defined. Zinc plays a determinative role both in primary and secondary T lymphocyte production. Experimental data support the notion that during intrathymic maturation, non-autoreactive, immunocompetent T cell clones are selected from the excess of immature thymocytes as a result of expansion of bone marrow derived prothymocytes in response to pleiotropically acting alarmon (s) and a subsequent escape via the thymic stroma cells from nucleotide-mediated "biochemical suicide". The activity of alarmon (Ap4A), nucleotide metabolizing enzymes (TdT, DNA polymerase, thymidine kinase, 5'-nucleotidase) and some of the soluble stromal cell products (FTS) require constitutive zinc. In the peripheral lymphoid organs the magnitude and duration of antigen induced, T cell mediated immunoreactions are regulated by T-cell growth factor (IL-2). Using receptor specific monoclonal antibody probes, it has been established recently that the intracellular role of IL-2 is probably to induce the phenotypic expression of high affinity transferrin receptors, known to be the main zinc transporter system in T-lymphocytes. The coordinative role of zinc in T lymphocyte development via the inducible metallothionein system is emphasized. Some clinical aspects of zinc metabolism are discussed.
 ...
PMID:Zinc and immunity. 623 34

The products of the tumor suppressor genes are considered to function as specific inhibitors of tumor cell growth. In this communication, we present evidence to show that these proteins inhibit tumor cell proliferation by participating in the activation of tumor cell differentiation. The ML-1 human myeloblastic leukemia cells used in this study proliferate when treated with insulin-like growth factor I and transferrin but differentiate to monocytes when exposed to tumor necrosis factor alpha or transforming growth factor beta1, or to macrophage-like cells when treated with both these cytokines. Initiation of proliferation but not of differentiation was followed by a 20- to 25-fold increase in the nuclear level of the DNA polymerase-associated processivity factor PCNA and of the proliferation-specific transcription factor E2F1. In contrast, induction of differentiation but not of proliferation was followed by a 25- to 30-fold increase in the nuclear level of the tumor suppressor proteins p53 (wild type), pRb, and p130/Rb2 and of the p53-dependent cyclin kinase inhibitor p21/Cip1. p53 and p21/Cip1, respectively, inhibit the expression and activation of PCNA, whereas p130 and pRb, respectively, inhibit the expression and activation of E2F1. As a result, G1-S-associated DNA and mRNA synthesis is inhibited, growth uncoupled from differentiation, and maturation enabled to proceed. Where this function of the tumor suppressor proteins is impaired, the capacity for differentiation is lost, which leads to the sustained proliferation that is characteristic of the cancer cell.
 ...
PMID:Tumor suppressor proteins as regulators of cell differentiation. 976 53

This article reviews approaches on platinum speciation with respect to Pt drugs in anti-cancer therapies. The paper starts with the introduction of available platinum-based drugs and describes their assumed principle of action. It is now generally accepted that these Pt complexes exhibit their therapeutic action by coordination to DNA which leads to bending of the DNA structure and to an inhibition of the DNA polymerase progression. But dose-limiting side effects, including nephrotoxicity as well as resistance to some of these Pt compounds, are still a major problem. Platinum speciation moved increasingly into the focus of interest when it became clear that (1) the active drugs were the hydrolyzation products rather than the originally administered ones and (2) that the parallel formation of inactive Pt-protein complexes, which additionally reduce the efficacy of Pt anti-tumor agents, compete with the formation of the cytotoxic Pt-DNA lesions. Speciation analysis methods were employed based on chromatography or capillary electrophoresis respectively, each coupled to inductively coupled plasma (ICP)-mass spectrometry (MS) or electrospray ionization (ESI)-MS. The paper describes these Pt-speciation investigations, which started with exploring hydrolyzation kinetics in aqueous solutions. These experiments were followed by the speciation investigations in model solutions containing proteins or other sulphur-containing ligands, which could also be responsible for deactivation of the Pt agent in vivo. The experiments improved the understanding of the metabolite form, by which the metal complex enters the tumor cells, and whether and how this metabolized complex is already inactivated at this time. As an example, reaction kinetics of cisplatin (cis-[diamminedichloroplatinum(II)]) with albumin, transferrin, myoglobin, ubiquitin, and metallothionein were investigated and reaction products were speciated. Finally, Pt-speciation in serum of medicated cancer patients was conducted by several research groups, which are outlined in the Section "Investigations in serum". The section "Investigations in urine of cancer treated patients" deals with speciation experiments on the Pt-metabolites excreted by the organism. By these means an assessment of the in vivo metabolism of Pt-drugs may be possible. Finally, the development of new anti-cancer metallodrugs needs the respective analytical techniques reported in the last section of the paper.
 ...
PMID:Platinum speciation used for elucidating activation or inhibition of Pt-containing anti-cancer drugs. 2041 63