Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of HeLa cells with the anticancer agent N-methyl-N-nitrosourea (MNU) results in: (a) depression of intracellular nicotinamide adenine dinucleotide levels; (b) stimulation of the chromatin-associated, chromosomal protein-modifying enzyme polyadenosine diphosphoribose [poly(ADP-ribose)] polymerase, which uses nicotinamide adenine dinucleotide as substrate; and (c) some fragmentation of cellular DNA. DNase treatment of HeLa nuclei in vitro also stimulates poly(ADP-ribose) polymerase activity, but not in nuclei derived from MNU-treated cells unless they have been subsequently incubated to allow for recovery from MNU damage. DNA polymerase activity is stimulated in vitro by poly(ADP) ribosylation of nuclear proteins. By using intact nuclei derived from MNU-treated HeLa cells, the repair via elongation of single-strand DNA breaks is demonstrated in vitro. This repair is dependent on DNA polymerase activity and is enhanced by adenosine diphosphate ribosylation of histones. Inhibition of poly(ADP-ribose) polymerase with nicotinamide results in extensive degradation of MNU-damaged DNA. Taken as a whole, these results suggest that poly(ADP-ribose) polymerase may play a role in the repair of alkylation damage to cellular DNA and that the inhibition of this enzyme in vivo might be exploited to potentiate the antitumor and carcinogenic activities of MNU.
 ...
PMID:A putative role for nicotinamide adenine dinucleotide-promoted nuclear protein modification in the antitumor activity of N-methyl-N-nitrosourea. 19 15

The sequence divergence of mitochondrial DNAs (mtDNA) from rat, mouse, guinea pig, monkey, and chicken has been examined by DNA-DNA hybridization. mtDNAs, isolated as closed circular molecules by propidium iodide-CsCl centrifugation, were labeled in vitro by use of Escherichia coli DNA polymerase I, and renatured (Tm-35 degrees) in the presence of a 2500-fold excess of heterologous mtDNA. Single-stranded and duples DNA were separated by hydroxylapatite chromatography. The thermal stability of heteroduplexes was compared to the homoduplex by thermal elution chromatography on hydroxylapatite columns. Heteroduplex fromation between the tritiated myDNAs and a 2500-fole excess of rar mtDNA were 70, 59, 37, and 22%, respectively, for mouse, guinea pig, monkey, and chicken. Similar results were obrained in reciprocal hybridizations where one of the other mtDNAs was present in excess. Considerable mismatching of sequences in all the heterohybrids was indicated by a 18-24 degrees depression in the te50 of the heteroduplexes compared with the homoduplex. There was no apparent change in heteroduplex formation when the concentration ratio of driving DNA in excess to [3H]mtDNA was varied between 1250 and 7500. Furthermore, a second renaturation with excess driving DNA after completion of the first reaction resulted in no detectable augmenting of heteroduplex formation. Similar sequences appear to be conserved preferentially in different organisms, since the presence of two of fouf different heterologous mtDNAs in excess resulted in only moderate and nonadditive increases in heteroduplex formation. Evolutionary divergence of mtDNA sequences appears to have occurred at rates similar to that for unique sequences nuclear DNA.
 ...
PMID:Sequence homology between mitochondrial DNAs of different eukaryotes. 114 57

Damage to the lung may be caused by chemicals that gain access to the alveolar zone by inhalation or via the pulmonary circulation. Several agents toxic to the lung have recently been found to bind covalently to pulmonary macromolecules or to disrupt certain metabolic reactions. However, it has also been observed that extensive chemical lung injury is not necessarily preceded by a depression of pulmonary metabolic reactions. One possible explanation for this might be that biochemical changes due to cell death are often masked and/or compensated for by changes associated with lung tissue repair. Substantial cell proliferation as a response to toxic lung damage is a common phenomenon in lung pathology. This makes it necessary to develop models that permit analysis of the biochemical events triggering and accompanying cell growth in lung. We have recently examined some aspects of cell proliferation in mouse lung. Intraperitoneal injection of the antioxidant butylated hydroxytoluene (BHT) produces within 3-5 days extensive hypertrophy, hyperplasia, and general disorganization of the cellular components of the lung. Total lung weight and total DNA per lung almost double within this time and are accompanied by proportional increases in protein and lipids. RNA accumulates at a faster rate than DNA. The changes in lung composition are accompanied by dose-dependent increases in the in vivo incorporation of thymidine into DNA and of leucine into protein. The activities of several enzymes (thymidine kinase, DNA polymerase, uridine kinase, glucose-6-phosphate dehydrogenase, and 5'-nucleotidase) increase substantially after BHT. Administration of BHT to mice seems to offer a convenient tool to study cell growth in the lungs of mice.
 ...
PMID:Biochemical pathology of lung damage produced by chemicals. 124 36

In this report results of studies on the effect of different doses of low LET (linear energy transfer) radiations on the unscheduled DNA synthesis (UDS) and DNA polymerase activity as well as the induction of adaptive response in bone marrow cells (BMC) by low dose radiation were presented. It was found that whole-body irradiation (WBI) with X-ray doses above 0.5 Gy caused a dose-dependent depression of both UD5 and DNA polymerase activity, while low dose radiation below 250 mGy could stimulate the DNA repair synthesis and the enzyme activity. WBI of mice with low doses of X-rays in the range of 2-100 mGy at a dose rate of 57.3 mGy per minute induced an adaptive response in the BMC expressed as a reduction of chromosome aberrations following a second exposure to a larger dose (0.65 mGy). It was demonstrated that the magnitude of the adaptive response seemed to be inversely related to the induction dose. The possibility of induction of adaptive response in GO phase of the cell cycle and the possibility of a second induction of the adaptive response were discussed.
 ...
PMID:Effect of low-dose radiation on repair of DNA and chromosome damage. 209 21

The alteration of the hemopoiesis is the result of a lot of particular cases. The inhibition of the microtubuli assembly suppresses the cell division because of the missing of the spindle formation. This is associated with an inhibition of the supporting stroma of the bone marrow and of the different lymphocytes complicated with a depression of colony stimulating factors. There is also an alkylation of the nuclear and mitochondrial RNA, DNA and proteins together with an inactivation of the DNA polymerase. Immunosuppressive effects are associated with autoimmune events. Benzene is classified as a weak carcinogenic initiator.
 ...
PMID:[Current status of knowledge of the effect of benzene. Impairment of blood and hemopoiesis]. 218 78

Three hours following X-irradiation of chick embryos with doses of 4 and 8 Gy the in vitro incorporation of tritiated thymidine [( 3H]dT) into DNA (scheduled DNA synthesis, ss) of hepatocytes was reduced to about one-third. Within 24 h after the exposure, ss returned to control values. The return of ss to a normal rate could be strongly inhibited by 2',3'-dideoxythymidine (ddT), and to a lesser extent by 1-beta-D-arabinofuranosylcytosine (araC). In strong contrast to ss, the hydroxyurea (hu)-resistant [3H]dT incorporation (unscheduled DNA synthesis, us) showed a highly significant increase 24 h after treatment of the embryos with araC and/or X-irradiation. Autoradiographic studies revealed no change of total [3H]dT labelling frequency in the whole chick embryo liver 24 h after treatment with araC and/or X-irradiation, but a persistent depression of ss and a simultaneous increase of us. The histological discrimination between affected and non-affected areas argue for a stimulation of DNA synthesis as an antecedent of subsequent mitosis and reparative proliferation adjacent to cell necrosis. It is suggested that the fast recovery of ss in the 12-15-day-old chick embryo is due to an efficient DNA repair system for which DNA polymerase beta is important. The increase of hu-resistance may be an expression of an aberrant DNA synthesis.
 ...
PMID:Scheduled and unscheduled DNA synthesis in chick embryo liver following X-irradiation and treatment with DNA repair inhibitors in vivo. 257 Aug 18

Lipids which enter the composition of actively transcribed and repressed chromatin fractions are found to undergo a peroxidation. The peroxidation induction results in a depression of the endogenous DNA polymerase activity of these fractions. Tetrachloromethane increases the intensity of lipid peroxidation processes and induces a more marked depression of the DNA polymerase activity in all repressed chromatin fractions. It is assumed that selective action of tetrachloromethane on the studied indices of this chromatin fraction may be related to the differences of lipid composition of actively transcribed and repressed chromatin.
 ...
PMID:[Lipid peroxidation and the endogenous DNA polymerase activity of fractions of isolated liver chromatin in rats]. 271 66

The antileukemic agent 6-thioguanine (TG) is thought to inhibit DNA synthesis as a result of its incorporation into DNA. In the present study we have examined the nature of this inhibition, using replication of SV40 viral DNA as a model system. Addition of TG to SV40-infected CV1P cells from 22 to 24 hr post infection causes a dose-dependent inhibition of viral DNA synthesis. This inhibition plateaus between 250 and 2500 microM TG, resulting in a maximum decrease of viral DNA synthesis of about 50%. Pulse-chase experiments showed no detectable slowing of elongation of nascent DNA chains, whereas measurement of the conversion of incorporated 3H-dThd into supercoiled viral DNA suggested that elongation might be slightly inhibited, but by no more than 20%. Since inhibition of elongation could not account for the total depression of DNA synthesis, we hypothesized that inhibition of initiation of DNA replication takes place. This hypothesis was tested by radioactively labeling newly synthesized viral DNA and then assessing the ability of these molecules to reenter the replicating pool by density labeling with bromodeoxyuridine. The fraction of TG-containing molecules able to re-initiate replication was decreased 15%, compared to control. This effect, which was dependent on the concentration of TG added to the medium, was closely correlated to the extent of TG incorporation into the viral genome. We concluded that a portion of SV40 viral DNA synthesis inhibited by TG is due to an effect on initiation, and hypothesized that this effect may be caused by the substitution of TG for guanine in critical recognition sequences at the origin of replication. We proceeded to test this hypothesis by constructing SV40 origin sequences containing TG and then measuring their ability to bind T-antigen in vitro. The necessary deoxynucleoside triphosphate, TdGTP, was obtained by chemical phosphorylation of thiodeoxyguanosine. In order to selectively place TG within the desired region, a plasmid containing the T-antigen binding sequences was linearized so as to place these sequences at one end of the molecule, and then digested briefly with exonuclease III. The excised strand was resynthesized by use of the Klenow fragment of DNA polymerase I along with various nucleotide mixtures. Although resynthesis with mixtures containing TdGTP in place of dGTP was impeded somewhat, it was possible to achieve complete resynthesis with this analog.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Effects of incorporation of 6-thioguanine into SV40 DNA. 282 79

A tumor-derived factor that inhibits cellular DNA synthesis was identified. The factor was extractable from a small-cell lung carcinoma cell line grown in either chemically defined medium or nu/nu mice and inhibited tritiated thymidine ([3H]dThd) incorporation by tumor cell lines of autologous, allogeneic, and xenogeneic origins. The viability of nonproliferating cells from normal tissue was not affected. Tumor extract inhibitory activity was trypsin labile but was resistant to other proteases, neuraminidase, lipase, DNase, RNase, glucosidase, extremes of pH-temperature, and reducing conditions. Inhibitory activity was reversibly bound to helix pomatia lectin but not to lentil, wheat germ, or concanavalin A lectins. Purification by size-exclusion high-performance liquid chromatography yielded a bioactive unimodal 12-kilodalton (kd) peak. The bioactive 12-kd moiety could be eluted from sodium dodecyl sulfate-polyacrylamide gels. Redosing of populations of the T-lymphoblastoid cell line CEM achieved an early (24 hr) sustained depression of pulse [3H]dThd incorporation and ultimately led to decreased population density of factor-treated populations. DNA histogram analysis demonstrated no change in cell cycle phase distribution after factor treatment. 5-Bromo-2'-deoxyuridine (BrdUrd) vs. propidium iodide with the two-parameter Fluorescence-Activated Cell Sorter analysis showed relative inhibition of non-S-phase BrdUrd uptake at 24 hours. A cell-free DNA polymerase assay demonstrated significant inhibition of non-alpha-polymerase-associated DNA synthesis in factor-treated cells. These studies suggest that this tumor-derived inhibitor of DNA synthesis represents a class of cellular products involved in the autoregulation of growth by regulation of DNA synthetic activity.
 ...
PMID:Inhibition of DNA synthesis by a small-cell lung carcinoma-derived protein. 302 Mar 1

Recently, 2-halogenated deoxyadenosine analogs (F, Cl, and Br) have been shown to have antitumor activity. These analogs are phosphorylated by cells and are believed to exert their cytotoxic action at the nucleoside triphosphate level. In this work the interaction of these nucleoside triphosphate analogs with potential targets, such as DNA polymerase alpha, beta, and gamma, DNA primase, and ribonucleotide reductase was examined in detail. All of these compounds competitively inhibited the incorporation of dAMP into DNA by DNA polymerase alpha, beta, or gamma. F-dATP was able to completely substitute for dATP using DNA polymerase alpha and gamma, but not with DNA polymerase beta. Cl-dATP and Br-dATP substituted poorly for dATP using DNA polymerase alpha and beta. Extension of a 32P-labeled primer by DNA polymerase alpha, beta, or gamma on a single-stranded M13 template showed that these compounds were incorporated into the 3' end of the growing DNA chain and that elongation beyond the incorporated analogs was significantly retarded for Cl-dATP and Br-dATP using either DNA polymerase alpha or beta. DNA primase using poly(dC) as template was inhibited by these compounds at a concentration 4 to 5 times greater than that required for 2-F-araATP. The 2-halogenated dATP analogs were potent inhibitors of ADP reduction by ribonucleotide reductase. In conclusion, the cytotoxic action of 2-Cl-deoxyadenosine and 2-Br-deoxyadenosine may partially be mediated through the mechanism of "self-potentiation," by depression of the deoxynucleoside triphosphate pools due to inhibition of ribonucleotide reductase, which would facilitate their incorporation into DNA and result in the inhibition of DNA synthesis.
 ...
PMID:Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. 305 Apr 47


1 2 3 Next >>