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At least 775 records · Page 43Linked to original sources
PubMed1992

Ellagic acid protects rat embryos in culture from the embryotoxic effects of N-methyl-N-nitrosourea.

Ellagic acid is a naturally occurring plant phenol that has demonstrated anticarcinogenic and antimutagenic activity in several test systems. Given the common proposed etiopathogenic processes of mutagenesis, carcinogenesis, and teratogenesis induced by genotoxic chemicals, the present study was initiated to determine whether ellagic acid would protect rat embryos in culture from the teratogenic effects of N-methyl-N-nitrosourea (MNU). Ellagic acid alone (as used in these experiments; 50 microM in DMSO) was not embryotoxic. Ellagic acid (50 microM) significantly (P less than 0.01) prevented MNU (75 microM)-induced effects including mortality (absence of heart beat), abnormal formation of the cephalic neural tube derivatives, and delayed differentiation as assessed by a morphological scoring system. These embryoprotective effects were dose responsive. Sequential treatment of embryos with ellagic acid followed by MNU in fresh media also was embryoprotective with no diminution of effect. The site at which ellagic acid interrupts the critical teratogenic events induced by MNU is apparently within the embryo and/or placenta. This model of chemical embryoprotection may be useful in determining the role of cell death and/or mutation in the teratogenic mechanism of action of methylating agents.

Abnormalities, Drug-Induced↗
PubMed1983

Genetic dissection of the anterior optic tract of Drosophila melanogaster.

Electron microscopy shows that in wild-type Drosophila melanogaster the anterior optic tract (AOT) is formed by about 1260 fibers in males and slightly fewer in females. Golgi staining suggests that most AOT fibers connect the lobula with different regions of the central brain. In the sine oculis (so) and small optic lobes (sol) mutants the number of axons is drastically reduced, by 58% in sol and by 35% in so. In the double mutant sol:so there is a loss of up to 83% of the fibers in the AOT. Approximately half of the remaining 220 fibers form a well defined subbundle of very thin axons which is identifiable in wild type as well as in both single mutants. The fibers of this subbundle neither originate nor terminate in the visual ganglia: instead, they connect two different central brain regions. It is concluded that the combined action of the sol and so mutations abolishes more than 90% of the fibers of visual origin or destination in the AOT. Quantitative analysis of electron micrographs shows that the so and sol mutations act independently on nearly exclusive subsets of axons in the AOT.

Animals↗
PubMed1987

Biochemical and morphological characterization of primary kidney cell cultures from beige mutant mice.

Primary kidney cultures from adult beige-J (bgJ/bgJ) mice were selected for epithelial cell growth using D-valine medium. After 2 weeks of attachment and proliferation in vitro, the cells form a confluent or nearly confluent monolayer that retains several phenotypic characteristics of the beige-J mutant. These include large, multilamellar inclusion bodies that are apparently dysmorphic lysosomes, and higher concentrations of neutral glycosphingolipids and dolichols than control cells. beta-Glucuronidase activity, used as a lysosomal enzyme marker, is not elevated in beige-J-cultured kidney cells compared with controls, as it is in the intact kidney. The high levels of beta-glucuronidase activity in both control and mutant cells may mask expression of this difference in vitro. The action of the beige-J mutation in kidney cells is thought to be due to a block in exocytosis that results in the accumulation of abnormal lysosomes and their components. The maintenance of the beige phenotype in vitro indicates that the mutation is not suppressed in primary kidney cell cultures. The expression of the beige phenotype in vitro should be useful for studies concerning the primary lesion of this mutation.

Animals↗
PubMed1985

Biased intrachromosomal gene conversion in a chromosome lineage.

A model for the evolution of a family of tandemly repeated genes in a single chromosome lineage under intrachromosomal gene conversion [43] is analyzed further and extended. Direct and diffusion approximations are derived for the exact fixation probabilities, mean time to fixation or loss, and mean conditional fixation time of Nagylaki and Petes [43]. The distribution of the number of variant repeats under the joint action of gene conversion and reversible mutation is investigated; exact and approximate expressions are derived for the stationary distribution. It is shown that conversional bias greatly increases the amount of sequence homogeneity at equilibrium. The diffusion processes studied here also apply to selection and mutation in a finite population, and some new results are established for that classical problem.

Alleles↗
PubMed1994

Yeast Saccharomyces cerevisiae as a model system to study the cytotoxic activity of the antitumor drug camptothecin.

Eukaryotic DNA topoisomerase I catalyzes the relaxation of positively and negatively supercoiled DNA and plays a critical role in processes involving DNA, such as DNA replication, transcription and recombination. The enzyme is encoded by the TOP1 gene and is highly conserved in its amino acid sequence and sensitivity to the anti-neoplatic agent camptothecin. This plant alkaloid specifically targets DNA topoisomerase I by reversibly stabilizing the covalent enzyme-DNA intermediate. Presumably, it is the interaction of these drug-stabilized adducts with other cellular components, such as replication forks, that actually produces the DNA lesions leading to cell death. A conservation of the mechanism(s) of camptothecin-induced cell killing is also implicit in studies of the yeast Saccharomyces cerevisiae, where the camptothecin sensitivity of delta TOP1 yeast cells can be restored by plasmids expressing either yeast or human TOP1 sequences. This genetically tractable system is currently being exploited to describe the specific molecular interactions required for the cytotoxic action of camptothecin. The results of mutational analyses of yeast and human DNA topoisomerase I are presented, as well as a genetic screen designed to identify genes, other than TOP1, that are required for the cytotoxic activity of camptothecin.

Amino Acid Sequence↗
PubMed1997

Familial glucocorticoid deficiency: one syndrome, but more than one gene.

Familial glucocorticoid deficiency is a rare autosomal recessive disease characterised by resistance to the action of ACTH. A number of mutations in the ACTH receptor have been demonstrated in patients with this disorder which are likely to lead to loss of receptor function and thus would account for the syndrome. Several patients, however, do not have mutations in the ACTH receptor gene coding region, and it can be demonstrated by segregation analysis that another distant gene must account for the disease in some of these cases. The nature of several candidate genes for this normal receptor form of the disease is discussed.

Animals↗
PubMed1976

Effect of excision repair on azide-induced mutagenesis.

Azide mutagenesis was investigated in Salmonella typhimurium and Escherichia coli. Azide was highly effective in inducing his+ revertants in excision-repair deficient (uvrB) derivatives of S. typhimurium hisG46 and in inducing high frequencies of 5-fluorouracil resistant mutants in excision-repair deficient (uvrA) derivatives of E. coli B/r WP2. In excision-repair plus strains, azide was only a marginal or ineffective mutagen, demonstrating that the bacterial excision-repair system could repair nearly all azide-induced damage. This observation suggests that the initial azide-induced lesion causes a major DNA helix distortion recognizable by the excision-repair endonucleases. The presence of recombination deficient (recB or recC) genes in combination with uvrA increased E. coli sensitivity to azide killing, but depressed azide mutagenicity. These results are similar to those reported for UV-induced mutagenesis with the E. coli strains and suggest that post-replication repair might be the error-prone step in the repair process. Azide mutagenesis specificity is, however, unique and different from UV, as demonstrated by inability of azide to revert the ochre try locus in E. coli WP2s. These results show that the initial azide-induced DNA damage is highly specific but different from UV-induced DNA damage. Metabolic inhibitors, similar in action to azide, did not induce mutations in S. typhimurium strain TA1530, a strain highly susceptible to azide mutagenesis, thus ruling out the possibility that azide mutagenesis was due to peroxide accumulation. A mechanism based on in vivo activation of azide to the actual mutagen is proposed.

Azides↗
PubMed1979

Action spectrum for lethality of near-UV light on Haemophilus influenzae and lack of mutation.

Mutation and inactivation of H. influenzae have been measured following irradiation at various near-UV wavelengths. Inactivation takes place most readily at 334 nm (but is unaffected by absence of excision or postreplication repair), and decreases markedly at longer wavelengths. No induced mutations to resistance to novobiocin or streptomycin or to ability to utilize protoporphyrin instead of hemin were detected at any of the wavelengths used. There were also no detectable induced mutations in an excision-defective strain after 334-nm irradiation. These results are in contrast to the in vitro mutation of purified transforming DNA we previously observed.

DNA Repair↗
PubMedDate not supplied

Mutagenic lifestyles? A review of evidence of associations between germ-cell mutations in humans and smoking, alcohol consumption and use of 'recreational' drugs.

In humans, associations between germ-cell mutations and hypothetical aetiological factors can be investigated by (1) examining the relationship between the factor of interest and conditions known to be of genetic aetiology; (2) examining the relationship between conditions of unknown aetiology and route of exposure, especially paternal preconceptional exposure. As regards smoking, alcohol and 'recreational' drugs, the first approach has been applied in studies of retinoblastoma, Wilms' tumour and chromosomal anomalies. Only Down's syndrome has received intensive investigation, in relation to maternal smoking during pregnancy; the relative risks would be compatible with there being no association in all recognized conceptuses. The second approach has been applied in studies of sperm quality, miscarriage, congenital anomalies and childhood cancer. The available studies do not show a consistent relationship between smoking and sperm quality; there are few data on the effects of the other exposures. There are a substantial number of studies of childhood cancer and smoking by the father; the majority do not indicate any relationship. Some studies of childhood cancer suggest a positive association with use of 'recreational' drugs by the parents, but it has not been possible to clarify which route of exposure, or the specific type of drug which may be involved. Use of molecular techniques to detect individual genetic changes should enable progress to be made in elucidating the origin of mutation. In the meantime, public health actions are justified on the basis of the known non-genetic effects of these agents.

Abortion, Spontaneous↗
PubMed2006

Checkpoint deficient rad53-11 yeast cannot accumulate dNTPs in response to DNA damage.

Deoxyribonucleotide pools are maintained at levels that support efficient and yet accurate DNA replication and repair. Rad53 is part of a protein kinase regulatory cascade that, conceptually, promotes dNTP accumulation in four ways: (1) it activates the transcription of ribonucleotide reductase subunits by inhibiting the Crt1 repressor; (2) it plays a role in relocalization of ribonucleotide reductase subunits RNR2 and RNR4 from nucleus to cytoplasm; (3) it antagonizes the action of Sml1, a protein that binds and inhibits ribonucleotide reductase; and (4) it blocks cell-cycle progression in response to DNA damage, thus preventing dNTP consumption through replication forks. Although several lines of evidence support the above modes of Rad53 action, an effect of a rad53 mutation on dNTP levels has not been directly demonstrated. In fact, in a previous study, a rad53-11 mutation did not result in lower dNTP levels in asynchronous cells or in synchronized cells that entered the S-phase in the presence of the RNR inhibitor hydroxyurea. These anomalies prompted us to investigate whether the rad53-11 mutation affected dNTP levels in cells exposed to a DNA-damaging dose of ethylmethyl sulfonate (EMS). Although dNTP levels increased by 2- to 3-fold in EMS treated wild-type cells, rad53-11 cells showed no such change. Thus, the results indicate that Rad53 checkpoint function is not required for dNTP pool maintenance in normally growing cells, but is required for dNTP pool expansion in cells exposed to DNA-damaging agents.

Cell Cycle↗
PubMed2003

[Genetic features of atrial fibrillation].

Etiology of atrial fibrillation remains largely unknown. Molecular genetics is a powerful tool that may help to identify underlying mechanisms of the arrhythmia. As a matter of fact, a major step forward was the recent identification of the KCNQ1 gene coding a subunit of a potassium channel in IKS current as responsible for idiopathic atrial fibrillation in a familial autosomal dominant form. The KCNQ1 gain-of-function mutation may induce a shortening in action potential and in effective refractory periods leading to the initiation and persistence of atrial fibrillation. In the multifactorial forms of the disease, by far the most frequent, susceptibility genes and modifier genes are also currently being identified. This better understanding of the disease leads to new perspectives, particularly for therapeutists, and would enable them to work with more interest.

Atrial Fibrillation↗
PubMed1998

Cancer prevention: past, present, future.

There are many examples of different types of cancers that have been prevented by appropriate measures in the past. Most of them were related to occupational, iatrogenic or accidental factors, often as the outcome of heavy exposure of humans to specific carcinogenic agents. Cancer is a disease of DNA, and is generally associated with multiple genetic alterations, these being produced in the typical case by exposure to various carcinogens, each of which exists at minute concentrations. Thus, the impact of carcinogenic factors, xenobiotics and autobiotics, is due to their actions in concert. However, a single mutation yielding genomic instability exerts a disproportionately large influence by resulting in a large number of secondary mutational events. Epigenetic changes can also not be disregarded especially from the view point of prevention of neoplasia. The occurrence of multiple primary cancers among survivors of initial primaries, and the presence of hereditary groups with a high risk of cancer development provide a strong stimulus for establishment of effective approach for cancer prevention, which should be, in principle, multi-faceted. Therefore, a holistic approach is essential with improvement in life style including choosing a balanced diet and avoidance of cigarette smoking and other sources of carcinogens, as integral elements.

Anticarcinogenic Agents↗
PubMed2001

Toxicological profile of pollutants in surface water from an area in Taihu Lake, Yangtze Delta.

The environment in urbanized areas is often contaminated with a complex mixture of toxic compounds originating from industries, agriculture and private households. Most of the contaminants end up in surface waters, such as lakes, rivers and finally the sea. Toxic contaminants may disturb the biological condition of aquatic ecosystems and be harmful for humans, if they are transported to human food or drinking water. A variety of biological tests have been introduced for monitoring the toxicological profile of aquatic ecosystems. In the present investigation, genotoxic, hormone disrupting and Ah-receptor activity was analyzed in water collected in January 1999 at Meiliang Bay, Taihu Lake, China, near to the city of Wuxi in the Shanghai area. Significant mutagenic activity could be detected in water extracts with the Salmonella/microsome assay and the arabinose resistance test. Frame shift mutations were the predominant mode of action. Ah-receptor active compounds were detected by using a luciferase reporter gene assay (CALUX-assay). The estimated toxic equivalent factor-values ranged between 134 and 232 pg TCCD-equivalents per liter lake water. The estrogen-like potential of Taihu water was estimated with two luciferase reporter gene assays using transgenic human cell lines expressing estrogen receptor alpha. Estradiol equivalents obtained with water extracts were in the range of 2.2-12.1 ng/l. We also analyzed the concentrations of 17-beta-estradiol and ethinylestradiol in the extracts using a high-pressure liquid chromatography-method. The values obtained correlated with the biologically determined estradiol equivalents, indicating that the estrogenic activity is mainly due to natural and synthetic hormones rather than xenoestrogens.

Cell Line↗
PubMed1999

Symmetry breaking and adaptation: evidence from a 'toy model' of a virus.

We argue that an induced breaking of the genetic synonym symmetry due to the action of genetic operators such as mutation can enhance the adaptability of a species to changes in the environment. In the case of a virus, the claim is that the codon bias in the neutralization epitope improves the virus' ability to generate mutants that evade the induced immune response. We support our claim with a simple 'toy model' of a viral epitope evolving in competition with the immune system. The effective selective advantage of a higher mutability leads to a dominance of codons that favor non-synonymous mutations. As further evidence we present a simple model for a genetic regulatory network that leads to adaptive evolution in a population of giraffes by means of an induced symmetry breaking rather than through any direct selective advantage.

Adaptation, Physiological↗
PubMed2003

Interaction of HLA-DR with an acidic face of HLA-DM disrupts sequence-dependent interactions with peptides.

HLA-DM (DM) edits major histocompatibility complex class II (MHCII)-bound peptides in endocytic compartments and stabilizes empty MHCII molecules. Crystal structures of DM have revealed similarity to MHCII but not how DM and MHCII interact. We used mutagenesis to map a MHCII-interacting surface on DM. Mutations on this surface impair DM action on HLA-DR and -DP in cells and DM-dependent peptide loading in vitro. The orientation of DM and MHCII predicted by these studies guided design of soluble DM and DR molecules fused to leucine zippers via their beta chains, resulting in stable DM/DR complexes. Peptide release from the complexes was fast and only weakly sequence dependent, arguing that DM diminishes the selectivity of the MHCII groove. Analysis of soluble DM action on soluble DR/peptide complexes corroborates this conclusion.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2002

Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases.

Protein aggregation and the formation of highly insoluble amyloid structures is associated with a range of debilitating human conditions, which include Alzheimer's disease, Parkinson's disease, and the Creutzfeldt-Jakob disease. Muscle acylphosphatase (AcP) has already provided significant insights into mutational changes that modulate amyloid formation. In the present paper, we have used this system to investigate the effects of mutations that modify the charge state of a protein without affecting significantly the hydrophobicity or secondary structural propensities of the polypeptide chain. A highly significant inverse correlation was found to exist between the rates of aggregation of the protein variants under denaturing conditions and their overall net charge. This result indicates that aggregation is generally favored by mutations that bring the net charge of the protein closer to neutrality. In light of this finding, we have analyzed natural mutations associated with familial forms of amyloid diseases that involve alteration of the net charge of the proteins or protein fragments associated with the diseases. Sixteen mutations have been identified for which the mechanism of action that causes the pathological condition is not yet known or fully understood. Remarkably, 14 of these 16 mutations cause the net charge of the corresponding peptide or protein that converts into amyloid deposits to be reduced. This result suggests that charge has been a key parameter in molecular evolution to ensure the avoidance of protein aggregation and identifies reduction of the net charge as an important determinant in at least some forms of protein deposition diseases.

Alzheimer Disease↗
PubMed1989

Bacteriophage T4 DNA topoisomerase is the target of antitumor agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia coli.

The mammalian type II DNA topoisomerase has been proposed to be the intracellular target of a variety of antitumor agents, including m-AMSA [4'-(9-acridinylamino)-methanesulfon-m-anisidide]. Because the bacteriophage T4-encoded topoisomerase resembles the mammalian enzyme, we are using T4 as a simple model system to investigate the mechanism of action of m-AMSA. A mutation that renders T4 growth m-AMSA-resistant is closely linked to an amber mutation in T4 gene 39, which encodes one of the topoisomerase subunits. In addition, the gene 39 subunit from the m-AMSA-resistant mutant phage has an altered net charge, strongly indicating that the drug-resistance mutation is within gene 39. Topoisomerase purified from mutant phage-infected Escherichia coli exhibits drug-insensitive DNA relaxation and DNA cleavage activities. Because a single mutation results in both drug-resistant phage growth and a drug-insensitive viral topoisomerase, we conclude that the T4-encoded type II DNA topoisomerase is the physiological target of m-AMSA in phage-infected E. coli.

Amsacrine↗
PubMed1997

HIV Rev-dependent binding of SF2/ASF to the Rev response element: possible role in Rev-mediated inhibition of HIV RNA splicing.

Production of the structural and enzymatic proteins of type 1 human immunodeficiency virus (HIV-1) is controlled by the rev regulatory gene product. The 116-amino acid Rev protein acts by binding to the Rev response element (RRE), a complex RNA stem-loop structure located within the env gene of HIV. Rev exerts a series of posttranscriptional effects, including the inhibition of viral RNA splicing, the activation of nuclear export of incompletely spliced viral RNAs, and the enhancement of translation of RRE-containing RNAs. Our studies now demonstrate that at least one member of the SR family of splicing factors, SF2/ASF, specifically binds to a subregion of the RRE in vitro in a Rev-dependent manner. Furthermore, expression of high levels of SF2/ASF inhibits Rev function and impairs HIV replication in vivo. Both the in vitro binding of SF2/ASF to the Rev/RRE complex and the in vivo inhibition of Rev action by SF2/ASF are abrogated by mutation of the N-terminal RNA recognition motif but are not affected by mutation of the C-terminal arginine-serine-rich domain. These findings suggest that Rev inhibition of HIV splicing likely involves recruitment of the essential splicing factor SF2/ASF to the Rev/RRE complex. However, these inhibitory effects of Rev on viral RNA splicing are apparently overcome by augmenting the intracellular levels of SF2/ASF expression.

Animals↗