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PubMed1992

Action of the Brachyury gene in mouse embryogenesis.

The murine developmental mutation T identifies a gene required in mesoderm formation. T/T mutant embryos develop normally to the primitive streak stage; during early organogenesis they show insufficient mesoderm and absence of the notochord. The mutants die at around 10 days of gestation because of the lack of the allantois. We have localized the T mutation relative to DNA markers and used a combination of genetic and molecular techniques to clone the T gene. Expression of the T gene is restricted to nascent mesoderm and to the notochord, the tissues most strongly affected by the mutation. Recent results suggest that the T gene encodes a nuclear factor involved in establishing notochord cell identity and differentiation, and is directly or indirectly involved in the organization of axial development.

Animals↗
PubMed1989

Mutagenic action of heavy ions on Escherichia coli cells.

Induction of direct mutations in the lactose operon of E. coli cells by gamma-radiation and accelerated heavy ions with different LET was studied. The experiments were performed with the wild-type PolA and LexA strains. A quadratic dependence of the mutation rate on the dose of different radiations for the wild-type strain and the PolA mutant was observed. However, different types of radiation showed different relative genetic effectivenesses (RGE). The dependence of RGE on LET for the wild-type and PolA strain has a maximum. A LexA strain showed much reduced mutation rates and a linear dose response. The RGE decreased with increasing LET of ionizing radiation.

Bacterial Proteins↗
PubMed1999

Cerebellar GABA(A) receptors and anxiolytic action of diazepam.

Alcohol-sensitive ANT rats have a point mutation in the cerebellum-enriched GABA(A) receptor alpha6 subunit, which makes this subunit and the ANT rats in vivo highly sensitive to benzodiazepine agonists. In the elevated plus maze test of anxiety, diazepam produced a greater anxiolytic response in the ANT rats than in the control, alcohol-insensitive AT rats. The ANT rats were less sensitive to the sedative effect of diazepam in the staircase test of exploration. The results thus suggest that the mutant cerebellar granule cell layer receptors can participate in GABA(A) receptor-activation-induced anxiolysis.

Analysis of Variance↗
PubMed1999

Mutant human alpha(1)beta(1)(T262Q) GABA(A) receptors are directly activated but not modulated by pentobarbital.

Pentobarbital activates GABA(A) receptors and enhances GABA-activated currents. A threonine residue (262) in the second membrane spanning region at the 12' position in the beta(1) subunit, alpha(1)beta(1)(T12'Q), is necessary for the potentiating action of pentobarbital. We examined whether T12'Q-mutated receptors expressed in Spodoptera frugipedra (Sf 9) cells responded to direct activation by pentobarbital. In both mutant and wild type receptors, pentobarbital (100 microM to 1 mM) evoked a current response. The pentobarbital EC(50) values were similar; 119 and 158 microM for alpha(1)beta(1) and alpha(1)beta(1)(T12'Q) receptors, respectively. The results show it is possible to discriminate between agonistic and potentiating effects of pentobarbital, suggesting these actions involve separate mechanisms.

Amino Acid Substitution↗
PubMedDate not supplied

[Mutagenic action of platinum and palladium compounds on bacteria].

Platinum complex compounds are shown to cause mutations in S. typhimurium strains, TA-100 and TA-98 bearing plasmid pKM-101 but not in isogenic strains TA-1535 and TA-1538 lacking the plasmid. The mutagenic action depended on the ligand nature in the complex and did not depend on the extent of the central atom oxidation. No mutagenic activity of the palladium compounds tested was found.

Cisplatin↗
PubMed2002

Effects of mutations in the insulin-like growth factor signaling system on embryonic pancreas development and beta-cell compensation to insulin resistance.

Insulin and insulin-like growth factors (IGF) play overlapping and complementary roles in pancreatic beta-cell function and peripheral metabolism. In this study, we have analyzed mice bearing loss-of-function mutations of the insulin/IGF signaling systems. Combined inactivation of insulin receptor (Insr) and Igf1 receptor (Igf1r), but not of either receptor alone, resulted in a 90% decrease in the size of the exocrine pancreas, because of decreased cellular proliferation. In contrast to the findings in the exocrine compartment, endocrine alpha- and beta-cell development was unperturbed. Combined ablation of Igf1 and Igf2, the ligands for these two receptors, resulted in an identical phenotype. We also examined the effect of heterozygous null Igf1r mutations on glucose homeostasis in adult mice. Igf1r haploinsufficiency did not affect insulin action and compensatory beta-cell growth in insulin-resistant mice with combined Insr and Igf1r heterozygous null mutations, resulting in a considerably milder phenotype than combined haploinsufficiency for Insr and its main signaling substrates, Irs1 and Irs2. We conclude that Igf1r and Insr are required for embryonic development of the exocrine but not of the endocrine pancreas and that defects of Igf1r do not alter glucose homeostasis as long as the insulin receptor system remains intact.

Animals↗
PubMed1983

Role of gene and chromosomal mutations in cell transformation.

To understand the role of mutagenesis in carcinogenesis fully, we must consider all types of mutations including gene, chromosomal, and gene-number mutations and all changes involved in the progressive development of neoplastic cells. We have found that certain known human carcinogens (i.e., DES and asbestos), which were classified as epigenetic carcinogens based on gene-mutation assays, have mutational activity at the chromosomal level that correlates with their ability to induce cell transformation. This should caution against classification of chemicals as genotoxic or epigenetic without a complete understanding of their mechanism of action. Furthermore, our studies indicate that more than gene-mutation assays is needed for carcinogen testing. In particular, chromosomal changes induced by chemicals, both aberrations and aneuploidy, need to be carefully assessed. In addition, the role of all types of mutation in the overall process of neoplastic transformation needs to be determined. This can only be examined by studying each individual change involved in neoplastic progression. Thus, any attempt to assess a chemical's carcinogenic potential should consider not only all types of mutational changes but both early and late changes involved in neoplastic transformation.

2-Aminopurine↗
PubMed1996

An efficient laboratory protocol for the sequencing of large numbers of lacI mutants recovered from Big Blue transgenic animals.

Mutational spectra provide a powerful approach to investigate both the mutagenic potential and the mechanism of action of suspected mutagens and carcinogens. Recently, transgenic techniques have made it possible to generate mutational spectra in animals. Such a spectrum may consist of 50 to 200 mutants depending on the nature of the mutations, and many spectra can be generated depending on the design of the experiment. This report describes a practical approach for the processing and sequencing of large numbers of lacI mutants recovered from Big Blue animals.

Animals↗
PubMed2004

Functional implications of a novel EA2 mutation in the P/Q-type calcium channel.

Episodic ataxia type 2 (EA2) is an autosomal dominant condition characterized by paroxysmal attacks of ataxia, vertigo, and nausea, typically lasting minutes to days in duration. These symptoms can be prevented or significantly attenuated by the oral administration of acetazolamide; however, the mechanism by which acetazolamide ameliorates EA2 symptoms is unknown. EA2 typically results from nonsense mutations in the CACNA1A gene that encodes the alpha1A (Cav2.1) subunit of the P/Q-type calcium (Ca2+) channel. We have identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore-forming region of the P/Q-type Ca2+ channel. Functional analysis of P/Q-type channels containing the mutation show that the H1736L alteration affects several channel properties, including reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values. Although these findings are consistent with an overall loss of P/Q-type channel function, the mutation also caused some biophysical changes consistent with a gain of function. We also tested the direct effect of acetazolamide on both wild-type and H1736L mutated P/Q-type channels and did not observe any direct action on channel properties of this pharmacological agent used to treat EA2 patients.

Acetazolamide↗
PubMed1986

Identification and characterization of mutations in Escherichia coli that selectively influence the growth of hybrid lambda bacteriophages carrying the immunity region of bacteriophage P22.

Mutations in two Escherichia coli genes, sipA and sipB, result in a specific inhibition of the growth of certain hybrid lambdoid bacteriophages, lambda immP22, that have the early regulatory regions and adjacent genes from bacteriophage P22. The sipB391 mutation maps near minute 56 and exerts the strongest inhibitory effect on the growth of the hybrid phages. The sipA1 mutation maps near minute 72 and plays an auxiliary role: enhancing the action of sipB391. Such a role is not limited to sipA1, since there is a similar enhancement by the nusA1 and nusE71 mutations. The Sip-imposed restriction on the growth of lambda immP22 phages is not observed if the phage carries a mutation in the c1 gene. Perhaps this reflects the fact that the c1 product regulates phage DNA replication and is a major determinant in the decision governing whether the phage takes the lytic or lysogenic pathway. Consistent with this idea is the observation that lambda immP22 DNA replication is severely inhibited in bacteria carrying the sipB391 mutation. It is suggested that sip mutations exaggerate the normal role of c1 in limiting lytic growth. This causes a failure in the expression of sufficient amounts of some or all of the lytic gene products required for phage growth.

Bacteriophage lambda↗
PubMed1987

[Genetic characteristics and protective properties of neamin-resistant mutant Salmonella typhimurium and S. dublin of the Nea(r) Str(s) and Nea(r) Str(r) 500 classes].

The genetic analysis of attenuated mutants, class Nea(r) Str(s), with the use of bacteriophage P 22 has shown that mutation rendering the mutants resistant to neamine is localized in gene nea A. In experiments with the intraperitoneal infection of mice, the appearance of this mutation in S. typhimurium and S. dublin virulent strains has been found to lead to the decrease of virulence in 100% of clones. On the basis of the data obtained in this investigation, region str-spc in S. typhimurium and S. dublin has been mapped. In contrast to mutation spc A, mutations nea A and str A have been shown to inhibit the action of amber suppressor. The investigation has confirmed the regularity, previously established for Shigella flexneri, concerning the relationship between the influence of mutations, occurring in the genes which determine resistance to neamine and streptomycin and control the synthesis of ribosomal proteins S4, S5, S12 and S17, on the virulence of S. typhimurium and S. dublin and the effect of these mutations on the accuracy of the translation of genetic information in the biosynthesis of protein: mutation spc A has been found to produce no changes in the virulence of salmonellae, while mutations nea A and str A cause its loss. Salmonella strains carrying mutations nea A and nea B have shown pronounced protective properties in experiments on mice.

Animals↗
PubMed1979

Chromosomal and extrachromosomal control of senescence in the ascomycete Podospora anserina.

In Podospora anserina senescence leading to cellular death occurs regularly after prolonged vegetative propagation. However, the life span of this ascomycete may be extended by various means: 1. Mutations in a least 8 morphogenetic genes belonging to 4 linkage groups postpone drastically or even prevent in certain pairwise combinations (e.g. i viv) the onset of senescence. 2. Inhibitors of mt DNA and of mitochondrial protein synthesis show a life prolonging effect when added in low concentrations to the growth medium. 3. A similar effect was found when mycelia were fed exclusively on non repressive carbon sources. Whereas the anti-aging effect of specific mutated genes is rather permanent, the life prolonging action of the inhibitors and carbon sources is restricted and temporary. These substances have no long lasting effect, since after their removal from the medium aging proceeds. Physiological experiments have further shown the existence of three phases in the life span of Podospora anserina. During the juvenile phase aging is prevented by all of these compounds; during the presenescent phase aging is prevented by inhibitors of mt DNA only, and during the senescent phase aging is irreversible. Senescence may be induced in juvenile protoplasts by DNA extracted from senescent mycelia. This, together with the well known fact that senescence is extrachromosomically inherited, points to extrachromosomal DNA as the causative agent of senescence. This kind of DNA may be connected with or perhaps located in the mitochondria. Collectively, the data are consistent in showing that the syndrome of senescence in Podospora anserina is controlled by a chromosomal-extrachromosomal interaction. In this system, extrachromosomal DNA, perhaps a mt DNA, is identical with the infectious principle initiating the decay of the cell, and nuclear genes supervise its expression.

Aging↗
PubMed1991

Mutations in the guanine nucleotide-binding domains of a yeast G alpha protein confer a constitutive or uninducible state to the pheromone response pathway.

Several domains of guanine nucleotide-binding proteins are conserved and form the guanine nucleotide-binding pocket. Mutations in these domains in EF-Tu, ras, and Gas have been shown to result in informative phenotypes. We made several analogous changes in SCG1, which encodes the alpha subunit of the G protein involved in pheromone response in yeast. The scg1Lys388 and scg1Ala391 mutations resulted in severe growth and cell morphology defects; this phenotype is similar to the null phenotype and results from constitutive activation of the pheromone response pathway. On the basis of the model for the action of the yeast G protein, the effect of these mutations is consistent with the effect of analogous mutations in ras, which result in a transforming phenotype. The SCG1Ala322 mutation resulted in pheromone response and mating defects. This effect is similar to the effect of the analogous G alpha s mutation, which results in a defect in stimulation of adenylate cyclase. The scg1Val50 mutation, which is analogous to the transforming mutation rasVal12, resulted in multiple effects, including defects in growth, cell morphology, and mating. Some of our results and interpretations are different from previously published results of others for the same mutation in SCG1; specifically, our gene replacement of this mutation resulted in high basal activation of the pheromone response pathway, consistent with a GTPase defect, which was not seen previously with scg1Val50 on a low-copy plasmid. Implications of these phenotypes are discussed.

Base Sequence↗
PubMed2001

Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA.

Macrolides represent a clinically important class of antibiotics that block protein synthesis by interacting with the large ribosomal subunit. The macrolide binding site is composed primarily of rRNA. However, the mode of interaction of macrolides with rRNA and the exact location of the drug binding site have yet to be described. A new class of macrolide antibiotics, known as ketolides, show improved activity against organisms that have developed resistance to previously used macrolides. The biochemical reasons for increased potency of ketolides remain unknown. Here we describe the first mutation that confers resistance to ketolide antibiotics while leaving cells sensitive to other types of macrolides. A transition of U to C at position 2609 of 23S rRNA rendered E. coli cells resistant to two different types of ketolides, telithromycin and ABT-773, but increased slightly the sensitivity to erythromycin, azithromycin, and a cladinose-containing derivative of telithromycin. Ribosomes isolated from the mutant cells had reduced affinity for ketolides, while their affinity for erythromycin was not diminished. Possible direct interaction of ketolides with position 2609 in 23S rRNA was further confirmed by RNA footprinting. The newly isolated ketolide-resistance mutation, as well as 23S rRNA positions shown previously to be involved in interaction with macrolide antibiotics, have been modeled in the crystallographic structure of the large ribosomal subunit. The location of the macrolide binding site in the nascent peptide exit tunnel at some distance from the peptidyl transferase center agrees with the proposed model of macrolide inhibitory action and explains the dominant nature of macrolide resistance mutations. Spatial separation of the rRNA residues involved in universal contacts with macrolides from those believed to participate in structure-specific interactions with ketolides provides the structural basis for the improved activity of the broader spectrum group of macrolide antibiotics.

Anti-Bacterial Agents↗
PubMed1989

Defective sterol C5-6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals.

Two azole resistant isolates of Saccharomyces cerevisiae carried mutations allelic to erg 3 and were blocked to differing degrees at the C5-6 desaturation step of ergosterol biosynthesis. When treated with the sterol 14 alpha-demethylation inhibitor fluconazole the wild-type sensitive strain accumulated lanosterol and 14 alpha-methyl-erogosta-8,24(28)-dien-3 beta, 6 alpha-diol (14-methyl-3,6 diol). The stringent desaturase mutant, A2, accumulated 14 alpha-methyl-8,24(28)-dien-3 beta-ol (14-methyl fecosterol) and lanosterol as the major sterol components when treated with fluconazole. Resistant isolate A3 accumulated 14-methyl-3,6-diol, 14-methyl fecosterol, and lanosterol and was only partially blocked at sterol C5-6 desaturation. We conclude that functional sterol C5-6 desaturase is required for the synthesis of 14-methyl-3,6-diol under conditions of azole inhibition. We present a new hypothesis for the mode of action of azole antifungals based on the inability of 14-methyl-3,6-diol to support growth, and suggest that growth can occur through utilisation of 14-methyl fecosterol, produced by a combination of azole inhibition and defective sterol C5-6 desaturation.

Antifungal Agents↗
PubMed1989

Actions of dendrotoxin on K+ channels and neuromuscular transmission in Drosophila melanogaster, and its effects in synergy with K+ channel-specific drugs and mutations.

The blockade of K+ channels and enhancement of neuromuscular transmission by dendrotoxin (DTX), a convulsant peptide from mamba snake venom, were examined in normal and mutant larval preparations of Drosophila. Two-microelectrode voltage-clamp experiments showed that DTX reduced the transient K+ current, IA, in muscle membrane. This effect was suppressed by raising the Mg2+ concentration or by lowering the temperature. The interaction of DTX with Mg2+ was further analyzed at a low cation concentration, at which DTX reduced both IA and the delayed rectifier IK. These results were correlated with the action of DTX on the neuromuscular junction. Its facilitatory effect on excitatory junctional potentials (EJPs) was relatively mild but the effect was drastically enhanced when combined with certain mutations and K+ channel blocking drugs, leading to repetitive or prolonged giant EJPs. Only the mutations or drugs that reduced IK or the Ca2(+)-dependent K+ current, ICF, could yield these synergistic effects with DTX. In contrast, the abnormal EJPs caused by the mutation or drug that blocked IA were not further enhanced by DTX, indicating that DTX also affects IA at the neuromuscular junction. Thus, the A-type K+ channels in muscle and nerve terminals appeared very similar in their sensitivity to the specific toxin, drugs and mutations examined here.

4-Aminopyridine↗
PubMed1975

Mutagenic activity of hydrazine and its combinations with maleic mydrazide and X-rays in barley.

The study was undertaken to investigate the mutagenic activity of hydrazine hydrate a structural isomer of the nucleic acid base thymidine in barley. The treatments were administered alone or in the presence of maleic hydrazide and X-rays. Hydrazine was able to produce chlorophyll mutations in the M1-generation itself if applied alone, in a mixture or as a last treatment in a sequence. In the M2-generation, however, segregation for chlorophyll mutations was observed in all the treatments. The possible mode of action of the mutagen is discussed.

Edible Grain↗
PubMed1996

Relationship between insulin sensitivity and insulin receptor substrate-1 mutations in non-diabetic relatives of NIDDM families.

Insulin receptor substrate-1 (IRS-1) occupies a key position in the insulin-signalling pathway. Two mutations of the IRS-1 gene (Gly(972)Arg and Ala(513)Pro) have been described, although their roles in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. Insulin resistance has been described in non-diabetic relatives of NIDDM families, suggesting that it may be due to an inherited defect of insulin action. We therefore examined the relationships between the two mutations and insulin sensitivity in 93 non-diabetic first degree relatives from North European families with 2 or more living NIDDM subjects. Anthropometric measurements, an oral glucose tolerance test, and an insulin tolerance test to assess insulin sensitivity (K(ITT)) were performed. Basal insulin sensitivity was assessed by homeostasis model assessment (HOMA). Comparisons were made between the following relative subgroups: with (n = 9) and without (n = 84) the 972 mutation; with (n = 5) and without (n = 88) the 513 mutation; and with either one or both mutations (n = 13) or without either (n = 80). General linear model analysis was used to compare K(ITT) and HOMA between the subgroups with the anthropometric variables known to influence insulin sensitivity as covariates. There were no significant differences between the subgroups for K(ITT) and HOMA. In conclusion, the 513 and 972 mutations, alone and in combination, are not associated with decreased insulin sensitivity in non-diabetic relatives of NIDDM families.

Adult↗