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PubMed2004

The Booroola (FecB) mutation is associated with smaller adrenal glands in young adult ewes.

The Booroola (FecB) phenotype is associated with a mutation in the bone morphogenetic protein (BMP) receptor 1B. The BMP action is important during development; surprisingly the only differences so far observed in adult animals are restricted to the ovaries where precocious development of the antral follicles and increased ovulation rate of mutant ewes is observed. The internal organs of 17 ewes homozygous for the mutation (BB) and 18 wild-type ewes (++) were macroscopically examined and weighed. No macroscopic differences were found, and the weight of the heart, liver, lungs, kidneys, and spleen were similar for both genotypes (P > 0.05). In contrast, the adrenals of BB ewes were lighter than those of ++ ewes (P < 0.05). The effect of the mutation on the adrenal function of cortisol secretion was measured at basal level and after an adrenocorticotrophic hormone challenge, before and after dexamethasone suppression. The Booroola mutation had no effect (P > 0.05) in any of these conditions. These findings indicate that the Booroola mutation also affects the size of the adrenal glands and suggest that the mutated gene could be important in the development of other organs in addition to the ovary. However, in the mutant ewes the function of the adrenal glands is not compromised or it is compensated.

Adrenal Glands↗
PubMed1998

[Determination of the mutagenic activity of cyclohexane extract of atmospheric air dust and polycyclic aromatic hydrocarbons on various strains of Drosophila melanogaster].

Using the test of somatic mutation and recombination (SMART) the mutagenic activity was studied in two cross-breed Drosophila melanogaster strains. In the strain mwh x ORR;flr3/TM3, Ser the concentration of cytochrome P-450-associated enzymes necessary faetivation of many promutagens, e.g. benzo(a)pyrene is many times higher. Cyclohexane extracts of atmospheric dust and certain polycyclic aromatic hydrocarbons were studied separately or in combination of two different ones. The study showed that: reliable results of the determinations of the mutagenicity of various polycyclic aromatic hydrocarbons were obtained only with the strain with high activity of enzymes activating promutagens, that is strain OR;flt3/TM3,Ser; mixtures of promutagens in concentrations of several mmols can show lower mutagenicity than the most mutagenic component of the mixture given separately. This could be the cause of stopped rise of the dose-response curve; an overwhelming majority of mutations in studies of tar substances is not due to the action of strongly acting promutagens among the polycyclic aromatic hydrocarbons studied here, including BaP.

Air↗
PubMed1984

[Genetic activity of base analogs in Salmonella typhimurium and Escherichia coli and Saccharomyces cerevisiae].

The study of 6-N-hydroxylaminopurine (HAP) and 2-amino-6-N-hydroxylaminopurine (AHAP) activity in bacteria and the yeast was undertaken. AHAP was found to be more effective as a mutagen in bacteria and HAP--in the yeast. Mutagenic and lethal effects or analogues were independent of excision and mutagenic repair both in bacteria and the yeast. Deletion in uvrB region of Salmonella genome leads to hypersensitivity to lethal and mutagenic action of analogues. Both of the latter only cause reversions of base-substitution but not frameshift mutations. Considering the data obtained and the information from published papers, we proposed that HAP and AHAP exert their mutagenic action, like classical analogues, by means of incorporation into DNA and disturbing the regular replication laws.

4-Nitroquinoline-1-oxide↗
PubMed1999

Ca2+ sensitization and potentiation of the maximum level of myofibrillar ATPase activity caused by mutations of troponin T found in familial hypertrophic cardiomyopathy.

Human wild-type cardiac troponin T, I, C and five troponin T mutants (I79N, R92Q, F110I, E244D, and R278C) causing familial hypertrophic cardiomyopathy were expressed in Escherichia coli, and then were purified and incorporated into rabbit cardiac myofibrils using a troponin exchange technique. The Ca2+-sensitive ATPase activity of these myofibrillar preparations was measured in order to examine the functional consequences of these troponin mutations. An I79N troponin T mutation was found to cause a definite increase in Ca2+ sensitivity of the myofibrillar ATPase activity without inducing any significant change in the maximum level of ATPase activity. A detailed analysis indicated the inhibitory action of troponin I to be impaired by the I79N troponin T mutation. Two more troponin T mutations (R92Q and R278C) were also found to have a Ca2+-sensitizing effect without inducing any change in maximum ATPase activity. Two other troponin T mutations (F110I and E244D) had no Ca2+-sensitizing effects on the ATPase activity, but remarkably potentiated the maximum level of ATPase activity. These findings indicate that hypertrophic cardiomyopathy-linked troponin T mutations have at least two different effects on the Ca2+-sensitive ATPase activity, Ca2+-sensitization and potentiation of the maximum level of the ATPase activity.

Animals↗
PubMed2005

The suppressed proliferation and premature senescence by ganciclovir in p53-mutated human non-small-lung cancer cells acquiring herpes simplex virus-thymidine kinase cDNA.

The concerted actions of molecular networks determine how cells undergo proliferation, death or aging. Here we show that the highly invasive, tumorigenic human non-small-cell-lung cancer (NSCLC) cells carrying mutated p53 alleles were transfected with herpes simplex virus-thymidine kinase (HSV-tk) cDNA and the selected clone was susceptible to exogenous ganciclovir (GCV). The work further indicated that, in the stable HSV-tk transfectants, GCV suppressed cell proliferation by inducing G(2)/M cell cycle arrest and premature senescence and the potency can be amplified through bystander effect. The growth suppression of the established tumor xenografts in nude mice can be successfully targeted by GCV. These data showed that the GCV-suppressed tumor cell proliferation can be coordinated by cell cycle arrest and cellular senescence in HSV-tk transfectant lacking wild-type p53.

Animals↗
PubMed2001

Identification of crucial hydrogen-bonding residues for the interaction of herpes simplex virus DNA polymerase subunits via peptide display, mutational, and calorimetric approaches.

The catalytic subunit, Pol, of herpes simplex virus DNA polymerase interacts via its extreme C terminus with the processivity subunit, UL42. This interaction is critical for viral replication and thus a potential target for antiviral drug action. To investigate the Pol-binding region on UL42, we engineered UL42 mutations but also used random peptide display to identify artificial ligands of the Pol C terminus. The latter approach selected ligands with homology to residues 171 to 176 of UL42. Substitution of glutamine 171 with alanine greatly impaired binding to Pol and stimulation of long-chain DNA synthesis by Pol, identifying this residue as crucial for subunit interactions. To study these interactions quantitatively, we used isothermal titration calorimetry and wild-type and mutant forms of Pol-derived peptides and UL42. Each of three peptides corresponding to either the last 36, 27, or 18 residues of Pol bound specifically to UL42 in a 1:1 complex with a dissociation constant of 1 to 2 microM. Thus, the last 18 residues suffice for most of the binding energy, which was due mainly to a change in enthalpy. Substitutions at positions corresponding to Pol residue 1228 or 1229 or at UL42 residue 171 abolished or greatly reduced binding. These residues participate in hydrogen bonds observed in the crystal structure of the C terminus of Pol bound to UL42. Thus, interruption of these few bonds is sufficient to disrupt the interaction, suggesting that small molecules targeting the relevant side chains could interfere with Pol-UL42 binding.

Alanine↗
PubMed1995

CNTF variants with increased biological potency and receptor selectivity define a functional site of receptor interaction.

Human CNTF is a neurocytokine that elicits potent neurotrophic effects by activating a receptor complex composed of the ligand-specific alpha-receptor subunit (CNTFR alpha) and two signal transducing proteins, which together constitute a receptor for leukemia inhibitory factor (LIFR). At high concentrations, CNTF can also activate the LIFR and possibly other cross-reactive cytokine receptors in the absence of CNTFR alpha. To gain a better understanding of its structure-function relationships and to develop analogs with increased receptor specificity, the cytokine was submitted to affinity maturation using phage display technology. Variants with greatly increased CNTFR alpha affinity were selected from a phage-displayed library of CNTF variants carrying random amino acid substitutions in the putative D helix. Selected variants contained substitutions of the wild-type Gln167 residue, either alone or in combination with neighboring mutations. These results provide evidence for an important functional role of the mutagenized region in CNTFR alpha binding. Affinity enhancing mutations conferred to CNTF increased potency to trigger biological effects mediated by CNTFR alpha and enhanced neurotrophic activity on chicken ciliary neurons. In contrast, the same mutations did not potentiate the CNTFR alpha-independent receptor actions of CNTF. These CNTF analogs thus represent receptor-specific superagonists, which should help to elucidate the mechanisms underlying the pleiotropic actions of the neurocytokine.

Amino Acid Sequence↗
PubMed1993

The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.

Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.

Animals↗
PubMed2003

KCNQ1 gain-of-function mutation in familial atrial fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming alpha subunit of the cardiac I(Ks) channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.

Action Potentials↗
PubMedDate not supplied

[Mutagenic effects of gamma-rays on plasmid DNA in Escherichia coli].

A purified and dried DNA of plasmid pKO482 (galK+) is 10 times more resistant to the inactivating action of 60Co-gamma-rays than that of lambda phage. gamma-Irradiation of the plasmid DNA induces forward mutations of galK, the frequency of which increases linearly with the dose. The efficiency of the mutagenic action of gamma-rays on the plasmid galK locus is 10(-12) per 1 rad and per 1 base pair. The mutagenic effect of gamma-radiation but slightly depends upon bacterial recA+ gene and upon the SOS-repair system induced by UV-irradiation of the recipient cells. It is assumed that the premutational lesions induced in the purified DNA by the direct effect of gamma-radiation are fixed into mutations by misreplication.

DNA, Bacterial↗
PubMed1992

Mutations recovered in the Chinese hamster aprt gene after exposure to carboplatin: a comparison with cisplatin.

Platinum-based compounds such as cisplatin and carboplatin are currently used for the treatment of a variety of solid tumors. Their primary mode of action involves the production of cross-links in DNA. These compounds induce mutations in bacterial as well as in mammalian cells. Previously we determined the sequence specificity and mutational outcome in the Chinese hamster aprt gene in mutants isolated after exposure to cisplatin. The second-generation platinum drug, carboplatin, is of clinical relevance because it displays different and less toxic effects. Here we report the mutagenic specificity of this related compound. Mutations recovered after exposure to carboplatin display the same preference for sequences that contain 5'-AGG-3', 5'-AGA-3' and 5'-GAG-3' as was found for cisplatin. We thus conclude that the mutagenic outcome of exposure to carboplatin and cisplatin respectively, is similar, if not identical.

Adenine Phosphoribosyltransferase↗
PubMed1998

Distinct structural requirements for the direct and indirect actions of the anaesthetic etomidate at GABA(A) receptors.

1. The intravenous anaesthetic etomidate augments GABA-gated chloride currents (indirect action) and, at higher concentrations, evokes chloride currents in the absence of GABA (direct action). 2. In order to identify amino acid residues essential for these actions, site directed mutagenesis was performed on the beta3 subunit. 3. Mutation of an asparagine to a serine residue at position 290 dramatically reduced both etomidate-induced chloride currents and its ability to enhance [3H]flunitrazepam binding in HEK293 cells expressing alpha1beta3gamma2 recombinant GABA(A) receptors. 4. In contrast, the indirect effect of etomidate was retained, though its potency was reduced. 5. These findings indicate that there are distinct requirements for these dual actions of etomidate at GABA(A) receptors.

Anesthetics, Intravenous↗
PubMed1998

Depression by miconazole of heat-induced respiratory-deficiency in Saccharomyces cerevisiae.

Miconazole, at 0.2 microM, decreased, by two orders of magnitude, the specific mutation rate of Saccharomyces cerevisiae to respiratory-deficient mutants (petites), which had been induced at either 37 degrees C or 39 degrees C. Identical concentrations of ketoconazole did not change the mutation rate. The results fit in the mechanisms of action which have been proposed for imidazole antimycotics, and constitute further support for the hypothesis that the targets of thermal death, in petite-positive associately-profiled yeasts, lie in the mitochondria.

Antifungal Agents↗
PubMed1984

Bacterial resistance to antibiotics.

Effective antibacterial drugs have been available for nearly 50 years. After the introduction of each new such drug, whether chemically synthesized or a naturally occurring antibiotic, bacterial resistance to it has emerged. The genetic mechanisms by which bacteria have acquired resistance were quite unexpected; a new evolutionary pathways has been revealed. Although some antibiotic resistance has resulted from mutational changes in structural proteins--targets for the drugs' action--most has resulted from the acquisition of new, ready-made genes from an external source--that is, from another bacterium. Vectors of the resistance genes are plasmids--heritable DNA molecules that are transmissible between bacterial cells. Plasmids without antibiotic-resistance genes are common in all kinds of bacteria. Resistance plasmids have resulted from the insertion of new DNA sequences into previously existing plasmids. Thus, the spread of antibiotic resistance is at three levels: bacteria between people or animals; plasmids between bacteria; and transposable genes between plasmids.

Anti-Bacterial Agents↗
PubMed1981

A possible role of iron deficiency in gastric cancer in Colombia.

Through the efforts of Correa, Cuello, Haenszel, Tannenbaum and others it was learned that the incidence of gastric cancer in certain areas of Narino (Colombia) was among the highest in the world. These areas of high risk for gastric cancer were adjacent to an area of substantially lower risk. Gastric biopsies from healthy volunteers residing in the "high risk" area exhibited a greater incidence of superficial gastritis and chronic atrophic gastritis with and without intestinal metaplasia than those from the low risk area. The latter pathological finding is considered to be a precursor lesion to gastric cancer. Volunteers from the "low risk" area as well as individuals from Cali in the coastal region and Cartegena on the coast, also exhibited a similar spectrum of pathology but at a substantially reduced frequency. Natives of both cities were also at lower risk for gastric cancer than inhabitants of Narino. It was found that the water supply of the "high risk" area contained a higher concentration of nitrate than water in the "low risk" area. Correa et al. hypothesized that the high nitrate concentrations of well water contributed to the formation of N-nitroso compounds in the stomachs of these individuals early in life. The occurrence of this putative carcinogen in combination with the abrasive action of dietary grains contributed to a series of mutations in the gastric epithelium progressing through a sequence of pathologic changes, loss of gastric acid and culminating in gastric cancer. In the current report individuals in a Medellin population who were admitted with abdominal complaints and were found to be iron deficient exhibited the same spectrum of gastric pathology described by previous investigators. Superficial gastritis, chronic atrophic gastritis and achlorhydria have also been described in association with chronic iron deficiency (and/or associated nutritional defects) per se. The development of these lesions are likely to occur within the first two decades of life when iron requirements are maximal. It is suggested that these changes preceed the development of gastric cancer. Bacterial colonization of the achlorhydric stomach may facilitate nitrate reduction and the formation of a putative carcinogen N-nitroso compound(s) from nitrate in the water supply. Additionally, the effects of chronic iron deficiency on host immune defense may compromise these mechanisms and permit tumor growth with minimal immune intervention.

Achlorhydria↗
PubMed1984

Near-ultraviolet radiation blocks SOS responses to DNA damage in Escherichia coli.

Escherichia coli cells in which the recA promoter is fused to a lac structural gene, (Mu) Mud(Ap,lac)::rec, were irradiated with two far-ultraviolet light wavelengths (254 and 290 nm), selected monochromatic near-ultraviolet (NUV) wavelengths 313 nm, 334 nm, 365 nm, or broad band solar-UV (290-420 nm) from a solar simulator. Irradiation with the two far-ultraviolet wavelengths was followed by high yields of beta-galactosidase, lambda prophage induction, and Weigle reactivation. These end points were not observed after irradiation with the selected NUV wavelengths or the broad spectrum solar-UV. Thus, neither broad spectrum solar-UV nor monochromatic NUV wavelengths resulted in the derepression of the recA promoter. Further, prior exposure of the cells either to the selected monochromatic NUV wavelengths or to solar-UV inhibited (a) the induction of beta-galactosidase by subsequent 254-nm radiation, (b) subsequent 254-nm induction of lambda prophage, (c) Weigle reactivation, and (d) mutation frequency. These observations are consistent with the hypothesis that NUV blocks subsequent recA protease action.

Bacteriophage lambda↗
PubMed2000

Structure and function of small heat shock/alpha-crystallin proteins: established concepts and emerging ideas.

Small heat shock/alpha-crystallin proteins are defined by conserved sequence of approximately 90 amino acid residues, termed the alpha-crystallin domain, which is bounded by variable amino- and carboxy-terminal extensions. These proteins form oligomers, most of uncertain quaternary structure, and oligomerization is prerequisite to their function as molecular chaperones. Sequence modelling and physical analyses show that the secondary structure of small heat shock/alpha-crystallin proteins is predominately beta-pleated sheet. Crystallography, site-directed spin-labelling and yeast two-hybrid selection demonstrate regions of secondary structure within the alpha-crystallin domain that interact during oligomer assembly, a process also dependent on the amino terminus. Oligomers are dynamic, exhibiting subunit exchange and organizational plasticity, perhaps leading to functional diversity. Exposure of hydrophobic residues by structural modification facilitates chaperoning where denaturing proteins in the molten globule state associate with oligomers. The flexible carboxy-terminal extension contributes to chaperone activity by enhancing the solubility of small heat shock/alpha-crystallin proteins. Site-directed mutagenesis has yielded proteins where the effect of the change on structure and function depends upon the residue modified, the organism under study and the analytical techniques used. Most revealing, substitution of a conserved arginine residue within the alpha-crystallin domain has a major impact on quaternary structure and chaperone action probably through realignment of beta-sheets. These mutations are linked to inherited diseases. Oligomer size is regulated by a stress-responsive cascade including MAPKAP kinase 2/3 and p38. Phosphorylation of small heat shock/alpha-crystallin proteins has important consequences within stressed cells, especially for microfilaments.

Animals↗
PubMed2003

Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.

The SLC6 family is a diverse set of transporters that mediate solute translocation across cell plasma membranes by coupling solute transport to the cotransport of sodium and chloride down their electrochemical gradients. These transporters probably have 12 transmembrane domains, with cytoplasmic N- and C-terminal tails, and at least some may function as homo-oligomers. Family members include the transporters for the inhibitory neurotransmitters GABA and glycine, the aminergic transmitters norepinephrine, serotonin, and dopamine, the osmolytes betaine and taurine, the amino acid proline, and the metabolic compound creatine. In addition, this family includes a system B(0+) cationic and neutral amino acid transporter, and two transporters for which the solutes are unknown. In general, SLC6 transporters act to regulate the level of extracellular solute concentrations. In the central and the peripheral nervous system, these transporters can regulate signaling among neurons, are the sites of action of various drugs of abuse, and naturally occurring mutations in several of these proteins are associated with a variety of neurological disorders. For example, transgenic animals lacking specific aminergic transporters show profoundly disturbed behavioral phenotypes and probably represent excellent systems for investigating psychiatric disease. SLC6 transporters are also found in many non-neural tissues, including kidney, intestine, and testis, consistent with their diverse physiological roles. Transporters in this family represent attractive therapeutic targets because they are subject to multiple forms of regulation by many different signaling cascades, and because a number of pharmacological agents have been identified that act specifically on these proteins.

Biological Transport↗