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At least 109 records · Page 6Linked to original sources
PubMed1999

Growth hormone (GH) receptor blockade with a PEG-modified GH (B2036-PEG) lowers serum insulin-like growth factor-I but does not acutely stimulate serum GH.

B2036-PEG, a GH receptor (GH-R) antagonist, is an analog of GH that is PEG-modified to prolong its action. Nine mutations alter the binding properties of this molecule, preventing GH-R dimerization and GH action. A potential therapeutic role of B2036-PEG is to block GH action, e.g. in refractory acromegaly. A phase I, placebo-controlled, single rising-dose study was performed in 36 normal young men (ages, 18-37 yr; within 15% ideal body weight). Four groups received a single s.c. injection of either placebo (n = 3 in each group, total n = 12) or B2036-PEG (0.03, 0.1, 0.3, or 1.0 mg/kg; n = 6 each dose). B2036-PEG and GH concentrations were measured 0, 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h after dosing. Serum insulin-like growth factor-I was measured before and 1-7 days after dosing. All doses were well tolerated, with no serious or severe adverse reactions. B2036-PEG, at 1.0 mg/kg, reduced insulin-like growth factor-I by 49 +/- 6% on day 5 (P < 0.001 vs. placebo). GH was measured by two independent methods: 1) modified Nichols chemiluminescence assay (empirically corrected for B2036-PEG cross-reactivity); and 2) direct GH two-site immunoassay, using monoclonal antibodies that did not react with B2036-PEG. There was good agreement between the two methods. GH did not change substantially at any B2036-PEG dose, suggesting that B2036-PEG does not interact with hypothalamic GH-Rs to block short-loop feedback. B2036-PEG may thus block peripheral GH action without enhancing its secretion.

Adolescent↗
PubMedDate not supplied

Two types of mutants affecting voltage-sensitive sodium channels in Drosophila melanogaster.

Voltage-sensitive sodium channels have a key role in the genesis of propagated action potentials. Mutations that affect these channels might be used like specific pharmacological agents in studies of channel structure and regulation. We have found that mutations which cause a reversible, temperature-induced paralysis in the fruit fly Drosophila melanogaster often affect the voltage-sensitive sodium channel. Using 3H-saxitoxin binding to membrane preparations, we have now identified two types of presumptive sodium channel mutants. One mutation, seizurets-2 (seits-2), appears to alter saxitoxin-binding sites structurally. The second, no-action-potential (napts) (refs 5, 6), reduces the number of saxitoxin-binding sites, but appears not to alter the receptor structure.

Animals↗
PubMed2004

Mutations in the synthesis and action of estrogen: the critical role in the male of estrogen on pubertal growth, skeletal maturation, and bone mass.

The discovery of males with mutations in CYP19, the gene that encodes aromatase, the enzyme catalyzing the final step in the conversion of androgen to estrogen, and of a man with a mutation in the estrogen receptor alpha gene has led to increasing recognition of the critical role of estrogen in the male. The diverse roles of estrogen in the male, both circulating and locally synthesized, is supported by extensive studies in male mice generated with disruption of the aromatase gene or the genes encoding the alpha- and beta-estrogen receptor. This presentation focuses on the crucial role of estradiol in the human male on the pubertal growth spurt, skeletal maturation and the cessation of linear growth, and the accrual of bone mass.

Adolescent↗
PubMed1999

Counterfactual thinking and regulatory focus: implications for action versus inaction and sufficiency versus necessity.

Counterfactual thinking is associated with regulatory focus in a way that explains previous empirical incongruities, such as whether additive counterfactuals (mutations of inactions) occur more or less frequently than subtractive counterfactuals (mutations of actions). In Experiment 1, regulatory focus moderated this pattern, in that additive counterfactuals were activated by promotion failure, whereas subtractive counterfactuals were activated by prevention failure. In Experiment 2, additive counterfactuals evoked a promotion focus and expressed causal sufficiency, whereas subtractive counterfactuals evoked a prevention focus and expressed causal necessity. In Experiment 3, dejection activated additive counterfactuals, whereas agitation activated subtractive counterfactuals. These findings illuminate the interconnections among counterfactual thinking, motivation, and goals.

Adult↗
PubMed1998

Increasing complexity of Ras signaling.

The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to define a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was defined and conserved in worms, flies and man. This was a remarkable achievement in our efforts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identification of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular effectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple effectors.

Amino Acid Sequence↗
PubMed1994

Expression of mutationally activated G alpha s stimulates growth and differentiation of thyroid FRTL5 cells.

The alpha subunit of the GTP-binding protein Gs mediates hormonal stimulation of adenylyl cyclase. Human pituitary and thyroid tumours harbour mutations of G alpha s that constitutively activate the protein by inhibiting its intrinsic GTPase activity. We have investigated the mitogenic action of mutationally activated alpha s in thyroid FRTL5 cells, a cell line dependent upon thyroid-stimulating hormone (TSH) for both growth and differentiation. Introduction of alpha s carrying the substitution of glutamine-227 with leucine (Q227L alpha s) by retroviral infection of FRTL5 cells resulted in the expected stimulation of membrane adenylyl cyclase activity and in increased intracellular accumulation of cAMP. Measurements of cytosolic Ca2+ levels did not detect any concomitant effect on the polyphosphoinositide-Ca2+ signalling pathway. Expression of Q227L alpha s conferred to FRTL5 cells the ability to synthesize DNA in the absence of TSH, as revealed by [3H]thymidine incorporation experiments, and to proliferate independently of the mitogenic hormone, although with a rate of growth slower than that observed with TSH stimulation. The effect of Q227L alpha s on cell proliferation was associated with the constitutive activation of iodide uptake. The results indicate that expression of mutationally activated G alpha s is sufficient to bypass the requirement for TSH and promotes autonomous growth and activation of thyroid-specific differentiated functions in FRTL5 cells.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Selective uncoupling of RGS action by a single point mutation in the G protein alpha-subunit.

Heterotrimeric G proteins function as molecular relays, shuttling between cell surface receptors and intracellular effectors that propagate a signal. G protein signaling is governed by the rates of GTP binding (catalyzed by the receptor) and GTP hydrolysis. RGS proteins (regulators of G protein signaling) were identified as potent negative regulators of G protein signaling pathways in simple eukaryotes and are now known to act as GTPase-activating proteins (GAPs) for G protein alpha-subunits in vitro. It is not known, however, if Galpha GAP activity is responsible for the regulatory action of RGS proteins in vivo. We describe here a Galpha mutant in yeast (gpa1(sst)) that phenotypically mimics the loss of its cognate RGS protein (SST2). The gpa1(sst) mutant is resistant to an activated allele of SST2 in vivo and is unresponsive to RGS GAP activity in vitro. The analogous mutation in a mammalian Gqalpha is also resistant to RGS action in transfected cells. These mutants demonstrate that RGS proteins act through Galpha and that RGS-GAP activity is responsible for their desensitizing activity in cells. The Galphasst mutant will be useful for uncoupling RGS-mediated regulation from other modes of signal regulation in whole cells and animals.

Animals↗
PubMed1994

Evidence that the Drosophila olfactory mutant smellblind defines a novel class of sodium channel mutation.

The smellblind (sbl) gene of Drosophila is associated with olfactory defects, and the paralytic (para) gene encodes a voltage-gated sodium channel. sbl and para have similar genetic map positions, many combinations of sbl and para mutations fail to complement, and two sbl mutations contain molecular lesions within the para transcription unit. sbl mutations also behave like para mutations in that they are enhanced by the mutation no action potential temperature-sensitive (mlenapts1). The simplest interpretation of these results is that sbl and para are the same gene. Two sbl mutations produce olfactory defects not characteristic of classic sodium channel mutations and do not show typical heat-sensitive paralysis, suggesting that these sbl mutants define a novel class of sodium channel mutation.

Alleles↗
PubMed1998

Alteration of HERG current profile during the cardiac ventricular action potential, following a pore mutation.

HERG is believed to encode the major sub-unit of the cardiac 'rapid' delayed rectifier K channel (I(Kr)). Both I(Kr) and HERG exhibit marked inward rectification at positive membrane potentials due to rapid inactivation and this is thought to influence significantly the contribution of the current to cardiac action potential (AP) repolarisation. We investigated directly the role played by rapid inactivation, by measuring current activated by a ventricular AP waveform, from Chinese Hamster Ovary cells transfected with HERG cDNA with a point-mutation (S631A) in the pore region. Square command pulses elicited HERG-S631A current which increased progressively in magnitude with test potential up to +30/+40 mV (n=6). During test pulses to +40mV, HERG-S631A exhibited little inactivation compared to wildtype HERG. During an action potential command, WT-HERG current developed progressively during the AP plateau and slow repolarisation phase, showing maximal current between -30mV and -40 mV (n=10). In contrast, HERG-S631A current increased earlier during the AP plateau, with a maximal amplitude near +30mV (n=7). Current then declined as the AP proceeded, giving rise to a 'bow'- or 'inverted-U-' shaped current profile. A mathematical model with inactivation removed from the HERG current reproduced the I-V profile of HERG-S631A. These data provide a direct demonstration that rapid inactivation normally plays a critical role in determining both time-course and voltage dependence of HERG/I(Kr) -current during the cardiac ventricular AP.

Action Potentials↗
PubMed2006

A novel mutation in ALK-1 causes hereditary hemorrhagic telangiectasia type 2.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant bleeding disorder and has two variants, HHT1 and HHT2, associated with mutations in the ENG and ALK-1 genes, respectively. We identified one Chinese HHT2 family to investigate the pathogenic gene and its possible mechanism of action by mutation screening and functional study. One substitution mutation (1717C>T) in exon 10 of the ALK-1 was found by sequencing of all exons of ENG and ALK-1 and caused a R479X mutation in the ALK-1 protein. ALK-1 mRNA and plasma thrombomodulin were measured by real-time quantitative PCR and ELISA, respectively. There was no significant difference in the expression levels of ALK-1 mRNA between patients and healthy individuals. A significantly higher level of thrombomodulin was found in HHT patients. These findings indicate that the mutation causes truncation of the ALK-1 protein at the post-transcriptional level; the plasma thrombomodulin may provide an easy diagnostic indicator in HHT patients.

Activin Receptors, Type II↗
PubMed2003

Local anaesthetics have different mechanisms and sites of action at the recombinant N-methyl-D-aspartate (NMDA) receptors.

(1) Although the principal pharmacological targets of local anaesthetics (LAs) are voltage-gated Na(+) channels, other targets have also been suggested. Here we examined the effects of LAs on the N-methyl-D-aspartate (NMDA) receptor, a receptor involved in the process of nociception. (2) LAs (bupivacaine, lidocaine, procaine, and tetracaine) reversibly and concentration-dependently inhibited recombinant epsilon1/zeta1 and epsilon2/zeta1 NMDA receptors expressed in Xenopus oocytes (IC(50)s for bupivacaine, lidocaine, procaine, and tetracaine were 1032.0, 1174.1, 642.1 and 653.8 micro M at the epsilon1/zeta1 receptor; and 1090.8, 1821.3, 683.0 and 662.5 micro M respectively (at the epsilon2/zeta1 receptor). Bupivacaine and procaine were non-competitive antagonists; bupivacaine possesses non-competitive and competitive actions when interacting with glycine, whereas procaine has only non-competitive action. (3) Mutation of asparagine residue at position 598 (Asp(598)) in the zeta1 subunit, a residue associated with the blockade site for Mg(2+) and ketamine, to glutamine or arginine reduced the sensitivity to procaine but not to bupivacaine. Thus, procaine may interact with sites of action that are closely related to those of Mg(2+) and ketamine blockade. (4) These results suggest that LAs inhibit the NMDA receptor by various mechanisms.

Anesthetics, Local↗
PubMed1998

Osmotin, a plant antifungal protein, subverts signal transduction to enhance fungal cell susceptibility.

The plant pathogenesis-related protein osmotin is an antifungal cytotoxic agent that causes rapid cell death in the yeast S. cerevisiae. We show here that osmotin uses a signal transduction pathway to weaken defensive cell wall barriers and increase its cytotoxic efficacy. The pathway activated by osmotin includes the regulatory elements of the mating pheromone response STE4, STE18, STE20, STE5, STE11, STE7, FUS3, KSS1, and STE12. Neither the pheromone receptor nor its associated G protein alpha subunit GPA1 are required for osmotin action. However, mutation of SST2, a negative regulator of G alpha proteins, resulted in supersensitivity to osmotin. Phosphorylation of STE7 was rapidly stimulated by osmotin preceding any changes in cell vitality or morphology. These results demonstrate that osmotin subverts target cell signal transduction as part of its mechanism of action.

Antifungal Agents↗
PubMed1998

Mutation-selection balance with multiple alleles.

Human genetic disorders provide an extraordinary richness of data on the diversity of defective alleles. Well over 100 defective alleles for each of several human genetic disorders have been identified, including breast cancer (BRCA1), cystic fibrosis (CFTR), muscular dystrophy (DZM), and phenylketonuria (PAH). These observations raise the classical question of balance between the action of mutation generating new defective alleles and selection removing those alleles from the population. The problem of multiple-allele, mutation-selection balance was considered by Crow and Kimura, who obtained some approximate results showing that the level of dominance and degrees of interallelic complementation are important in determining the equilibrium allele frequencies. Here those deterministic results are reviewed and extended, showing that there are conditions yielding surprisingly high equilibrium frequencies of defective alleles. Just as the equilibrium mutation load is independent of the level of dominance, it is also independent of the number of defective alleles.

Alleles↗
PubMed1987

Heat shock phenomena in Aspergillus nidulans. II. Combined effect of heat and bleomycin to heat shock protein synthesis, survival rate and induction of mutations.

The combined action of hyperthermia and Bleomycin on Aspergillus nidulans was studied at three different levels: mycelial protein synthesis, spore viability and induction of mutations. It was found that Bleomycin treatment of preincubated mycelia during the heat shock enhances the incorporation of 35S-methionine into heat shock bands. Furthermore, simultaneous treatment with hyperthermia (43 degrees C) and Bleomycin results in greater cytotoxic activity in spores and in a higher induction rate of point mutations.

Aspergillus nidulans↗
PubMed1998

Self-adaptation in evolving systems.

A theoretical and experimental analysis is made of the effects of self-adaptation in a simple evolving system. Specifically, we consider the effects of coding the mutation and crossover probabilities of a genetic algorithm evolving in certain model fitness landscapes. The resultant genotype-phenotype mapping is degenerate in fitness space, there being no direct selective advantage for one probability versus another. Thus there is a "symmetry" between various genotypes that all correspond to the same phenotype. We show that the action of mutation and crossover lifts this degeneracy, that is, the genetic operators induce a breaking of the genotype-phenotype symmetry, thus leading to a preference for those genotypes that propagate most successfully into future generations. We demonstrate that this induced symmetry breaking allows the system to self-adapt in a time-dependent environment.

Adaptation, Physiological↗
PubMed1999

A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans.

The molecular mechanisms underlying general anesthesia are unknown. For volatile general anesthetics (VAs), indirect evidence for both lipid and protein targets has been found. However, no in vivo data have implicated clearly any particular lipid or protein in the control of sensitivity to clinical concentrations of VAs. Genetics provides one approach toward identifying these mechanisms, but genes strongly regulating sensitivity to clinical concentrations of VAs have not been identified. By screening existing mutants of the nematode Caenorhabditis elegans, we found that a mutation in the neuronal syntaxin gene dominantly conferred resistance to the VAs isoflurane and halothane. By contrast, other mutations in syntaxin and in the syntaxin-binding proteins synaptobrevin and SNAP-25 produced VA hypersensitivity. The syntaxin allelic variation was striking, particularly for isoflurane, where a 33-fold range of sensitivities was seen. Both the resistant and hypersensitive mutations decrease synaptic transmission; thus, the indirect effect of reducing neurotransmission does not explain the VA resistance. As assessed by pharmacological criteria, halothane and isoflurane themselves reduced cholinergic transmission, and the presynaptic anesthetic effect was blocked by the resistant syntaxin mutation. A single gene mutation conferring high-level resistance to VAs is inconsistent with nonspecific membrane-perturbation theories of anesthesia. The genetic and pharmacological data suggest that the resistant syntaxin mutant directly blocks VA binding to or efficacy against presynaptic targets that mediate anesthetic behavioral effects. Syntaxin and syntaxin-binding proteins are candidate anesthetic targets.

Aldicarb↗
PubMed2004

[Molecular analytical evaluation of macrolide- and ketolide-resistant Streptococcus pneumoniae--mechanism of action of telithromycin and resistance to it].

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a worldwide epidemiologic survey for investigating drug susceptibility against major bacterial pathogens in respiratory tract infections, and that is also designed to identify the action mechanism of telithromycin (TEL), a ketolide antibacterial agent, on the resistant Streptococcus pneumoniae and the resistance mechanism for TEL on the TEL-resistant S. pneumoniae strain, in addition to determine macrolide/ketolide resistant S. pneumoniae activities of TEL using molecular analysis. TEL exerted the antibacterial action on the macrolide-resistant S. pneumoniae regardless maintaining the macrolide-resistant mechanism and exhibited the potent antibacterial activity against all of ermB gene-positive strains, mefA gene-positive strains and ribosome variants. This result was considered to reflect the fact that TEL did not induce resistance to ermB and had extremely low ability to select resistant strain by mutation. These actions of TEL were considered to be derived from its novel chemical structure and might be characteristics of ketolides not possessed by macrolides. In the survey of PROTEKT in 1999 to 2002, among 13,864 strains of S. pneumoniae isolated worldwide, ketolide-resistant strain (TEL MIC > or = 4 microg/ml) was observed in 10 strains (0.07%). MIC of these 10 strains was 4 or 8 microg/mL and all of these strains were ermB-positive strains. Based on this fact, potential involvement of adenine demethylase (ermB gene product) was considered in the background of development of ketolide-resistant S. pneumoniae.

Anti-Bacterial Agents↗
PubMed1991

[Presence of specific mutation of Ha-ras oncogene in skin tumors of mice induced under different experimental conditions].

The mutation was revealed with substitution of A for T in the second position of the 61 Ha-ras oncogene codon in the DNA of 31 skin tumours (26 papillomas and 5 carcinomas) and in 23 mice treated with 12-O-tetradecanoyl phorbol-13-acetate (TPA). Part of these mice were F progeny (n-6) and F progeny (n-4) following DMBA administration during pregnancy, another part F progeny (n-5) following ENU action on males prior to mating, the rest mice (n-3) did not undergo additional actions. The mutation under study was revealed only in 3 out of 5 papillomas and in all 5 carcinomas of mice subjected to DMBA administration during pregnancy.

9,10-Dimethyl-1,2-benzanthracene↗