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PubMed1980

[Relationship between the body's adaptation to heat and the modifying effect of extreme temperature on the effect of radiation. III. Role of genotype and environment in determining the intensity of the mutation process].

The modifying action of extremal temperatures (33 degrees C, 37 degrees C and 0 degrees C) on the effect of radiation (dominant lethals) was demonstrated in Canton-S and heat-resistant (T-32) stocks of Drosophila. The effect depended on genetic adaptation. Successive action of irradiation (406 rad, 137Cs) and extremal temperature in Canton-S stock have given more than additive effect (the after-effect was +13, +14 and +15%), the same treatment in the T-32 stock have produced lower than additive effect (the after-effect was -11, -10, -16 and -19%). The role of genotype and environment, i.e. ontogenetic and genotypic adaptation, in determination of modifying action of temperature on the radiation effect was differentiated. The effect was different under equal treatments of females of the heat-resistant stock developing under different temperature conditions. If the after-effect was negative under development temperature of 32 degrees C, it always was more than additive (the after-effect was +20, +50, +13, +40) under 25 degrees C. Similar pattern was observed for X-chromosome losses. Temperature 37 degrees C enhanced the radiation effect regardless of development temperature (the after-effect was 150 and 130%), and temperature 33 degrees C enhanced the radiation effect only if fly development occurred at 25 degrees C (the after-effect was 200%). Thus, ontogenetic adaptation takes an important part in determination of mutagenesity of environmental factors.

Adaptation, Physiological↗
PubMed2000

The c-Myc transactivation domain is a direct modulator of apoptotic versus proliferative signals.

We have assayed the oncogenic, proliferative, and apoptotic activities of the frequent mutations that occur in the c-myc gene in Burkitt's lymphomas. Some alleles have a modest (50 to 60%) increase in transforming activity; however, the most frequent Burkitt's lymphoma allele (T58I) had an unexpected substantial decrease in transforming activity (85%). All alleles restored the proliferation function of c-Myc in cells that grow slowly due to a c-myc knockout. There was discordance for some alleles between apoptotic and oncogenic activities, but only the T58A allele had elevated transforming activity with a concomitant reduced apoptotic potential. We discovered a novel missense mutation, MycS71F, that had a very low apoptotic activity compared to wild-type Myc, yet this mutation has never been found in lymphomas, suggesting that there is no strong selection for antiapoptotic c-Myc alleles. MycS71F also induced very low levels of cytochrome c release from mitochondria, suggesting a mechanism of action for this mutation. Phosphopeptide mapping provided a biochemical basis for the dramatically different biological activities of the transformation-defective T58I and transformation-enhanced T58A c-Myc alleles. Furthermore, the antiapoptotic survival factor insulin-like growth factor 1 was found to suppress phosphorylation of T58, suggesting that the c-Myc transactivation domain is a direct target of survival signals.

Animals↗
PubMed1995

Androgen action.

Androgens are C-19 steroids that provide major regulatory influences on male reproductive function. Testosterone, the principal androgenic steroid, is secreted by the Leydig cells of the testes. Both testosterone and its 5 alpha reduced derivative 5 alpha-dihydrotestosterone (DHT) are physiological ligands for the androgen receptor (AR). Ligand-activated AR acts as a nuclear transcription factor and mediates androgen action. AR, along with receptors for a number of C-21 steroids such as glucocorticoid, mineralocorticoid, and progesterone, share the same 15 base pair consensus element composed of 5'-GGA/TACAnnnTGTTCT-3'. Despite this cross-reactivity at the level of the DNA, physiologically, androgens regulate their target genes with a high degree of receptor specificity. Such a regulatory specificity appears to be due to multiphasic interactions involving enzymatic activation/inactivation of the steroid ligand, interaction with specific receptor-associated nuclear factors on or around the hormone response element, and differential regulation of the receptor gene expression. Conversion of testosterone to 5 alpha-dihydrotestosterone in target cells is a widespread activation mechanism that amplifies the androgenic signal. Unlike the testosterone-AR complex, DHT-activated AR has a longer half-life, and thus prolongs androgen action. Oxido-reduction of androgens by 17 beta-hydroxysteroid dehydrogenase and sulfurylation by androgen sulfotransferase are two major pathways of androgen inactivation in target cells. Prenatal deprivation of androgen action, due to mutations in either the AR or the 5 alpha-reductase gene, results in developmental abnormalities of male reproductive tissues and also cause partial or complete androgen-insensitivity syndromes. Elucidation of various molecular steps in androgen action is allowing development of improved therapeutic agents for the management of disorders of androgen action such as the prostatic hypertrophy and neoplasia.

Androgens↗
PubMed1985

Interaction of an antimutator gene with DNA repair pathways in Escherichia coli K-12.

A mutation in the purB gene of E. coli K-12, isolated and partially characterized by Geiger and Speyer (1977), confers a temperature sensitive requirement for adenine and an antimutator phenotype at 30 degrees C. Several hypotheses about the mechanism of action of this mutation, named mud for mutation defective, were tested in the present work. The mud mutation has no effect upon the induction of the SOS response, so the antimutator phenotype is unlikely to be due to repression of mutagenic repair. Mud cells are resistant to the cytotoxic and mutagenic effects of alkylating agents such as MNNG, but this resistance is not due simply to derepression of the adaptive response. DNA isolated from mud cells is not undermethylated relative to DNA from purB+ cells, so the antimutator phenotype of mud cannot be due to reduced hotspot base-substitution mutation at methylated cytosine residues. Nor is there a longer lag in post-replicative DNA methylation, which indicates that there is no enhancement of mismatch repair resulting from an extended time window for strand discrimination. Measurement of nucleotide pool levels demonstrated an elevation of dCTP in mud cells and a reduction of all other nucleoside triphosphates.

Bacteriophage lambda↗
PubMed1995

Clonal variations among multiple primary mammary tumors and within a tumor of individual mice: insertion mutations of int oncogenes.

Laboratory mice infected with the mouse mammary tumor virus (MMTV) often develop multiple mammary tumors. However, no comprehensive studies have been done addressing the question of whether or not different primary tumors of individual mice are related ontogenetically to each other. Further, it is not known to what extent individual tumors vary in their cellular composition. We, therefore, examined intertumor and intratumor patterns of the rearrangements in int-1 (Wnt-1), int-2 (Fgf-3), and int-3 protooncogenes, since mutations in ints caused by MMTV result in the development of mammary tumors in mice and thus provide the most suitable genetic markers for the tumor cells. Our results show that, irrespective of the genetic background of the mice and/or the strain of MMTV, the pattern of MMTV integration in the different tumors of individual mice varies as widely as is found with the tumors of different mice. Of the 79 tumors obtained from 25 mice of different genetic backgrounds, 31 showed insertional mutations in int-1 (39%). By contrast only 9 of the 65 tumors tested had mutations in int-2 (14%). None of the tumors showed mutations in int-3. Interestingly, tumors from individual mice also showed variations in their pattern of int gene mutation, indicating that multiple tumors that develop in a mouse bear no ontogenetical link. The analysis of the pattern of intratumor MMTV integration, int mutation, and int expression revealed that several int mutational events as well as variations in int expression may occur in the same tumor. The diversity of int activation within individual tumors may suggest that the initiation and progression of most mammary tumors, if not all, occur through the concerted action of different mutational events in the same cell or through interactions of different cell populations, each of which acquired different int mutations.

Animals↗
PubMed2000

An analysis of bone and head sinus cancers in radium dial painters using a two-mutation carcinogenesis model.

Bone and head sinus cancer incidence after ingestion of 226Ra and 228Ra by radium dial painters is analysed using a two-mutation clonal expansion model for radiation carcinogenesis, taking into account the retention and radiation patterns of these nuclides in the body. The best fit is obtained for compact bone retention and efficient diffusion of 222Rn to the bone cavities and radiation action on both mutation rates of the cancer model, as found in a similar analysis of bone sarcomas after 226Ra injection in beagles. The model parameters of the best fit are consistent with cellular radiobiological data and a previous analysis of lung cancer in uranium miners. Due to the low background incidence of bone and head sinus cancer, the resulting dose-effect relationships for these cancers are linear-quadratic with radium ingestion and alpha radiation dose. These results do not support a threshold dose concept, but the risks at low doses calculated by the model come out to about a factor 10 lower than using a linear extrapolation of the data to low doses, a procedure currently applied by ICRP and EPA. Furthermore, the model results indicate radiation risks at low doses to be related with background cancer incidence between relative and absolute radiation risk projections. The results, which are dependent on the model assumptions, might be more generally applicable for bone seekers and will therefore need further study to arrive at better radiation risk estimations.

Adult↗
PubMed2003

Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation.

Tau, a microtubule binding protein, is not only a major component of neurofibrillary tangles in Alzheimer's disease, but also a causative gene for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show here that an FTDP-17 tau mutation (V337M) in SH-SY5Y cells reduces microtubule polymerization, increases voltage-dependent calcium current (ICa) density, and decreases ICa rundown. The reduced rundown of ICa by V337M was significantly inhibited by nifedipine (L-type Ca channel blocker), whereas omega-conotoxin GVIA (N-type Ca channel blocker) showed smaller effects, indicating that tau mutations affect L-type calcium channel activity. The depolarization-induced increase in intracellular calcium was also significantly augmented by the V337M tau mutation. Treatment with a microtubule polymerizing agent (taxol), an adenylyl cyclase inhibitor, or a protein kinase A (PKA) inhibitor, counteracted the effects of mutant tau on ICa. Taxol also attenuated the Ca2+ response to depolarization in cells expressing mutant tau. Apoptosis in SH-SY5Y cells induced by serum deprivation was exacerbated by the V337M mutation, and nifedipine, taxol, and a PKA inhibitor significantly protected cells against apoptosis. Our results indicate that a tau mutation which decreases its microtubule-binding ability augments calcium influx by depolymerizing microtubules and activating adenylyl cyclase and PKA.

Calcium↗
PubMed2000

Mode of action and application of Scorpion primers to mutation detection.

Scorpion primers can be used to detect PCR products in homogeneous solution. Their structure promotes a unimolecular probing mechanism. We compare their performance with that of the same probe sequence forced to act in a bimolecular manner. The data suggest that Scorpions indeed probe by a unimolecular mechanism which is faster and more efficient than the bimolecular mechanism. This mechanism is not dependent on enzymatic cleavage of the probe. A direct comparison between Scorpions, TaqMan and Molecular Beacons on a Roche LightCycler indicates that Scorpions perform better, particularly under fast cycling conditions. Development of a cystic fibrosis mutation detection assay shows that Scorpion primers are selective enough to detect single base mutations and give good sensitivity in all cases. Simultaneous detection of both normal and mutant alleles in a single reaction is possible by combining two Scorpions in a multiplex reaction. Such favourable properties of Scorpion primers should make the technology ideal in numerous applications.

Alleles↗
PubMed1999

Mechanisms of GDF-5 action during skeletal development.

Mutations in GDF-5, a member of the TGF-beta superfamily, result in the autosomal recessive syndromes brachypod (bp) in mice and Hunter-Thompson and Grebe-type chondrodysplasias in humans. These syndromes are all characterised by the shortening of the appendicular skeleton and loss or abnormal development of some joints. To investigate how GDF-5 controls skeletogenesis, we overexpressed GDF-5 during chick limb development using the retrovirus, RCASBP. This resulted in up to a 37.5% increase in length of the skeletal elements, which was predominantly due to an increase in the number of chondrocytes. By injecting virus at different stages of development, we show that GDF-5 can increase both the size of the early cartilage condensation and the later developing skeletal element. Using in vitro micromass cultures as a model system to study the early steps of chondrogenesis, we show that GDF-5 increases chondrogenesis in a dose-dependent manner. We did not detect changes in proliferation. However, cell suspension cultures showed that GDF-5 might act at these stages by increasing cell adhesion, a critical determinant of early chondrogenesis. In contrast, pulse labelling experiments of GDF-5-infected limbs showed that at later stages of skeletal development GDF-5 can increase proliferation of chondrocytes. Thus, here we show two mechanisms of how GDF-5 may control different stages of skeletogenesis. Finally, our data show that levels of GDF-5 expression/activity are important in controlling the size of skeletal elements and provides a possible explanation for the variation in the severity of skeletal defects resulting from mutations in GDF-5.

Amino Acid Sequence↗
PubMed1977

[Mutation of bacteriophage T4 restoring phage supressor psul+ activity in bacterial strain Escherichia coli BN].

The mutant of bacteriophage T4psu1+XF2 carrying a mutational aleration in the central region of proline-serine tRNA precursor is isolated. The mutational alteration results in the recovery of amber suppressor activity of phage psu1+ serine tRNA in Escherichia coli BN in which the synthesis of this tRNA is normally blocked. Since the amber suppressor activity of mutant serine tRNA becomes sensitive to a restrictive action of strR mutations, its structure seems to be different from that of parental suppressor serine tRNA.

Base Sequence↗
PubMed2004

Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.

GABAA receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions, and the enhancement of GABAA receptor-mediated fast synaptic inhibition is the basis for the pharmacotherapy of various neurological and psychiatric disorders. Two kinds of GABAA receptor-targeted mutant mice have been generated: (a) knockout mice that lack individual GABAA receptor subunits (alpha1, alpha5, alpha6, beta2, beta3, gamma2, delta, and rho1) and (b) knockin mice that carry point mutations affecting the action of modulatory drugs [alpha1(H101R), alpha2(H101R), alpha3(H126R), alpha5(H105R), and beta3(N265M)]. Whereas the knockout mice have provided information primarily with respect to the regulation of subunit gene transcription, receptor assembly, and some physiological functions of individual receptor subtypes, the point-mutated knockin mice in which specific GABAA receptor subtypes are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepam and general anesthetics.

Anesthetics, General↗
PubMed2000

From genome to physiome: integrative models of cardiac excitation.

The last decade has generated extensive information on the genetic and molecular basis of disease. A major challenge remains the integration of this information into the physiological environment of the functioning cell and tissue. This article illustrates the use of computational biology in meeting this challenge in the context of cardiac excitation and arrhythmia. (1) Genetics to Cell Function: Mutations that alter the kinetics of the cardiac sodium channel, INa, give rise to a congenital form of the long QT syndrome that can lead to sudden death. Using a computer modelof the cardiac cell, we simulated the effects of the mutations on the action potential, demonstrating its prolongation at slowrate and the develop-rate and the development of arrhythmogenic early afterdepolarizations due to reactivation of L-type Ca channels, ICa(L) [Clancy and Rudy, Nature (London) 400:566, 1999]. (2) Multicellular Tissue: Slow conduction is an important property of propagation arrhythmias (reentry). Very slow conduction is supported by reduced intercellular coupling through gap junctions. Using a multicellular fiber model, we have shown that slow conduction is very stable and, in contrast to normal conduction which depends solely on INa, requires a major contribution from ICa(L) (Shaw and Rudy, Circ. Res. 81:727, 1997).

Action Potentials↗
PubMed1983

[Expression of the amino acid operons in Escherichia coli strains with an altered transcription and translation apparatus. III. The effect of mutations in the rpoB gene coding for the beta-subunit of RNA-poly-merase on ilv-operon expression].

The influence of rifampicin resistance mutations on expression of the ilv operon of Escherichia coli was investigated. Some of these mutations, like those previously described in our works, occur in translation machinery of E. coli and inhibit derepression of the ilv operon. However, another group of mutations stimulated the expression of the operon when mutated cells were transferred from rich to minimal growth medium. The possible mechanisms of the effects of rifampicin resistance mutations on the action of coupled transcription--translation system are discussed.

Amino Acids↗