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At least 847 records · Page 47Linked to original sources
PubMed2004

Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease.

Dominant mutations in the gene for alpha-synuclein, a small presynaptic protein, can cause Parkinson's disease. Although there is still substantial debate about the precise mechanisms, alpha-synuclein is toxic to vulnerable neurons, probably as a result of its tendency to aggregate. Opposing this is another gene product that, when mutated, causes a recessive form of parkinsonism, parkin. Parkin has been recently shown to protect cells against alpha-synuclein toxicity. However, the precise details of the mechanism are unclear. This review will discuss the concept that there are multiple neuronal functions that are targeted by mutant alpha-synuclein, and in many cases, there is evidence that parkin can protect cells against damage to the same systems. The authors will also discuss ways in which to test some of these ideas, by using newly identified genes such as DJ-1 that cause similar phenotypes.

Animals↗
PubMed2005

Anti-cancer drugs: molecular mechanisms of action.

Genetic alterations are responsible for all cancers. These mutations produce, in turn, alterations in key proteins of certain signaling pathways. Amongst the best known and studied alterations related to malignant transformations are those which occur in Ras protein and p53. In most cases mutations in Ras and p53 lead to the appearance of practically most malignant transformations. Mutated Ras genes exist in approximately 20 to 30% of all human cancers. Ras proteins are switches that regulate diverse functions such as cell proliferation, differentiation and apoptosis. Normal p53 expression, also known as the "genome guardian", is a key molecule for suppressing cell proliferation. The great importance of these proteins rests on their intimacy with the events leading to cell proliferation or death. The comprehension of the extent of transformation on Ras and p53, and of the diverse biochemical pathways of intracellular signaling, activated by them, is of extreme importance for the understanding of malignant transformation, as well as its control, through the creation, for example, of new drugs which contribute to the elimination of these cells. To clarify the consequences originated by transformed Ras, p53 and their biochemical interlinks in the different intracellular pathways, besides the possible intervening points and pharmacological controls presently used in combating cancer, are the aims of this review.

Alkyl and Aryl Transferases↗
PubMed2002

Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father.

In humans, mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). However, only about 10-15% of the cases of PGD can be explained by mutations within the SRY open reading frame, suggesting the existence of other sex-determining genes. Although SRY is known to bind and bend DNA, its target and mode of action remain elusive. Here, we describe a novel mutation in SRY at codon 127, resulting in a tyrosine (Y) to phenylalanine (F) substitution in the protein. This sequence variant was found not only in the XY female patient but also in her father, who is a phenotypically normal male. However, this Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggest that the Y127F variant is a novel mutation with functional consequences and not simply a polymorphism. The allelic variant of SRY transmitted in this family and shared by both a phenotypic female (proband) and a phenotypic male (proband's father) emphasizes the importance of modifier genes in the sex determination pathway.

Amino Acid Substitution↗
PubMed2005

Evaluation of steroid receptor function by gene targeting in mice.

Corticosteroid hormones regulate a variety of developmental, physiological and pathological processes via their cognate receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Using modern genetic technologies, including bacterial artificial chromosome-based transgenesis and conditional gene targeting, we have generated a panel of tissue-specific and function-selective mutations of the two corticosteroid hormone receptors in the mouse. These mouse models have allowed us to gain new insights into corticosteroid hormone signaling in vivo. By investigating a hepatocyte-specific GR mutation, it has been possible to define a novel biological action of GR, namely to function as a coactivator for Stat5-mediated gene transcription in the control of body growth. The investigation of brain-specific mutations have not only allowed us to better understand hypothalamo-pituitary-adrenal (HPA) axis regulation by glucocorticoids, but also to analyse corticosteroid action in various aspects of brain function like anxiety-related or addiction-related behaviour, and learning and memory. A function-selective mutation in the GR has allowed us to dissect different pathways in the gene expression regulation by this receptor, namely to separate DNA response element-binding dependent gene activation from response element-independent gene regulation via interference with other transcription factors. These different transcriptional activities of GR play an important role in glucocorticoid-mediated immunosuppression.

Alleles↗
PubMed2005

Overexpression of RasN17 fails to neutralize endogenous Ras in MCF7 breast cancer cells.

Receptor tyrosine kinases of the ErbB family have been implicated in the onset/progression of a number of neoplasias. In these diseases, ErbB receptor expression may be accompanied by constitutive activation caused by molecular alterations, overexpression, or ligand binding. An important signaling route activated by these receptors that has been linked to the stimulation of cell proliferation is the Ras route. Here we have investigated the action of a mutant Ras form, H-RasN17, on the proliferation of the breast cancer epithelial cell line MCF7 cells. In these cells expression of RasN17 failed to affect serum or ErbB receptor-stimulated proliferation. Analysis of the action of RasN17 indicated that overexpression of this mutant form of Ras did not affect neuregulin or protein kinase C-induced activation of Erk1/2. In addition, RasN17 failed to prevent activation of endogenous N-Ras and H-Ras even though the levels of the latter were much lower than those of the RasN17 form. The failure of RasN17 to prevent endogenous Ras activation did not appear to be due to deficient processing or sorting of the mutated form. These data indicated that the action of RasN17 as a bona fide inhibitor of Ras depends on the cell type and requires detailed analysis of the biochemical and biological properties of RasN17, particularly with respect to the activation of endogenous Ras.

Animals↗
PubMed1975

Toxicologic and hygienic investigation of potatoes irradiated with a beam of fast electrons and gamma-rays to control sprouting.

Potatoes exposed either to gamma-rays at a dose of 20 krad, or irradiated with a beam of fast electrons at a dose of 30 krad to inhibit the sprouting of tubers, were studied for mutagenic effects. Toxic action and influence on the fertility were also investigated. Extracts of irradiated potatoes (10 krad gamma-rays), stored and then boiled, were also studied for their mutagenic effects. The induction of dominant lethal mutations (DLM) was used as indicator of mutagenic action of potatoes in male rats, that of the extracts of potatoes in male mice. Experimental animals (white rats) were fed with irradiated potatoes. Neither a toxic, nor a mutagenic action was found. Oral treatment of male mice with extracts of irradiated potatoes also did not increase the frequency of DLM in male mice.

Animals↗
PubMed2006

Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid.

Isoniazid is one of the most effective antituberculosis drugs, yet its precise mechanism of action is still controversial. Using specialized linkage transduction, a single point mutation allele (S94A) within the putative target gene inhA was transferred in Mycobacterium tuberculosis. The inhA(S94A) allele was sufficient to confer clinically relevant levels of resistance to isoniazid killing and inhibition of mycolic acid biosynthesis. This resistance correlated with the decreased binding of the INH-NAD inhibitor to InhA, as shown by enzymatic and X-ray crystallographic analyses, and establishes InhA as the primary target of isoniazid action in M. tuberculosis.

Antitubercular Agents↗
PubMed2004

A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations.

A novel presenilin-1 (PS1) mutation (P117S) in an American pedigree is described. We compare clinical, neuropathological and cell culture phenotypes produced by this mutation with another codon 117 mutation that was earlier discovered by our group in a Polish kindred. Both mutations are associated with an unusually severe Alzheimer disease (AD) phenotype, with the onset starting before the third decade of life, rapid disease progression and acute presentation of clinical symptoms. The severity of clinical phenotype was closely correlated with the abundance of pathology: massive deposition of Abeta42 in plaques, severe neurofibrillary degeneration and neuronal loss. When overexpressed in mouse neuroblastoma N2a cells, both mutations caused loss of an ability to promote neurite outgrowth and produced an increase in the ratio of secreted Abeta42/40 amyloid peptides. In stably transfected N2a cell lines only mutant proteins were endoproteolytically cleaved indicating some dependability of this process on the presence of mutation. Taken together, our results show that clinical and cell culture phenotypes produced by these 2 codon 117 mutations are closely related suggesting that the pathogenic action of PS1 may involve effect on neurite outgrowth and endoproteolytic cleavage of the full-length protein. Given the high potency in vivo and in vitro of both codon 117 mutations, this site of PS1 must be particularly important for its normal/pathogenic function.

Adult↗
PubMed2004

PCR-RFLP analysis of a point mutation in codons 315 and 463 of the katG gene of Mycobacterium tuberculosis isolated from patients in Silesia, Poland.

Resistance to antituberculous agents is an important cause of ineffectiveness of antimicrobial therapy. The resistance of M. tuberculosis to antituberculous agents is a result of mutations in genes participating in those agent's action. The antituberculous drug--isoniazid can be activated by Mycobacterium tuberculosis either through a hydroperoxidase I/II or a superoxide-dependent oxyferrous pathway. The present study analyzed the frequency of the mutations occurring in codons 315 and 463 in katG gene of Mycobacterium tuberculosis strains, isolated from patients with pulmonary tuberculosis from Silesia, Poland. In this study 23 isoniazid-resistant Mycobacterium tuberculosis strains were analyzed. For RFLP analysis, a 620 bp amplified fragment of katG gene was digested with restriction endonuclease MspI. Among 24 isoniazid-resistant strains, isolated from patients between 2000-2001, point mutations were found in 30% of analyzed isoniazid-resistant strains in codons 315 or 463 (7 strains). In contrast, no mutations in codons 315 and/or 463 katG gene were found in 16 strains (70%). Obtained results suggests that point mutations S315T (AGC-->ACC) and R463L in katG gene are infrequent in the analyzed population.

Antitubercular Agents↗
PubMed1976

How chemicals may induce cancer.

Recent studies which lead to a better understanding of chemical carcinogenesis are reviwed. Almost all carcinogens require an activation by metabolic processing in order to operate "in vivo" or "in vitro". Some chemicals and drugs induce the enzymes which metabolize carcinogens. This induction seems to be of fundamental importance to the development of human cancers resulting from environmental pollution. Nearly all the lesions in cellular DNA caused by chemical carcinogens can be repaired by a DNA repair system. Failure to repair some lesions or the action of "error prone" repair can lead to mutations. The mutagenic effect of some chemicals provides a rapid screening test for the detection of their carcinogenic activity. Such tests are described and analyzed in detail. Finally, a general and overall scheme for possible mechanisms of action of chemical carcinogens is proposed.

Animals↗
PubMed2002

Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis.

Progressive external ophthalmoplegia (PEO) is a heritable mitochondrial disorder characterized by the accumulation of multiple point mutations and large deletions in mtDNA. Autosomal dominant PEO was recently shown to co-segregate with a heterozygous Y955C mutation in the human gene encoding the sole mitochondrial DNA polymerase, DNA polymerase gamma (pol gamma). Since Tyr-955 is a highly conserved residue critical for nucleotide recognition among family A DNA polymerases, we analyzed the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis by the purified human mutant polymerase in complex with its accessory subunit. The Y955C enzyme retains a wild-type catalytic rate (k(cat)) but suffers a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate (K(m)). The Y955C derivative is 2-fold less accurate for base pair substitutions than wild-type pol gamma despite the action of intrinsic exonucleolytic proofreading. The full mutator effect of the Y955C substitution was revealed by genetic inactivation of the exonuclease, and error rates for certain mismatches were elevated by 10-100-fold. The error-prone DNA synthesis observed for the Y955C pol gamma is consistent with the accumulation of mtDNA mutations in patients with PEO.

Amino Acid Sequence↗
PubMed2003

On the origin of G --> T transversions in lung cancer.

G-->T transversions in the TP53 gene are more common in lung cancers from smokers than in any other cancer except for hepatocellular carcinomas linked to aflatoxin. The high frequency of G-->T transversions in lung cancer has been attributed to the mutagenic action of cigarette smoke components, in particular polycyclic aromatic hydrocarbons (PAH). In a recent review [Mutat. Res. 508 (2002) 1-19], Rodin and Rodin have questioned the direct mutagenic action of PAH-like compounds and have suggested that other factors, such as selection of pre-existing endogenous mutations by smoke-induced stress, can better explain the excess of G-->T transversions in lung tumors. Their two main arguments against an involvement of PAH are that smoking may inhibit the repair of G-->T primary lesions on the non-transcribed strand and that lung cancer cell lines show a higher frequency of G-->T transversions than primary lung tumors suggesting that these mutations are not related to smoking. We illustrate here that both of these suggestions are incompatible with available evidence and that the abundance and sequence specificity of G-->T transversions in lung tumors is best explained by a direct mutagenic action of PAH compounds present in cigarette smoke.

DNA Damage↗
PubMed2004

Mechanisms of action of the principal prolific genes and their application to sheep production.

The prolificacy variation in sheep makes it an excellent animal model to understand the mechanisms regulating ovulation rate. Identification of mutations responsible for the increased prolificacy of the Inverdale, Booroola, Javanese, Cambridge and Belclare sheep open new avenues of investigation for the paracrine control of folliculogenesis. To date, all known mutations are in genes from ligands or receptors of the transforming growth factor beta superfamily, and point to the bone morphogenetic protein family of peptides as local regulators of ovarian follicle growth. The mechanism of action of the mutated genes is not fully understood, but results in the ovulation of a higher number of follicles with smaller diameter and fewer granulosa cells than that of the wildtype, thus speeding the differentiation of ovulatory follicles. Comparisons of the performance of Booroola-crossed flocks in different countries showed that carriers of the prolificacy mutation have higher ewe productivity but also higher perinatal mortality and lighter weight lambs. Their economic impact on the sheep industry depends on farm environment and management. Nevertheless, the diagnostic tests now available to identify the genetic mutations resulting in increased ovulation rate, will simplify the introduction of these mutations and their monitoring in flocks for research and commercial purposes.

Animals↗
PubMed2003

Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers.

OBJECTIVE: Mutations in the ABCB1 gene have been associated with decreased expression and net function of P-glycoprotein (P-gp). We investigated the modulation of the central nervous effects of loperamide resulting from ABCB1 genetic variants. METHODS: On two occasions, 20 healthy volunteers received 24 mg loperamide suspension orally and, in a double-blind randomized two-way crossover fashion, 800 mg quinidine or placebo orally 1 h before loperamide. Pupil size was measured for 5 h following loperamide administration, and plasma concentrations of loperamide and quinidine were measured for 6 h. Single nucleotide polymorphisms and haplotypes including G2677T(A) (exon 21) and C3435T (exon 26) were analysed for their relation to plasma concentrations of quinidine and loperamide and to the miotic effects of loperamide. RESULTS: Loperamide plasma concentrations with quinidine co-administration were about twice as high as those without quinidine. The ABCB1 haplotype G2677/T3435 was associated with the highest loperamide plasma concentrations, which were about 1.5 times higher than in non-carriers of this haplotype. Plasma concentrations of quinidine did not differ among carriers and non-carriers of genetic variants. When quinidine was co-administered with loperamide, pupil size decreased. Without quinidine it changed only minimally. The ABCB1 TT3435 genotype was associated with the most pronounced increase of the miotic effects of loperamide when quinidine was co-administered. This was accompanied by a tendency toward higher plasma loperamide in TT3435 carriers. CONCLUSIONS: Our data support a functional importance of the ABCB1 mutations for plasma concentrations and central nervous actions of the opioid loperamide.

Administration, Oral↗
PubMed2003

Evaluation and understanding of myocilin mutations in Indian primary open angle glaucoma patients.

PURPOSE: To screen for mutations in the MYOC gene of patients with Primary Open Angle Glaucoma (POAG) in India and to better understand the mutations using a possible model of myocilin. METHODS: We analyzed DNA for mutations in 107 subjects with POAG and 90 normal control subjects. The exonic sequences of the MYOC gene from all subjects were amplified by Polymerase Chain Reaction (PCR). We carried out Single Strand Conformation Polymorphism (SSCP) for all the PCR products. The DNA samples which showed mobility shift in the banding pattern in SSCP gel were sequenced. We also analyzed the presence of the common mutation Gln368Stop using a specific restriction enzyme Taa 1. The mutations observed here and elsewhere have been mapped onto a possible model built for myocilin using a knowledge-based consensus modeling approach. RESULTS: Two heterozygous mutations Gly367Arg (1099G>A) and Thr377Met (1130C>T) were identified in exon3 of the MYOC gene of probands 40-1 and 51-1 respectively, from material obtained from the 107 unrelated subjects with POAG. These two mutations were not present in the normal controls studied. We identified a Single Nucleotide Polymorphism (SNP) Gly122Gly (366C>T) in exon1 of proband 57-1 as a non-disease causing variation. The common mutation Gln368Stop found in the Western population was not observed in the POAG cases screened in Indian population. The possible structural model for myocilin suggests a predominantly [beta]-strand rich C-terminal region (181-504) which is connected by the [alpha]-helical mid-region (111-180) to the N-terminal region (34-110) which has low secondary structure content. Both the mutations, Gly367Arg and Thr377Met identified in our study, map on to the C-terminal region. These mutations disfavor burial of this region during oligomer formation due to the charged or bulky nature of the mutants. Most of the other mutations known for myocilin also are surface exposed on the C-terminal region. CONCLUSIONS: Our findings indicate that the mutation frequency of the MYOC gene is 2% in the Indian population affected with POAG, which is not a well-studied ethnic group of the Asian continent. The variations identified in our study have been previously reported in the Western population. The nonsense mutation Gln368Stop was not observed in the present study and thereby suggests that it may not be a common disease-causing mutation in the Indian population. Amongst other Asian populations, studies in Japan also didn't report this nonsense mutation. The location of these mutations suggest that a plausible mode of action could be by disruption of dimer or oligomer formation by the C-terminal region allowing greater chances of nucleation of aggregation by the N-terminal region.

Adolescent↗
PubMed2001

Molecular interactions between two long-QT syndrome gene products, HERG and KCNE2, rationalized by in vitro and in silico analysis.

The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the ECG. Mutations in either of the two molecular components of the rapid delayed rectifier (I(K,r)), HERG and KCNE2, have been linked to heritable or acquired long-QT syndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear. In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics and density of ionic current, incorporation of these effects into a quantitative model of the action potential predicts that only changes in current density significantly affect repolarization. Thus, the primary functional consequence of hKCNE2 on action potential morphology is through modulation of I(K,r) density, as predicted by the model. Mutations associated with long-QT syndrome that result only in modest changes of gating kinetics may be epiphenomena or may modulate action potential repolarization via interaction with alternative pore-forming potassium channel alpha subunits.

Action Potentials↗
PubMed2002

Volatile anesthetic actions on the GABAA receptors: contrasting effects of alpha 1(S270) and beta 2(N265) point mutations.

Previous studies have suggested that two specific amino acid residues in transmembrane segments 2 and 3 of the GABA(A) receptor alpha 2 subunit, Ser270 and Ala291, are critical for the enhancement of GABA(A) receptor function by inhaled anesthetics. The aim of this study was to determine the effects of amino acid substitutions in alpha 1 beta 2 gamma 2s GABA(A) receptors at alpha 1(S270) and at the homologous beta 2(N265) on receptor gating and anesthetic potentiation of GABA-induced responses. The wild-type and mutant receptors were transiently expressed in HEK 293 cells and GABA-induced currents were recorded using whole-cell voltage clamp. Potentiation of responses to a submaximal concentration of GABA by the anesthetics halothane and isoflurane was also examined. Some of the point mutations caused shifts in the GABA dose-response curve, indicating that the mutations changed the apparent affinity of the receptor for GABA. In receptors mutated at alpha 1(S270), the GABA EC(50) is inversely correlated with the volume of the residue of 270. On the contrary, there was no clear relationship between the physical properties of the amino acid residue at 265 in the beta 2 subunit and either the GABA EC(50) or anesthetic modulation, although mutations at N265 altered both parameters in a quantitative manner. These data are consistent with the results of previous work using other subunit combinations, in confirming that alpha 1(S270) may be involved in channel gating, and also may be important in anesthetic binding; the role of beta 2(N265) is less clear.

Amino Acid Sequence↗
PubMed1999

Concurrent teratogenic and mutagenic action of 2-methoxyethanol in Drosophila melanogaster larvae resulted in similar phenotypes: close resemblance to directed mutations.

Early third instar larvae of wild-type Drosophila melanogaster were transferred to medium supplemented with 2-methoxyethanol (2-ME) or ethylene glycol monomethyl ether. 2-ME produced terata in adult flies as wing notches and duplications of macrochaetae similar to feeding with methoxyacetic acid (MAA), the oxidation product of 2-ME. Larval feeding with 2-ME also affected the fertility of both females and males. 2-ME or more likely its intermediate oxidation product, methoxyacetaldehyde (MAALD), concurrently generated mutations in the premeiotic stages of the oocytes in the early third instar larvae. The mutagenicity of 2-ME has been confirmed in subsequent small scale experiments. The mutation frequency ranged from 4 x 10(-4) to 1 x 10(-2). Although terata were not supposed to be heritable, 1.1 to 8.7% of the affected females produced offspring with phenotypic similarity to the female parent. This phenomenon looked like a classical example of inheritance of an acquired character. The question is addressed why a Notch-like phenocopy, generated by larval 2-ME treatment, could bring forth Notch and rudimentary mutants in particular. Administration of 2-ME to larvae, containing the highly active alcohol dehydrogenase variant ADH-71k, exposed the mitotic germ cells and the mitotic somatic cells of the imaginal discs simultaneously to the mutagen MAALD and the teratogen MAA, respectively. The chances for specific gene mutations, though non-adaptive, were likely increased by a feedback mechanism: gene-products that were inhibited or disturbed by the teratogen demanded increased transcription of their encoding genes. Transcribed genes are more susceptible to mutagens.

Abnormalities, Drug-Induced↗