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At least 919 records · Page 51Linked to original sources
PubMed1997

A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.

The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

[Mutagenic action of acenaphthene on haploid and diploid cultures of Candida scottii].

Acenaphthene used as vapour increases the frequency of morphological mutations as well as mutations yielding strains with a reduced activity of respiration in Candida scottii. The diploid culture has more mutants than the haploid culture. The frequency of mutants depends on the duration of acenaphthene action. Cells more resistant to the action of acenaphthene vapour are selected in the haploid culture when C. scottii cells are transferred many times into new wort drops. As a result, the frequency of mutations decreases. When the diploid culture is exposed to the action of acenaphthene vapour for a longer time, the frequency of mutations rises. Apparently, the diploid culture has a lower activity of reparation of premutational damages than the haploid culture and therefore the number of mutant cells increases.

Acenaphthenes↗
PubMed1993

Biological actions of oncogenes.

Cancer, in many cases, results from multistep genetic mutation. Certain genes can have a predisposed susceptibility to mutations that lead to cancer because of chromosome location or their importance in the control of cell cycles. Mutations that deregulate the expression or activity of enzymes involved in the biochemical pathways of growth and differentiation or that suppress the expression of negative cell cycle control factors result in activation of oncogenesis. The study of oncogenes and tumor suppressor genes has greatly influenced our understanding of the molecular origins of cancer. We focus here on the normal biological action of proto-oncogenes compared with the transforming activities of oncogenes and tumor suppressor genes, and we discuss possible mechanisms of oncogenic transformation.

Animals↗
PubMed1997

Mutational analysis of slyD, an Escherichia coli gene encoding a protein of the FKBP immunophilin family.

slyD encodes a 196 amino acid polypeptide that is a member of the FKBP family of cis-trans peptidyl-prolyl isomerases (PPlases). slyD mutations affect plaque formation by the phage phiX174 by blocking the action of the phage lysis protein E. Here we describe the selection of a set of spontaneous slyD mutations conferring resistance to the expression of gene E from a plasmid. These mutations occur disproportionately in residues of SlyD that, based on the structure of the prototype mammalian FKBP12, make ligand contacts with immunosuppressing drug molecules or are conserved in other FKBP proteins. A wide variation in the plating efficiency of phiX174 on these E(R) strains is observed, relative to the parental, indicating that these alleles differ widely in residual SlyD activity. Moreover, it is found that slyD mutations cause significant growth rate defects in Escherichia coli B and C backgrounds. Finally, overexpression of slyD causes filamentation of the host. Thus, among the FKBP genes found in organisms across the evolutionary spectrum, slyD is unique in having three distinct drug-independent phenotypes.

Alleles↗
PubMed2004

On the excess of G --> T transversions in the p53 gene in lung cancer cell lines. Reply to Pfeifer and Hainaut.

Our recent retrospective analysis of the lung cancer-associated p53 mutation data [Mutat. Res. 508 (2002) 1] showed the possibility of (i) inhibiting action of tobacco smoke on repair of G --> T primary lesions in the non-transcribed strand of the p53 gene and (ii) the origin of new p53 mutations, predominantly G --> T transversions, in lung cancer cell lines apparently unexposed to tobacco smoke. In summary, our arguments suggest that (i) in addition to polycyclic aromatic hydrocarbons (PAH)-DNA adducts there exist other lung cancer-specific, rather than smoke-specific sources of G --> T transversions and (ii) a direct mutagenic action is not the only smoke-associated cause of the prevalence of this class of p53 mutations in lung cancer. In the subsequent critical commentary [Mutat. Res. 526 (2003) 39], Pfeifer and Hainaut suggested our arguments to be "incompatible with available evidence". We would like to address their critique, and appreciate the editors of Mutation Research giving us an opportunity to do so.

Humans↗
PubMed1995

Sensitivity and cellular response to different anticancer agents of a human ovarian cancer cell line expressing wild-type, mutated or no p53.

BACKGROUND: The cytotoxicity and gene expression induced by anticancer drugs with different mechanisms of action was tested in clones from a human ovarian cancer cell line expressing no p53, mutated p53 or wild type (wt) p53. MATERIALS AND METHODS: We used clones from SKOV3 cells transfected with a temperature-sensitive mutant p53 which expresses mutated p53 at 37 degrees C and a wild type-like p53 at 32 degrees C. Cytotoxicity and expression of p53-related genes (WAF1 and GADD45) were tested after 24 hours of treatment with different drugs. RESULTS: All of the drugs were equally active in the different systems, independently of the presence of p53, with the exception of doxorubicin which was less cytotoxic in cells expressing a wtp53. An increase in the transcription of WAF1 and GADD45 genes was found in cells expressing p53 and treated with the drugs. GADD45 and WAF1 expression was also found in cells not expressing p53 but treated with the drugs, suggesting that these genes can also be activated by DNA damage through a pathway independent of p53. A highly DNA-sequence-specific alkylator, tallimustine (FCE 24517), which causes a very small number of DNA lesions, does not increase the expression of these genes. Cyclin D1 gene expression was not changed after treatment with the drugs tested in cells both expressing and not expressing wtp53. CONCLUSIONS: Our data suggest that p53 expression does not play a role in increasing the susceptibility of cells not undergoing apoptosis after DNA damage, but that, at least in the case of doxorubicin, it can enhance the repair systems and reduce the cytotoxicity.

Antineoplastic Agents↗
PubMed2005

Fatty acids induce L-CPT I gene expression through a PPARalpha-independent mechanism in rat hepatoma cells.

Liver carnitine palmitoyl transferase (L-CPT) I is a key regulatory enzyme of long-chain fatty acid (LCFA) oxidation that ensures the first step of LCFA import into the mitochondrial matrix. In rat hepatocytes, we showed previously that L-CPT I gene expression was induced by LCFAs as well as by fibrates. The aim of this study was to determine whether LCFA-induced L-CPT I gene expression was mediated by PPARalpha. For this purpose, we constructed a PPARalpha-dominant negative receptor to inhibit endogenous PPARalpha signaling. Highly conserved hydrophobic and charged residues (Leu459 and Glu462) in helix 12 of the ligand-binding domain were mutated to alanine. These mutations led to a total loss of transcriptional activity due to impaired coactivator recruitment. Furthermore, competition studies confirmed that the mutated PPARalpha receptor abolished the wild-type PPARalpha receptor action and thus acted as a powerful dominant negative receptor. When overexpressed in rat hepatoma cells (H4IIE) using a recombinant adenovirus, the mutated PPARalpha receptor antagonized the clofibrate-induced L-CPT I gene expression, whereas it did not affect LCFA-induced L-CPT I. These results provide the first direct demonstration that LCFAs regulate L-CPT I transcription through a PPARalpha-independent pathway, at least in hepatoma cells.

Adenoviridae↗
PubMedDate not supplied

Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale.

The etiology of Alzheimer disease (AD) is not well understood; therefore, neither prevention strategies nor long-term effective treatment modalities are available for this disease. Based on laboratory and clinical studies, it appears that reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are generated extracellularly and intracellularly by various mechanisms are among the major intermediary risk factors that initiate and promote neurodegeneration in idiopathic AD. Therefore, multiple antioxidant supplements could be useful in the prevention of AD, and as an adjunct to standard therapy in the treatment of AD. The products of inflammatory reactions such as prostaglandins (PGs; PGE1 and PGA1), free radicals, cytokines, and complement proteins are neurotoxic. Nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit the synthesis of PGs, reduce the rate of deterioration of cognitive functions in patients with advanced AD. Cholinergic drugs are routinely used in the treatment of AD to improve cognitive functions. Therefore, we propose that a combination of multiple antioxidants and NSAIDs may be more beneficial in the prevention of AD, and that this combination taken together with cholinergic drugs may be more effective in the treatment of AD than the individual agents alone. We also hypothesize that, in idiopathic AD, epigenetic components of neurons such as mitochondria, membranes, other membranous structures, and protein modifications--rather than the genes of neurons--are the primary targets for the action of neurotoxins including free radicals. In some familial AD, mutations in amyloid precursor protein and presenilins are associated with the risk of early onset of this disease; however, their mechanisms of action are not fully understood.

Alzheimer Disease↗
PubMed1982

[Biological effects of heavy ion exposure].

Experiments with accelerated heavy ions may contribute to the understanding of biological radiation action. After outlining the theoretical background experiments are described which were carried out at the UNILAC-machine (Gesellschaft für Schwerionenforschung, Darmstadt, Germany) where ions up to uranium can be accelerated to maximal specific energies of 10 MeV/u. Yeast cells served as biological test systems with the synthesis of ribosomal RNA (r-RNA), colony-forming ability and mutation induction as experimental endpoints. A relationship between action and energy deposition by individual particles can be demonstrated for the inhibition of r-RNA synthesis, in other cases the ion energy plays also an important role indicating that the interaction of sigma-electrons from different particles contributes significantly to the biological effect.

Dose-Response Relationship, Radiation↗
PubMed2004

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

Animals↗
PubMed2001

I(Kr): the hERG channel.

G.-N. Tseng. I(Kr): The hERG Channel. Journal of Molecular and Cellular Cardiology (2001) 33, 835-849. The rapid delayed rectifier (I(Kr)) channel is important for cardiac action potential repolarization. Suppressing I(Kr)function, due to either genetic defects in its pore-forming subunit (hERG) or adverse drug effects, can lead to long-QT (LQT) syndrome that carries increased risk of life-threatening arrhythmias. The implication of I(Kr)in cardiac arrhythmias and in anti-arrhythmic/pro-arrhythmic actions of drugs has driven intensive research interests in its structure-function relationship, the linkage between LQT-associated mutations and changes in channel function, and the mechanism of drug actions. This review will cover the following topics: (1) heterogeneous contribution of I(Kr)to action potential repolarization in the heart, (2) structure-function relationship of I(Kr)/hERG channels, (3) role of regulatory & bgr; subunits in I(Kr)/hERG channel function, (4) structural basis for the unique pharmacological properties of I(Kr)/hERG channels, and (5) I(Kr)/hERG channel modulation by changes in cellular milieu under physiological and pathological conditions of the heart. It is anticipated that further advances in our understanding of I(Kr)/hERG, particularly in the areas of roles of different (& agr; and & bgr;) subunits in native I(Kr)function, alterations in I(Kr)function in diseased hearts, and the 3-dimensional structure of the I(Kr)/hERG pore based on homology modeling using the KcsA model, will help us better define the role of I(Kr)in arrhythmias and design therapeutic agents that can increase I(Kr)and are useful for LQT syndrome.

Action Potentials↗
PubMed2005

p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the sumoylation of its binding partners.

The p14ARF tumour suppressor regulates a series of cell cycle regulatory proteins to promote cell cycle arrest in response to abnormal hyperproliferative growth stimuli. p14ARF alterations are common in human cancers and, when inherited, confer susceptibility to cutaneous melanoma. We now propose that the mechanism of p14ARF action may involve the covalent modification of its binding partners with the small ubiquitin-related protein SUMO-1. In particular, we demonstrate that p14ARF interacts with the SUMO E2 conjugating enzyme, Ubc9 and enhances the sumoylation of its binding partners, hdm2, E2F-1, HIF-1alpha, TBP-1 and p120E4F. Furthermore, p14ARF-induced sumoylation is abrogated by a subset of melanoma-associated p14ARF mutations. These results provide a mechanism for p14ARF action through a common modification of diverse binding partners.

Adenovirus E4 Proteins↗
PubMed1997

Localized gene action controlling intestinal neoplasia in mice.

Mice heterozygous for the ApcMin (Min) mutation develop adenomas throughout the intestinal tract. Apc is believed to be involved in cell migration, adhesion, and polarity. Adenoma multiplicity and growth rate are modulated by an unlinked modifier locus, Mom1. The secretory phospholipase Pla2g2a is a candidate for Mom1. Here, we investigate the range of action of Apc and Mom1. Analysis of chimeric Min mice indicates that the actions of both Apc and Mom1 are localized within the cell lineage that gives rise to intestinal tumors.

Adenoma↗
PubMed2006

Structural requirements of transmembrane domain 3 for activation by the M1 muscarinic receptor agonists AC-42, AC-260584, clozapine, and N-desmethylclozapine: evidence for three distinct modes of receptor activation.

Transmembrane domain 3 (TM3) plays a crucial role mediating muscarinic acetylcholine receptor activation by acetylcholine, carbachol, and other muscarinic agonists. We compared the effects of point mutations throughout TM3 on the interactions of carbachol, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine hydrogen chloride (AC-42), a potent structural analog of AC-42 called 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), N-desmethylclozapine, and clozapine with the M(1) muscarinic receptor. The binding and activation profiles of these ligands fell into three distinct patterns; one exemplified by orthosteric compounds like carbachol, another by structural analogs of AC-42, and a third by structural analogs of N-desmethylclozapine. All mutations tested severely reduced carbachol binding and activation of M(1). In contrast, the agonist actions of AC-42 and AC-260584 were greatly potentiated by the W101A mutation, slightly reduced by Y106A, and slightly increased by S109A. Clozapine and N-desmethylclozapine displayed substantially increased maximum responses at the Y106A and W101A mutants, slightly lower activity at S109A, but no substantial changes in potency. At L102A and N110A, agonist responses to AC-42, AC-260584, clozapine, and N-desmethylclozapine were all substantially reduced, but usually less than carbachol. D105A showed no functional responses to all ligands. Displacement and dissociation rate experiments demonstrated clear allosteric properties of AC-42 and AC-260584 but not for N-desmethylclozapine and clozapine, indicating that they may contact different residues than carbachol to activate M(1) but occupy substantially overlapping spaces, in contrast to AC-42 and AC-260584, which occupy separable spaces. These results show that M(1) receptors can be activated in at least three distinct ways and that there is no requirement for potent muscarinic agonists to mimic acetylcholine interactions with TM3.

Benzoxazines↗
PubMed1981

Four-base codons ACCA, ACCU and ACCC are recognized by frameshift suppressor sufJ.

The frameshift suppressor sufJ acts to correct a set of +1 frameshift mutations having very different sequences at their mutant sites. This suppressor acts by reading a 4 base codon located near, but not at, the site of each suppressible mutation. Suppression thus necessitates out-of-phase translation of the short stretch of mRNA between the site of action of the suppressor tRNA and the site of the frameshift mutation. We have identified the site read by sufJ by mutationally creating a series of such sites in the neighborhood of a previously nonsuppressible frameshift mutation. Each of the newly generated sites was formed by base substitution. Four independently generated sites were analyzed by DNA sequencing. At each site the quadruplet codon ACCX was generated (where X is A, U or C). Thus sufJ is able to read a 4 base codon in which any of three bases is acceptable in the fourth position. This is the first frameshift suppressor that does not read a run of three repeated bases in the first three positions of its codon.

Base Sequence↗
PubMed1994

A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea.

Embryonal kidney cell tumors develop in rats given the alkylating agent N-nitroso-N'-methylurea as neonates. These tumors resemble the childhood Wilms tumors in their histopathology. Deletions and mutations in the Wilms tumor suppressor gene, WT1, are present in up to 6% of childhood nephroblastomas. To investigate the role of WT1 in rat kidney tumorigenesis, we studied the genetic alterations in WT1 and its target genes. Point mutations were found in WT1 cDNA in 7 of 18 kidney tumors. Mesenchymal tumors contained G-->A transition mutations in codons 128, 364, and 372, typical of the methylating action of N-nitroso-N'-methylurea on DNA. Each of the four nephroblastomas contained the same T-->A mutation at codon 111 of WT1, reflective of transversion mutagenesis by N-nitroso-N'-methylurea in vivo. Like Wilms tumors, mRNA levels of WT1, IGF2, Pax-2, and MK genes were higher than newborn kidney in the majority of the tumors. The histopathology of the rat kidney tumors and the genetic alterations are reminiscent of those observed in Wilms tumors, establishing this as a relevant model system for the human disease.

Animals↗
PubMed1976

The induction of mutation in yeast by hydrogen peroxide.

The inactivation and mutation to respiratory deficiency of yeast cells by H2O2 are shown to vary progressively with the phase of cell growth, with a sharp transition occurring as the cells complete logarithmic growth. Respiratory deficient mutants isolated from the wild-type population are of two types, one of which is much more sensitive to H2O2 but forms only a small fraction of the mutant sub-population. Based upon the response of the more resistant type, mutation frequency increases appear to result from selection of pre-existing mutants in log phase populations, while induction occurs in stationary phase cells. The induced mutation frequency fits a (dose)2 relationship, but the frequency is depressed when the dose is high (or number of cells treated is low). All the induced mutants are extranuclear and of the resistant type, and show a wide range of suppressiveness in crosses to respiratory competent cells. This may indicate mitochondrial DNA is altered to different extents by H2O2; by the same criterion, the spontaneously occurring H2O2 -sensitive mutants retain a large amount of mitochondrial DNA information, in agreement with their colonial morphology. A small increase in forward mutation of nuclear genes was also found after H2O2 treatment. Parallels are drawn between the response of yeast cells to ionising radiation and to H2O2, and it is suggested that radical action may be involved in inactivation and mitochondrial genome mutation induced by both agents.

DNA↗
PubMed1990

Mapping mutations in influenza A virus resistant to norakin.

To elucidate the mode of action of norakin against influenza A virus we sequenced the hemagglutinin gene of 11 norakin-resistant mutants. Resistance was coupled with 1-3 amino acid exchanges. The majority of mutations was localized in the HA2 polypeptide and was mostly associated with changes in charge or polarity of the amino acids. The amino acid substitutions are discussed in the context of the 3D structure of X31 hemagglutinin considered to be representative of the influenza hemagglutinins. Most of the mutations appear to destabilize the pH 7.0 structure by distorting or destroying hydrogen bonds as well as salt-bridges which are responsible for intra- and intersubunit contacts, while others destabilize the location of the fusion peptide, facilitating conformational changes in the presence of the inhibitor.

Amino Acids↗