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1.
The role of O6-methylguanine-DNA methyltransferase in cell survival, mutagenesis and carcinogenesis 总被引:13,自引:0,他引:13
D B Yarosh 《Mutation research》1985,145(1-2):1-16
2.
Plasminogen activator and collagenase production by cultured capillary endothelial cells 总被引:33,自引:17,他引:16
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Cultured bovine capillary endothelial (BCE) cells produce low levels of collagenolytic activity and significant amounts of the serine protease plasminogen activator (PA). When grown in the presence of nanomolar quantities of the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), BCE cells produced 5-15 times more collagenolytic activity and 2-10 times more PA than untreated cells. The enhanced production of these enzymes was dependent on the dose of TPA used, with maximal response at 10(-7) to 10(-8) M. Phorbol didecanoate (PDD), an analog of TPA which is an active tumor promoter, also increased protease production. 4-O-methyl-TPA and 4α-PDD, two analogs of TPA which are inactive as tumor promoters, had no effect on protease production. Increased PA and collagenase activities were detected within 7.5 and 19 h, respectively, after the addition of TPA. The TPA-stimulated BCE cells synthesized a urokinase-type PA and a typical vertebrate collagenase. BCE cells were compared with bovine aortic endothelial (BAE) cells and bovine embryonic skin (BES) fibroblasts with respect to their production of protease in response to TPA. Under normal growth conditions, low levels of collagenolyic activity were detected in the culture fluids from BCE, BAE, and BES cells. BCE cells produced 5-13 times the basal levels of collagenolytic activity in response to TPA, whereas BAE cells and BES fibroblasts showed a minimal response to TPA. Both BCE and BAE cells exhibited relatively high basal levels of PA, the production of which was stimulated approximately threefold by the addition of TPA. The observation that BCE cells and not BAE cells produced high levels of both PA and collagenase activities in response to TPA demonstrates a significant difference between these two types of endothelial cells and suggests that the enhanced detectable activities are a property unique to bovine capillary and microvessel and endothelial cells. 相似文献
3.
Polymorphisms in DNA repair genes have been suggested to increase the risk of cancer and other diseases, but the epidemiological studies are often not consistent, and the results confusing. We have examined the effect of polymorphisms in base and nucleotide excision-repair genes, as well as regulatory and signalling genes, on cytotoxic sensitivity of tumour cell lines used for screening anticancer drugs by the National Cancer Institute. It was found that for the TP53 P72R and ERCC2 D312N polymorphisms, the heterozygous genotype was most sensitive, while for the OGG1 S326C and NOS3 g.-786T>C polymorphisms the homozygous-variant genotype was most sensitive. The biggest increase in sensitization was found with the XRCC1 R399Q homozygous dominant genotype. The sensitization was found across a broad range of drugs, indicating the importance of DNA repair responses. It was also found that while the other gene polymorphisms were in Hardy-Weinberg equilibrium, the TP53 P72R heterozygous genotype was relatively depleted. For the OGG1 polymorphism, the repair of 8-oxo-guainine from DNA was measured in three panel cell lines that differed in their OGG1 genotype. The cell line with the homozygous-variant genotype had a much poorer repair than the other genotypes, as predicted. The correlation of polymorphisms with cytotoxicity may be an approach to understanding their effects which may be difficult to reveal in epidemiological studies. 相似文献
4.
Aprille Seidel Ying Ye Lesley R. de Armas Maira Soto William Yarosh Renee A. Marcsisin Dat Tran Michael E. Selsted David Camerini 《PloS one》2010,5(3)
Defensins are antimicrobial peptides expressed by plants and animals. In mammals there are three subfamilies of defensins, distinguished by structural features: α, β and θ. Alpha and β-defensins are linear peptides with broad anti-microbial activity that are expressed by many mammals including humans. In contrast, θ-defensins are cyclic anti-microbial peptides made by several non-human primates but not humans. All three defensin types have anti-HIV-1 activity, but their mechanisms of action differ. We studied the anti-HIV-1 activity of one defensin from each group, HNP-1 (α), HBD-2 (β) and RTD-1 (θ). We examined how each defensin affected HIV-1 infection and demonstrated that the cyclic defensin RTD-1 inhibited HIV-1 entry, while acyclic HNP-1 and HBD-2 inhibited HIV-1 replication even when added 12 hours post-infection and blocked viral replication after HIV-1 cDNA formation. We further found that all three defensins downmodulated CXCR4. Moreover, RTD-1 inactivated X4 HIV-1, while HNP-1 and HBD-2 inactivated both X4 and R5 HIV-1. The data presented here show that acyclic and cyclic defensins block HIV-1 replication by shared and diverse mechanisms. Moreover, we found that HNP-1 and RTD-1 directly inhibited firefly luciferase enzymatic activity, which may affect the interpretation of previously published data. 相似文献
5.
6.
A common polygenic basis for quinine and PROP avoidance in mice 总被引:3,自引:2,他引:1
Inbred strains of mice (Mus musculus) differ greatly in ability to taste
various bitter compounds. For some compounds, the differences result from
allelic variation at a single locus. However, segregation patterns
incompatible with monogenic inheritance have been found for quinine
avoidance. The Soa bitter sensitivity locus exerts some influence on this
phenotype, but an unknown number of other loci also contribute. Relative
avoidance patterns for quinine sulfate in panels of naive inbred strains
resembled avoidance patterns for 6-n-propyl-2- thiouracil (PROP),
suggesting a common genetic basis. In particular, C57BL/6J mice strongly
avoided both 0.1 mM quinine sulfate and 1 mM PROP in two-bottle preference
tests, whereas C3H/HeJ mice were indifferent to both. Therefore, 12 BXH/Ty
recombinant inbred strains, derived from these strains, were tested with
both solutions to begin identification of the unknown bitter loci. Naive
mice were tested for four consecutive days with each compound (order
counterbalanced). Some BXH/Ty strain means resembled those of the parent
strains, but others were intermediate. This indicated recombination among
loci affecting avoidance, and therefore polygenic inheritance. The strain
means were highly correlated across compounds (r = 0.98), suggesting that
the same polygenes controlled both phenotypes. The BXH/Ty means for both
compounds were then compared with the strain genotypes at 212 chromosome
position markers distributed throughout the genome. Eight markers on five
chromosomes (3, 6, 7, 8 and 9) yielded significant correlations. Six of the
markers were correlated with both phenotypes, again suggesting common
polygenic inheritance. The marker with the highest correlation was Prp,
tightly linked to Soa on chromosome 6. The correlated marker regions likely
contain quantitative trait loci affecting bitter avoidance. The phenotypic
similarity of PROP to quinine, rather than to phenylthiourea, apparently
stemming from a common polygenic basis, indicates a difference between mice
and humans in gustatory organization related to bitters.
相似文献
7.
Carla DB Fernandez Fernanda F Bellentani Glaura SA Fernandes Juliana E Perobelli Ana Paula A Favareto André F Nascimento Antonio C Cicogna Wilma DG Kempinas 《Reproductive biology and endocrinology : RB&E》2011,9(1):32
Background
Obesity is rapidly becoming a worldwide epidemic that affects children and adults. Some studies have shown a relationship between obesity and infertility, but until now it remains controversial. Thus, the aim of the present study was to investigate the effect of high-fat diet-induced obesity on male reproductive parameters. 相似文献8.
Rockel N Esser C Grether-Beck S Warskulat U Flögel U Schwarz A Schwarz T Yarosh D Häussinger D Krutmann J 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(6):3604-3612
Organic osmolytes, such as taurine, are involved in cell volume homeostasis and cell protection. Epidermal keratinocytes possess an osmolyte strategy, i.e., they take up taurine upon hyperosmotic stress and express the corresponding transporter TAUT. UVB irradiation also triggers taurine uptake and TAUT expression in this cell type. We therefore asked whether taurine plays a role in photoprotection. By using a TAUT-deficient mouse model, lack of taurine in the skin was found to cause a significantly higher sensitivity to UVB-induced immunosuppression. This was not due to an increased generation or decreased repair of UVB-induced DNA photoproducts in the skin of these animals. Instead, decreased skin taurine levels were associated with an increased formation of the soluble immunosuppressive molecule platelet-activating factor (PAF) from the membranes of UVB-irradiated epidermal cells. Blocking PAF activity in taut-deficient mice with a PAF receptor antagonist abrogated their increased sensitivity to UVB-induced immunosuppression. Moreover, taut -/- mice were more sensitive to PAF-mediated immunosuppression than taut +/+ mice. These data suggest that taurine uptake by epidermal cells prevents undue PAF formation, and thereby photoimmunosuppression. Thus, similar to nucleotide excision repair, taurine uptake is critically involved in photoprotection of the skin. 相似文献
9.
Yarosh W Monserrate J Tong JJ Tse S Le PK Nguyen K Brachmann CB Wallace DC Huang T 《PLoS genetics》2008,4(1):e6
Mutations in optic atrophy 1 (OPA1), a nuclear gene encoding a mitochondrial protein, is the most common cause for autosomal dominant optic atrophy (DOA). The condition is characterized by gradual loss of vision, color vision defects, and temporal optic pallor. To understand the molecular mechanism by which OPA1 mutations cause optic atrophy and to facilitate the development of an effective therapeutic agent for optic atrophies, we analyzed phenotypes in the developing and adult Drosophila eyes produced by mutant dOpa1 (CG8479), a Drosophila ortholog of human OPA1. Heterozygous mutation of dOpa1 by a P-element or transposon insertions causes no discernable eye phenotype, whereas the homozygous mutation results in embryonic lethality. Using powerful Drosophila genetic techniques, we created eye-specific somatic clones. The somatic homozygous mutation of dOpa1 in the eyes caused rough (mispatterning) and glossy (decreased lens and pigment deposition) eye phenotypes in adult flies; this phenotype was reversible by precise excision of the inserted P-element. Furthermore, we show the rough eye phenotype is caused by the loss of hexagonal lattice cells in developing eyes, suggesting an increase in lattice cell apoptosis. In adult flies, the dOpa1 mutation caused an increase in reactive oxygen species (ROS) production as well as mitochondrial fragmentation associated with loss and damage of the cone and pigment cells. We show that superoxide dismutase 1 (SOD1), Vitamin E, and genetically overexpressed human SOD1 (hSOD1) is able to reverse the glossy eye phenotype of dOPA1 mutant large clones, further suggesting that ROS play an important role in cone and pigment cell death. Our results show dOpa1 mutations cause cell loss by two distinct pathogenic pathways. This study provides novel insights into the pathogenesis of optic atrophy and demonstrates the promise of antioxidants as therapeutic agents for this condition. 相似文献
10.
Whitehouse DB; Tomkins J; Lovegrove JU; Hopkinson DA; McMillan WO 《Molecular biology and evolution》1998,15(4):456-462
The expanding molecular database provides unparalleled opportunities for
characterizing genes and for studying groups of related genes. We use
sequences drawn from the database to construct an evolutionary framework
for examining the important glycolytic enzyme phosphoglucomutase (PGM).
Phosphoglucomutase plays a pivotal role in the synthesis and utilization of
glycogen and is present in all organisms. In humans, there are three
well-described isozymes, PGMI, PGM2, and PGM3. PGM1 was cloned 5 years ago;
however, repeated attempts using both immunological approaches and
molecular probes designed from PGM1 have failed to isolate either PGM2 or
PGM3. Using a phylogenetic strategy, we first identified 47 highly
divergent prokaryotic and eukaryotic PGM-like sequences from the database.
Although overall amino acid identity often fell below 20%, the relative
order, position, and sequence of three structural motifs, the active site
and the magnesium-- and sugar-binding sites, were conserved in all 47
sequences. The phylogenetic history of these sequences was complex and
marked by duplications and translocations; two instances of transkingdom
horizontal gene transfer were identified. Nonetheless, the sequences fell
within six well-defined evolutionary lineages, three of which contained
only prokaryotes. Of the two prokaryotic/eukaryotic lineages, one contained
bacterial, yeast, slimemold, invertebrate, and vertebrate homologs to human
PGM1 and the second contained likely homologs to human PGM2. Indeed, an
amino acid sequence, derived from a partial human cDNA, that fell within
the second cross-kingdom lineage bears several characteristics expected for
PGM2. A third lineage may contain homologs to human PGM3. On a general
level, our phylogenetic-based approach shows promise for the further
utilization of the extensive molecular database.
相似文献