Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide is a short-lived free radical produced by different isoforms of the enzyme nitric oxide synthase. It regulates a whole range of functions in the body, but little is known about its effects on bone. Rat osteoclasts and a human preosteoclast cell line (FLG 29.1) have been shown to produce nitric oxide and to express nitric oxide synthases. In the present study we investigated the role of a nitric oxide donor, 3-morpholinosydnonimine hydrochloride, on the FLG 29.1 cells. 3-Morpholinosydnonimine hydrochloride has been shown to significantly increase IL6 production and tartrate resistant acid phosphatase activity in FLG 29.1 cells, indicating a positive modulation of osteoclast differentiation. However FLG 29.1 cell adhesion on osteoblast-like cells was significantly inhibited, suggesting an inhibition of osteoclast motility. All these results confirm the bidirectional effect of nitric oxide whose basal production is necessary in promoting osteoclast differentiation, while at high levels it is effective in inhibiting osteoclast activity.
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PMID:Bioeffects of a nitric oxide donor in a human preosteoclastic cell line. 940 62

Chromosomal band 1q21 contains a number of genes, constituting the Epidermal differentiation complex (EDC), most of which are involved in the process of terminal differentiation of the human epidermis and implicated in several disorders of keratinization and cancer. The physical map of 1q21 has been refined by generating 400 YAC derivatives. These products have allowed us to localize EDC genes and additional ESTs precisely. The transcriptional map of the region has been extended by positioning 20 ESTs reported to map between D1S442 and D1S305. Eight of the ESTs are localized in two distinct clusters, confirmed by isolating PACs and chromosome 1-specific cosmids. Two of the ESTs correspond to the genes for YL1 and selenium-binding protein, both of which have potential tumor suppressor activity. Through the use of fragmented YACs and bacterial clones, the order of markers and ESTs in the region has been established as follows: cen-A002O32-Bda44g03-Cda10d12-Bdab5d06, H60056, A005K39-D1S442-WI5663-WI7969-Cx40-Cda0g e12-Cda0kh05-A002D26- A008S07-Cda0ff08-D1S498-S100A10-WI7815( THH)-WI7217(FLG)-D1S1664-INV-SPRR2A- LOR-A001X21-D1S305-tel.
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PMID:High-resolution YAC fragmentation map of 1q21. 959 7

We have analyzed the flowering behavior of two Arabidopsis ecotypes: the laboratory strain Landsberg erecta (Ler) and an ecotype from the tropical Cape Verde Islands (Cvi). They differ little in their flowering phenotypes and in their responses to photoperiod length changes and to vernalization treatment. However, segregating populations derived from crosses between them showed a much larger variation. An approach of quantitative trait locus (QTL) mapping in recombinant inbred lines (RILs) grown under three environments differing in day-length and/or vernalization treatment has been used to detect and locate flowering loci. Four main QTLs were identified, designated early day-length insensitive (EDI), flowering F, G, and H (FLF, FLG, and FLH, respectively), to which most of the flowering behavior differences could be attributed. To further characterize the individual loci, near isogenic lines were constructed by introgressing Cvi early alleles of EDI and FLH into the Ler genetic background. EDI-Cvi alleles produce earliness under both long- and short-day photoperiods, rendering Ler plants almost day-length neutral. In addition, RILs were selected to analyze FLF and FLG. These loci interact epistatically and RILs carrying late alleles at FLF and FLG were very responsive to vernalization and showed an increased response to photoperiod length changes. The possible role of these loci for the control of flowering is discussed in the context of the current Arabidopsis model.
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PMID:Analysis of natural allelic variation at flowering time loci in the Landsberg erecta and Cape Verde Islands ecotypes of Arabidopsis thaliana. 961 Nov 89

The rapid degradation and subsequent lack of efficacy of n-butyric acid in vivo has been improved by the synthesis of monosaccharide stable pro-drugs of butyric acid. We studied the effects of D1 (O-n-butanoyl-2,3-O-isopropylidene-alpha-D-mannofuranoside), G1 (1-O-n-butanoyl-D,L-xylitol), and F1 (1-O-n-butanoyl 2,3-O-isopropylidene-D,L-xylitol) on the maturation and proliferation of AML cell lines HL 60 and FLG 29.1 and of purified blast cells from 10 cases of de novo acute myeloid leukaemia (AML). AML cell maturation was measured by surface antigen expression, morphology and cytochemistry. Toxicology in mice was also evaluated (DL50 1000 mg/kg). In HL 60 cells G1 and D1 increased the expression of CD15 and CD11a (presenting 62% of promyelo-metamyelocytes), and in 7/10 cases of primary AMLs that of CD11a, CD11b, CD15, and myeloperoxidase. D1, G1 and F1 induced a dose-dependent inhibition of tritiated thymidine uptake. Apoptosis (evaluated by flow cytometry and agarose gel electrophoresis) was induced in AML blasts by D1 and F1 (79% and 94% respectively for HL 60 cells) and, with less effect, by G1 (27%). The persistence of maturative and apoptotic activity in these new pro-drugs of butyric acid, hydrolysed only inside the tumour cell, suggests a possible use in differentiation therapy of myelodysplastic syndromes and AMLs.
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PMID:Butyrate-stable monosaccharide derivatives induce maturation and apoptosis in human acute myeloid leukaemia cells. 963 98

In a recent comparative genomic hybridization (CGH) study of a panel of sarcomas, we detected recurrent amplification of 1q21-q22 in soft tissue and bone tumours. Amplification of this region had not previously been associated with sarcoma development, but occasional amplification of CACY/S100A6 and MUC1 in 1q21 had been reported for melanoma and breast carcinoma respectively. Initial screening by Southern blot analysis showed amplification of S100A6, FLG and SPRR3 in several sarcomas and, in a first attempt to characterize the 1q21-q22 amplicon in more detail, we have now investigated the amplification status of these and 11 other markers in the region in 35 sarcoma samples. FLG was the most frequently amplified gene, and the markers located in the same 4.5-Mb region as FLG showed a higher incidence of amplification than the more distal ones. However, for most of the 14 markers, amplification levels were low, and only APOA2 and the anonymous marker D1S3620 showed high-level amplifications (> tenfold increases) in one sample each. We used fluorescence in situ hybridization (FISH) to determine the amplification patterns of two overlapping yeast artificial chromosomes (YACs) covering the region between D1S3620 and FLG (789f2 and 764a1), as well as two more distally located YACs in nine selected samples. Six samples had amplification of the YAC containing D1S3620 and, in three, 764a1 was also included. Five of these tumours showed normal copies of the more distal YACs; thus, it seems likely that an important gene may be located within 789f2, or very close. Two samples had high copy numbers of the most distal YACs. Taken together, FISH and molecular analyses indicate complex amplification patterns in 1q21-q22 with at least two amplicons: one located near D1S3620/789f2 and one more distal.
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PMID:Molecular characterization of a novel amplicon at 1q21-q22 frequently observed in human sarcomas. 971 33

The recent observation that estrogen synthesis occurs in osteoblast-like cells has suggested the aromatase activity as a possible local modulator of bone remodeling in post-menopausal women. To provide further insights into the androstenedione conversion to estrogen in bone-derived cells, we examined the human leukaemic cell line FLG 29.1, which is induced to differentiate toward the osteoclastic phenotype by TPA and TGF-beta1. Southern blot of RT-PCR products with a 32P-labeled cDNA probe for the human aromatase demonstrated that FLG 29.1 cells express aromatase mRNA. The enzyme activity, determined by measuring [3H]H2O release from [3H]androstenedione, obeyed Michaelis-Menten kinetic with apparent Km and Vmax values ranging from 5 to 10 nM and from 200 to 400 fmol/mg protein/6 h. Gene expression, enzyme activity and protein immunoreactivity, evaluated by immunocytochemistry, were stimulated in a time-dependent fashion by 5% charcoal-stripped FCS and by either 1-100 nM TPA or 0.01-0.5 ng/ml TGF-beta1, with maximal responses after 2-3 h exposure. After 24 h incubation of FLG 29.1 cells in the absence of these stimuli the aromatase mRNA and the protein were barely detectable. These findings demonstrate that cells of the osteoclastic lineage synthesize estrogen in vitro and that local cytokines, such as TGF-beta1, are able to induce androstenedione conversion.
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PMID:Aromatase expression and activity in the human leukaemic cell line FLG 29.1. 971 44

Several lines of evidence suggest that the c-Src tyrosine kinase has a specific role in bone-resorbing osteoclasts. To investigate this further, we examined the expression of c-Src, its kinase family members, and their putative substrates in the human leukemia cell line FLG 29.1. Western blot analysis with specific antibodies against Src family members showed expression of Src, Fyn, and Lyn, lower levels of Yes and Hck, and the absence of Lck tyrosine kinase. During a 3-day treatment with phorbol 12-myristate, 13-acetate (PMA), which induces differentiation of FLG 29.1 cells toward an osteoclast-like phenotype, the levels of Src and Fyn increased and the levels of Lyn decreased. In a similar leukemia cell line, HL-60, Src protein was not constitutively expressed and not induced by PMA treatment, which leads to monocytic differentiation. PMA treatment of FLG 29.1 cells induced a strong increase in the expression of p120 Cbl and Pyk2 kinase, which are putative Src substrates. Pyk2 phosphorylation increased upon adherence of FLG 29.1 cells to fibronectin and to ST2 stromal cells. The expression of other Src substrates and interacting proteins, such as p120 Cas, p130 Cas, vinculin, Fak kinase, and the p85 phosphatidylinositol 3-kinase subunit either did not change or slightly increased during PMA treatment. The elevated total protein tyrosine phosphorylation in PMA-treated FLG 29.1 cells was abolished by herbimycin A, a Src inhibitor. These data are consistent with the proposed role of Src in the osteoclastic function and support the use of FLG 29.1 cells as a model to study Src substrates in the cells of the osteoclastic lineage.
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PMID:Expression of Src family kinases and their putative substrates in the human preosteoclastic cell line FLG 29.1. 984 6

Although compelling data have demonstrated the effectiveness of estrogen replacement therapy for the treatment of accelerated bone loss in postmenopausal osteoporosis and ovariectomized animals, the mechanisms by which estrogens reduce bone resorption remain to be elucidated. To address this issue, in the present study we investigated whether estrogens were able to induce programmed cell death or apoptosis in osteoclast precursors. To this purpose, a preosteoclastic cell line (FLG 29.1) was cultured in the absence or presence of nanomolar concentrations of 17beta-estradiol (17betaE2). Using time-lapse videomicroscopy, it was shown that 17betaE2 induced FLG 29.1 cell apoptosis in a dose- and time-dependent manner. Furthermore, a significant increase in the activity of caspase 3 enzyme and in the number of nuclei undergoing DNA fragmentation was observed in FLG 29.1 cells treated with 17betaE2 compared to untreated cells. Finally, transmission electron microscopy of the treated cells showed typical apoptotic morphology. These data indicate that 17betaE2 is able to promote in vitro apoptosis in preosteoclastic cells and suggest that estrogenic molecules may exert in vivo a direct role in negatively modulating the pool of undifferentiated bone marrow cells capable ultimately of maturing into osteoclasts.
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PMID:17beta-estradiol induces apoptosis in the preosteoclastic FLG 29.1 cell line. 1004 70

As a first step in determining whether there are polymorphisms in the nicotinic acetylcholine receptor (nAChR) genes that are associated with nicotine addiction, we isolated genomic clones of the beta2-nAChR genes from human and mouse BAC libraries. Although cDNA sequences were available for the human gene, only the promoter sequence had been reported for the mouse gene. We determined the genomic structures by sequencing 12 kb of the human gene and over 7 kb of the mouse gene. While the sizes of exons in the mouse and human genes are the same, the introns differ in size. Both promoters have a high GC content (60-80%) proximal to the AUG and share a neural-restrictive silencer element (NRSE), but overall sequence identity is only 72%. Using a 6-Mb YAC contig of Chr 1, we mapped the human beta2-nAChR gene, CHRNB2, to 1q21.3 with the order of markers cen, FLG, IVL, LOR, CHRNB2, tel. The mouse gene, Acrb2, had previously been mapped to Chr 3 in a region orthologous to human Chr 1. We refined mapping of the mouse gene and other markers on a radiation hybrid panel of Chr 3 and found the order cen, Acrb2, Lor, Iv1, Flg, tel. Our results indicate that this cluster of markers on human Chr 1 is inverted with respect to its orientation on the chromosome compared with markers in the orthologous region of mouse Chr 3.
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PMID:Genomic organization and mapping of the human and mouse neuronal beta2-nicotinic acetylcholine receptor genes. 1044 42

It is unclear how mechanical stress influences bone cells. Mechanical stress causes fluid shear stress (FSS) in the bone. Osteoblast lineage cells are thought to sense FSS and regulate bone remodeling. We therefore investigated the effects of FSS on human osteoblast-like osteosarcoma cells: SaOS-2 cells in vitro. The conditioned medium of the SaOS-2 cells after 24 h of FSS (24 h-FSS CM) showed such osteoclastic phenotype inductions as significantly increasing the number of tartrate-resistant acid phosphatase (TRAP) positive multinuclear cells in rat bone marrow cells and TRAP-positive cells in human preosteoclastic cells: FLG 29.1 cells. An enzyme-linked immunosorbent assay showed interleukin-11 (IL-11) protein to increase 7-fold in the 24 h-FSS CM. A Northern analysis showed that IL-11 mRNA increased 4-fold in the SaOS-2 cells after 6 h-FSS; however, no IL-6 mRNA expression was detected. Furthermore, the anti-human IL-11 antibody significantly neutralized the osteoclastic phenotype induction of the 24 h-FSS CM. The IL-11 mRNA up-regulation in SaOS-2 cells by the 6 h-FSS was not inhibited by the anti-human transforming growth factor-beta1 antibody, but it was significantly inhibited by indomethacin. An enzymeimmunoassay showed prostaglandin E2 to increase 7-fold in the 1 h-FSS CM. These findings thus suggest that FSS induces osteoblasts to produce IL-11 (mediated by prostaglandins) and thus stimulates bone remodeling.
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PMID:Fluid shear stress increases interleukin-11 expression in human osteoblast-like cells: its role in osteoclast induction. 1062 68


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