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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it was shown that both Bcr and Bcr-Abl can interact with xeroderma pigmentosum group B (XPB/ERCC3), a protein implicated in DNA repair after UV-induced damage. To further analyze the effect of Bcr-Abl on the DNA damage response, we used cell lines stably transfected with the BCR-ABL gene and their parental counterparts (MBA-1 versus MO7E and Bcr-AblT1 versus 4A2(+)-pZAP) and several assays reflecting DNA repair: the comet assay, a radioimmunoassay for cyclobutane pyrimidine dimers, and clonogenic assays. After exposure to UVC (0.5-5.0 joules m(-2)), the Comet assay demonstrated greater efficiency of DNA repair in the BCR-ABL-positive cells (both MBA-1 and Bcr-AblT1) when compared with their parental counterparts. Furthermore, there was less production of the UV-induced DNA adduct-cyclobutane pyrimidine dimers-as well as a more rapid rate of disappearance of these adducts and greater UV survival (clonogenic assays) in MBA-1 cells as compared with MO7E cells. Apoptosis (annexin V-FITC/propidium iodide staining) was markedly reduced in the BCR-ABL-positive cells. These results indicate that BCR-ABL confers enhanced resistance to UV radiation-induced damage and increased efficiency of DNA repair and that these changes are associated with a protective antiapoptotic effect.
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PMID:Impact of p210(Bcr-Abl) on ultraviolet C wavelength-induced DNA damage and repair. 1450 64

Signal transducers and activators of transcription (STAT) were originally discovered as components of cytokine signal transduction pathways. Persistent activation of one STAT, STAT3, is a common feature of prostate cancer. Activated STAT3 was found in pathology specimens obtained from prostatectomy in the cancerous areas but not in the normal margins. Because the activation of STAT3 is mediated by the action of an upstream Janus kinase (JAK) kinase, usually JAK1 or JAK2, the activation step for STAT3 might itself be a target for therapy in prostate cancer. However, the redundancy of upstream kinases may make this strategy unreliable for therapy. To develop molecular targets for prostate cancer treatment, JAK kinase and STAT3 inhibition of two prostate cancer lines were compared. DU145 and NRP-154 cells were treated with JAK kinase inhibitors, analyzed for onset of apoptosis, and measured by annexin V binding and propidium iodide uptake. Activation of caspases in the cells was determined by measuring cleaved caspase-3 following treatment. For determining the effect on mitochondrial membrane depolarization that accompanies apoptosis, the fluorescent dye JC-1 was used. STAT3 was specifically inhibited by transfecting either a dominant-negative (DN) STAT3 plasmid or antisense STAT3 oligonucleotides into the cells. To look for reduction in STAT3 levels within cells, fixed and permeabilized prostate cancer cells were stained with antibody to STAT3. We found that more than one JAK kinase is involved in STAT3 activation in prostate cancer lines. AG490 (JAK2 specific) induced apoptosis in DU145 but not in NRP-154 prostate cancer lines, whereas piceatannol (JAK1 specific) induced apoptosis in NRP-154 but not in DU145 cells. Next, we demonstrated efficacy of specific STAT3 inhibitors in prostate cancer lines. Both induction of apoptosis and reduction in intracellular STAT3 protein were observed following treatment with antisense STAT3 oligonucleotides, while transfection of a DN-STAT3 plasmid into both prostate cancer cell lines resulted in loss of viability and onset of apoptosis. We conclude that STAT3-specific inhibitors, rather than JAK kinase-specific inhibitors, should be more useful therapeutically in treating androgen-resistant prostate cancer and that STAT3 is an appropriate target in the treatment of prostate cancer.
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PMID:Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines. 1474 71

We present femtosecond time-resolved pump-probe experiments on iodine molecules enclosed into well-defined cages and channels of different crystalline SiO2 modifications of zeolites. The new experimental results obtained from iodine in TON (Silica-ZSM-22), FER (Silica-Ferrierit), and MFI (Silicalit-1) porosils are compared with data published earlier on the iodine/DDR (Decadodecasil 3R) porosil system [Flachenecker et al., Phys. Chem. Chem. Phys. 5, 865 (2003)]. A summary of all findings is given. The processes analyzed by means of the ultrafast spectroscopy are the vibrational relaxation as well as the dissociation and recombination reactions, which are caused by the interaction of the photo-excited iodine molecules with the cavity walls of the porosils. A clear dependence of the observed dynamics on the geometry of the surrounding lattice structure can be seen. These measurements are supported by temperature-dependent experiments. Making use of a theoretical model which is based on the classical Langevin equation, an analysis of the geometry-reaction relation is performed. The Brownian dynamics simulations show that in contrast to the vibrational relaxation the predissociation dynamics are independent of the frequency of collisions with the surroundings. From the results obtained in the different surroundings, we conclude that mainly local fields are responsible for the crossing from the bound B state to the repulsive a/a' states of the iodine molecules.
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PMID:The elementary steps of the photodissociation and recombination reactions of iodine molecules enclosed in cages and channels of zeolite crystals: a femtosecond time-resolved study of the geometry effect. 1526 45

A key feature in the molecular pathogenesis of liver fibrosis requires maintenance of the activated hepatic stellate cell (HSC) phenotype by both proliferation and inhibition of apoptosis. We provide evidence that leptin is a potent HSC mitogen and dramatically inhibits stellate cell apoptosis. Leptin proved to be as potent an HSC mitogen as platelet-derived growth factor (PDGF) as assessed by bromodeoxyuridine (BrdU) incorporation in isolated primary HSCs; data using fluorescent propidium iodide (PI) uptake revealed that leptin, like PDGF, increased HSC populations in the S- and G2/M-phases of the cell cycle. Leptin resulted in a robust increase in cyclin D1 expression. Using the chemical inhibitor of Janus kinase 2 (Jak2) activity, AG 490, and overexpression of the suppressor of cytokine signaling 3 (SOCS-3), we show that blockade of leptin receptor (Ob-Rb) phosphorylation blocks leptin-induced HSC proliferation. Leptin-associated phosphorylation of both extracellular regulated kinase (p44/p42, Erk) and Akt is also prohibited. Further, the PI-3 kinase inhibitor LY294002 and MAPK inhibitor PD98059 were found to significantly reduce leptin-induced HSC proliferation, thereby indicating that leptin induced HSC proliferation is Akt- and Erk-dependent. Akt was also protective against HSC apoptosis. Leptin abolished both cycloheximide-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, demonstrated by reduced caspase-3 activity, HSC-TUNEL staining, and DNA fragmentation. We conclude that leptin acts as a direct hepatic stellate cell survival agonist. Importantly, we have demonstrated that leptin-induced HSC proliferation and survival by Ob-Rb phosphorylation are both Erk- and Akt-dependent.
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PMID:Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. 1531 73

Imatinib (STI571, Gleevec) is a tailored drug for chronic myelogenous leukemia (CML), whereas arsenic compounds were used as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with imatinib and arsenic sulfide (As(4)S(4)). Analysis of cell proliferation and clonogenic ability showed that As(4)S(4) and imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34(+) cells from the nonleukemic donors. Examination of cell cycles showed that As(4)S(4) induced G(2)/M arrest whereas imatinib induced G(1) arrest. Using a number of parameters such as morphology, annexin V/propidium iodide (PI), mitochondrial transmembrane potential, caspase-3 activity, and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through the mitochondrial pathway. The 2 drugs also exhibited a synergistic effect in targeting BCR-ABL protein. While As(4)S(4) triggered its degradation and imatinib inhibited its tyrosine kinase activity, combined use of the 2 led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of imatinib and As(4)S(4) combination on CML.
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PMID:Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein. 1533 52

Using an automated oven evaporation technique combined with the coulometric Karl Fischer method, the mass fraction of water has been measured in cement, coal, and refined oil samples. The accuracy of this method was established by using SRM 2890, water-saturated 1-octanol that was added to white oil. The samples were analyzed for total reactive Karl Fischer reagent (KFR) material, for interfering materials, and for material that does not react with the aldehyde-ketone KFR. All of the samples yielded volatile material that reacted with the standard KFR. None of the samples contained significant masses of material that reacted with iodine. The cement and coal SRMs contained no material that reacted with methanol and very little material that did not volatilize at 107 degrees C. The refined oils contained some material that was volatile at 107 degrees C and some at 160 degrees C. However, none of this material reacted with the aldehyde-ketone reagent. These results show that the material in the solid samples is water and that the material in the refined oils is a material other than water which reacts with methanol to form water.
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PMID:Measurement of water by oven evaporation using a novel oven design. 1. Water in water-saturated 1-octanol, coal, cement, and refined oils. 1536 78

Exposure to the environmental toxicant arsenic is reported to produce a variety of effects including disruption of signal transduction pathways, cell proliferation, and apoptosis. This suggests that arsenite may not have specific targets but rather extremely broad effects. The present study was designed to test the hypothesis that arsenite alters signaling involved in focal adhesion structure and function in cultured myoblasts. H9C2 cells were exposed to 1, 2.5, 5, or 10 microM sodium arsenite for 48 h. MTT metabolism and staining by neutral red, trypan blue, and propidium iodide showed that sodium arsenite treatments of 5 microM or less were not overtly cytotoxic. At these doses, sodium arsenite did not affect the amount of polymerized actin in cells, rate of protein synthesis, or amounts of vinculin, talin, paxillin, and focal adhesion kinase (FAK) in cells. However, sodium arsenite-treated cells contained fewer focal adhesions with an altered distribution pattern. Sodium arsenite exposure caused a dose-dependent reduction in cell migration and cell attachment rates. The average area of substrate covered by a cell was also reduced, although the average volume of cells was not significantly affected. Sodium arsenite exposure resulted in reduced tyrosine phosphorylation of FAK, its substrate paxillin and the FAK auto- phosphorylation site, Tyr397. Our results indicate that sodium arsenite can alter focal adhesion structure and function, thus affecting cell attachment and migration and possibly other aspects of focal adhesion function such as integrin signaling. These diverse consequences may be mediated by a relatively specific inhibition of FAK tyrosine phosphorylation, modifying scaffolding proteins.
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PMID:Sodium arsenite exposure alters cell migration, focal adhesion localization and decreases tyrosine phosphorylation of focal adhesion kinase in H9C2 myoblasts. 1583 68

Pollutant particles induce apoptosis and inflammation, but the relationship between these two biological processes is not entirely clear. In this study, we compared the proapoptotic and proinflammatory effects of four particles: residual oil fly ash (ROFA), St. Louis particles SRM 1648 (SL), Chapel Hill PM10 (CHP), and Mount St. Helens dust (MSH). Human alveolar macrophages (AM) were incubated with these particles at 100 microg/ml. Cell death was assessed by annexin V (AV) expression, histone release, nuclear morphology, caspase 3-like activity and release of caspase 1 for apoptosis, and propidium iodide (PI) for necrosis, and inflammation was measured by interleukin (IL)-1beta and IL-6. We found that particle effects on these cell death measurements varied, and ROFA affected most (four out of five) endpoints, including nuclear morphological changes. CHP and SL also caused necrosis. For cytokine release, the potency was CHP > SL > ROFA > MSH. The proapoptotic and proinflammatory effects induced by the whole particles were unaltered after the particles were washed with water. The water-soluble fraction was relatively inactive, as were individual soluble metals (V, Ni, Fe). ROFA-induced nuclear fragmentation was associated with upregulation and mitochondrial release of apoptosis-inducing factor (AIF), a caspase-independent chromatin condensation factor, and upregulation of DNase II, a lysosomal acid endonuclease. These results indicate that the potential for particles to induce apoptosis does not correlate with their proinflammatory properties, although active components for both processes reside in the water-insoluble core. Both apoptosis and inflammatory endpoints should be included when the toxicity of different pollutant particles is assessed.
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PMID:Apoptotic and inflammatory effects induced by different particles in human alveolar macrophages. 1576 74

Overexpression of BCR-ABL and P-glycoprotein (Pgp) are two of the known mechanisms of imatinib resistance. As combination therapy may allow to overcome drug resistance, we investigated the effect of combination treatment with imatinib and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heat-shock protein 90 (Hsp90) inhibitor, on different imatinib-sensitive and imatinib-resistant CML cell lines. In imatinib-sensitive cells, combination index (CI) values obtained using the method of Chou and Talalay indicated additive (CI=1) or marginally antagonistic (CI>1) effects following simultaneous treatment with imatinib and 17-AAG. In imatinib-resistant cells both drugs acted synergistically (CI<1). In primary chronic-phase CML cells additive or synergistic effects of the combination of imatinib plus 17-AAG were discernible. Annexin V/propidium iodide staining showed that the activity of imatinib plus 17-AAG is mediated by apoptosis. Combination treatment with imatinib plus 17-AAG was more effective in reducing the BCR-ABL protein level than 17-AAG alone. Monotherapy with 17-AAG decreased P-glycoprotein activity, which may increase intracellular imatinib levels and contribute to the sensitization of CML cells to imatinib. The results suggest that combination of imatinib and 17-AAG may be useful to overcome imatinib resistance in a clinical setting.
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PMID:Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL--Inhibition of P-glycoprotein function by 17-AAG. 1590 98

Four conformationally flexible benzamide analogs having a high affinity and outstanding selectivity for sigma(2) versus sigma(1) receptors were synthesized and radiolabeled with carbon-11 by reaction with [(11)C]methyl iodide. The four (11)C-labeled radiotracers were evaluated for their potential to image the proliferative status of breast tumors with positron emission tomography (PET). In vivo studies in female BALB/C mice bearing EMT-6 breast tumors showed that one radiotracer, (2-methoxy-(11)C)-N-(4-(3,4-dihydro-6,7-dimethoxy-isoquinolin-2(1H)-yl)butyl)-5-methylbenzamide ([(11)C]2), had a high tumor uptake and suitable tumor/background ratio for imaging purposes. Blocking studies were consistent with the labeling of sigma(2) receptors in vivo. A study comparing the in vivo properties of [(11)C]2 and (18)F-3'-fluoro-3'-deoxy-L-thymidine ([(18)F]FLT) indicated that [(11)C]2 had either similar (lung, fat) or better (blood, muscle) tumor/organ ratios than [(18)F]FLT in the tissues that are important for breast tumor imaging. Consequently, [(11)C]2 is a potential radiotracer for imaging the proliferative status of breast tumors in vivo with PET.
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PMID:Carbon-11 labeled sigma2 receptor ligands for imaging breast cancer. 1598 71


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