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)

A variety of photodynamic sensitizers (chloroaluminum sulfonated phthalocyanine, tetraphenyl porphine sulfonate, mono-L-aspartyl chlorin e6, Photofrin, chlorin e6, and Uroporphyrin dihydrochloride I) were characterized by their ability to be retained in EMT-6 tumors growing in BALB/c mice. Two properties uniquely associated with tumors, proliferating neovasculature and vascular permeability, were tested for their relative importance in retaining the photosensitizer. A chick embryo model was used to compare photosensitizer uptake/retention in proliferating and nonproliferating neovasculature with retention in proliferating nonvascular tissue. Our results provide evidence that photosensitizers which are preferentially retained by tumors have a selective affinity for proliferating neovasculature. The chloroaluminum sulfonated phthalocyanine and tetraphenyl porphine sulfonate compounds possess the greatest affinity for proliferating neovasculature relative to nonvascular tissue, while the phthalocyanine has the largest tumor/normal differential in vivo of all the photosensitizers tested. Chlorin e6 and uroporphyrin dihydrochloride I were the only photosensitizers which were not retained in greater amounts by tumor tissues relative to normal tissues. Using a delayed-type hypersensitivity reaction, extended and constant vascular permeability was induced in BALB/c mice. Vascular permeability was quantitated by Evans blue extraction from the delayed-type hypersensitivity sites. Interestingly, leaky vessels alone did not result in photosensitizer retention, as seen with tumors. These data demonstrate that tumor-retained photosensitizers possess a selective affinity for proliferating neovasculature and that vascular permeability alone is not sufficient to retain these sensitizers.
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PMID:Role of neovasculature and vascular permeability on the tumor retention of photodynamic agents. 137 Oct 89

Pial arterioles of mice are studied by in vivo TV microscopy. Focal endothelial injury is produced by a laser/Evans blue technique. Moderate damage results in local platelet aggregation. Very slight damage, without electron microscopic evidence of injury, results in loss of many endothelium derived vasoactive factors. These include "EDRFs" for acetylcholine, bradykinin and calcium ionophore, and "EDCFs" for histamine and serotonin. In the cases of acetylcholine, histamine and serotonin, each agonist possesses an additional opposing action which is independent of endothelium. The latter action is unmasked by the endothelial injury. The balance between simultaneously acting endothelium dependent and endothelium independent actions is a determinant of the response to an agonist with two opposing actions. This balance is partly dependent upon initial tone. Thus the effect of the agonist depends on initial tone. One of the determinants of initial tone may be basal release of one or more EDRFs or EDCFs. Evidence in pial arterioles for the basal release of EDRF for acetylcholine, comes from our data showing that L-NMMA constricts these arterioles. L-NMMA is a known inhibitor of synthesis of "classical" EDRF from L-arginine. The response to L-ARG is relaxation. Both the response to L-NMMA and the response to L-ARG are abolished by laser/dye injury of the endothelium. Thus these agents are really acting via an endothelial mechanism in brain arterioles, just as has been reported for their actions in conductance vessels. Finally mild injury associated with loss of "EDRFs" is also accompanied by a reduced ability of pial arteriolar endothelium to repell activated platelets.
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PMID:Control of brain microcirculation by endothelium. 225 25

Janus tyrosine kinase (JAK) has recently been linked to signal transduction by cytokine receptors of the hematopoietin family. We have recently described a 116-kDa tyrosine kinase (p116) present in interleukin-2 (IL-2) receptor complexes in human YT cells that showed functional characteristics of a JAK kinase. These included receptor association, rapid and transient tyrosine phosphorylation kinetics in response to ligand, and in vitro autophosphorylating tyrosine kinase activity (Kirken, R. A., Rui, H., Evans, G. A., and Farrar, W. L. (1993) J. Biol. Chem. 268, 22765-22770). Here we extend these observations by demonstrating structural homologies between IL-2-modulated p116 and prolactin-modulated JAK2 in the rat T cell line Nb2. These include similar net charge as determined by nonequilibrium pH gradient electrofocusing and related primary structure based upon phosphopeptide mapping of V8 protease-digested hyperphosphorylated proteins. This putative JAK kinase underwent marked tyrosine phosphorylation in response to IL-2, IL-4, and IL-7, lymphoid growth factors that use the common IL-2 receptor gamma-chain, but not in response to prolactin. Furthermore, polyclonal antisera to JAK1, JAK2, or tyrosine kinase 2 did not recognize either rat or human p116. However, we identified the IL-2-modulated p116 as the recently cloned novel leukocyte Janus kinase, L-JAK, using an antiserum to a peptide corresponding to the COOH terminus of human L-JAK.
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PMID:Identification of interleukin-2 receptor-associated tyrosine kinase p116 as novel leukocyte-specific Janus kinase. 751 51

The role of vascular permeability in the preferential accumulation of photosensitizers in tumor tissue was investigated. Two murine tumors [experimental mammary tumor carcinoma (EMT-6) and methylcholanthrene-induced rhabdomyosarcoma (M1S)] and a human bladder carcinoma (EJ) were grown s.c. on the flank in athymic nude mice and analyzed for in vivo vessel permeability, vascular permeability factor (VPF) secretion, and accumulation of the photosensitizer, chloroaluminum sulfonated phthalocyanine. In vivo tumor vessel permeability and vascular volume were quantitated by measuring Evans blue extravasation and accumulation of a high molecular weight fluoresceinated dextran, respectively. VPF was isolated from serum-free tumor cell conditioned medium using heparin-Sepharose affinity chromatography. Dot and Western blots stained with anti-VPF antiserum positively identified VPF in samples from each tumor. Chloroaluminum sulfonated phthalocyanine pharmacokinetics in tumor-bearing mice were measured using a fiber-based spectrofluorometer. In vivo vessel permeability was found to be greatest in M1S tumors, next in EMT-6 tumors and finally in EJ tumors. Consistent with in vivo data, M1S and EMT-6 tumor cells in culture secrete significantly more VPF than EJ tumor cells. Chloroaluminum sulfonated phthalocyanine accumulation was approximately 2 times greater in M1S and EMT-6 tumors compared to EJ tumors. Our data present evidence that photosensitizer accumulation can be correlated to in vivo tumor vessel permeability and VPF secretion of that tumor. Taken together, the data support the hypothesis that vascular permeability differences among tumors play a significant role in the uptake and retention of photodynamic agents.
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PMID:Tumor-secreted vascular permeability factor/vascular endothelial growth factor influences photosensitizer uptake. 841 39

The effects of amygdala lesions on passive avoidance of drinking (dPA) and social interactions in a resident-intruder test were examined in two experiments that utilized different lines of Long-Evans hooded rats. The lesions were fairly well restricted to the rostral half of the central nucleus (rACe), or the cholinergically richly innervated basolateral nucleus (ABL) or the medial nucleus (AMe) of the amygdala. In both experiments, dPA deficits indicating disturbances in fear conditioning or fear expression were found with ABL and rACe lesions. The rACe lesions produced a greater deficit. AMe lesions caused no dPA deficit at all, which contrasts with the mild PA deficits reported by others employing larger lesions extending to the cortical nucleus and, perhaps, damaging the central nucleus. Social behavior was not affected by the lesions in any clear manner. In rats from a long-standing home colony, rACe lesions increased a behavior of plowing and kicking the wood-chip cage bedding during social encounters, and AMe lesions increased lateral defense behaviors. Both effects are paradoxical, suggesting increased anxiety in the fear-deficient rACe rats and increased defense with AMe lesions, despite several previous reports of decreased defense. In the second experiment, rats purchased from a supplier showed no lesion effects during social interactions; like the control group, all three lesion groups exhibited increases in offense associated with cohabitation with a female. The ABL lesions, particularly, had no effect comparable to the decreased offense recently reported to occur following neurotoxin lesions.
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PMID:Effects of small amygdala lesions on fear, but not aggression, in the rat. 897 32

The proto-oncogene product pp60(c-src) is the cellular homologue of the Rous sarcoma transforming gene, and it is a non-receptor-linked and membrane-associated tyrosine kinase. There is a close correlation between elevated pp60(c-src) activity and cell transformation. We have recently reported that pp60(c-src) was activated in hepatocellular carcinoma (HCC) of human and Long-Evans cinnamon (LEC) rats. However, the mechanisms involved in this process remain unknown. C-terminal Src kinase (Csk) is a novel cytoplasmic protein tyrosine kinase that inactivates the members of the Src family protein tyrosine kinase in vitro. We investigated the role of Csk in hepatocarcinogenesis by analyzing the location, amount of Csk, and its kinase activity levels in nontumorous cirrhotic and tumorous sections of HCC of patients and an animal model of LEC rats. Csk tyrosine kinase activity was significantly reduced in tumorous tissues compared with nontumorous sections of patients as well as LEC rats. A single immunoreactive band at 50 kd was detected with Csk antibody in normal liver (NL), chronic hepatitis (CH), and nontumorous cirrhotic (NTC) segments of HCC of patients and LEC rats. In human tumorous tissues, Western blot revealed a 53-kd immunoreactive band, which was slightly larger than the usual 50-kd band of Csk. These results suggest that the reduced activity of tyrosine kinase of Csk may play an important role in the malignant transformation of hepatocytes in human and LEC rat, and the appearance of 53-kd Csk-related protein may be closely involved in the progression of cirrhosis to HCC in humans, and that 50-kd Csk may act as an antioncogene through the negative regulation of pp60(c-src) in the development of human HCC.
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PMID:Reduced C-terminal Src kinase (Csk) activities in hepatocellular carcinoma. 991 13

Our previous studies have shown that the Galbeta1-3GalNAcalpha- (Thomsen-Friedenreich antigen)-binding lectin from the common edible mushroom Agaricus bisporus (ABL) reversibly inhibits cell proliferation, and this effect is a consequence of inhibition of nuclear localization sequence-dependent nuclear protein import after ABL internalization [Yu, L.G., Fernig, D.G., White, M.R.H., Spiller, D.G., Appleton, P., Evans, R.C., Grierson, I., Smith, J.A., Davies, H., Gerasimenko, O.V., Petersen, O.H., Milton, J.D. & Rhodes, J.M. (1999) J. Biol. Chem. 274, 4890-4899]. Here, we have investigated further the intracellular trafficking and fate of ABL after internalization in HT29 human colon cancer cells. Internalization of 125I-ABL occurred within 30 min of the lectin being bound to the cell surface. Subcellular fractionation after pulse labelling of the cells with 125I-ABL for 2 h at 4 degrees C followed by culture of the cells at 37 degrees C demonstrated a steady increase in radioactivity in a crude nuclear extract. The radioactivity in this extract reached a maximum after 10 h and declined after 20 h. Release of ABL from the cell, after pulse labelling, was assessed using both fluorescein isothiocyanate-labelled ABL and 125I-ABL and was slow, with a t1/2 of 48 h. Most of the 125I-ABL both inside cells and in the medium remained intact, as determined by trichloroacetic acid precipitation and SDS/PAGE, and after 48 h only 22 +/- 2% of ABL in the medium and 14 +/- 2% inside the cells was degraded. This study suggests that the reversibility of the antiproliferative effect of ABL is associated with its release from cells after internalization. The internalization and subsequent slow release, with little degradation of ABL, reflects the tendency of lectins to resist biodegradation and implies that other endogenous or exogenous lectins may be processed in this way by intestinal epithelial cells.
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PMID:Intracellular trafficking and release of intact edible mushroom lectin from HT29 human colon cancer cells. 1072 53

The use of isotope dilution analysis (IDA) with inductively coupled plasma-mass spectrometry (ICP-MS) for the determination of oxidized metallothionein (MT) by a Cd-saturation method is investigated. The method developed here is a modification of an earlier methodology which used a radioactive Cd isotope ((109)Cd). While retaining the many advantages of this previous approach, the procedure presented here uses stable isotope ratio measurements ((114)Cd/(111)Cd) for the determination of MT. Experimental parameters governing the instrumental precision and accuracy for isotope ratio measurements of Cd by ICP-MS were characterized. Systematic errors, including mass bias, detector dead time, and spectroscopic interferences, could be easily corrected. The isotope dilution ICP-MS method was validated by the determination of very low levels of cadmium in biological certified reference materials (NIST SRM 2670 freeze-dried urine, IAEA H-8 horse kidney, and BCR TP-25 lichens). Finally, the IDA procedure was evaluated for the determination of oxidized MT by a Cd-saturation method previously developed using radioactive (109)Cd. The final procedure was applied to the quantification of MT in Long-Evans Cinnamon rat liver cytosol samples and the results were compared with data obtained for the same samples using the reference (109)Cd methodology. A good agreement between the analytical values obtained by both methods was observed.
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PMID:Development of a stable isotope approach for the inductively coupled plasma-mass spectrometry determination of oxidized metallothionein in biological materials. 1087 73

Organophosphate pesticides such as chlorpyrifos reduce core temperature (Tc) in laboratory rodents. The mechanism(s) responsible for the chlorpyrifos-induced hypothermia are not well known. This study assessed the role of a key effector for thermoregulation in the rat, vasomotor control of heat loss from the tail, and its possible cholinergic control during chlorpyrifos-induced hypothermia. Tc and motor activity were monitored by telemetry in female Long-Evans rats maintained at an ambient temperature (Ta) of 25 degrees. Tail skin temperature (Tsk(t)) was measured hourly. Rats were dosed with chlorpyrifos (0 or 25 mg/kg orally). Two hr later the rats were dosed with saline or scopolamine (1.0 mg/kg intraperitoneally). Two hr after chlorpyrifos treatment there was a marked elevation in Tsk(t)) concomitant with a 0.5 degrees reduction in Tc. Scopolamine administered to control rats led to a marked elevation in Tc with little change in Tsk(t). Rats treated with chlorpyrifos and administered scopolamine underwent a marked vasoconstriction and elevation in Tc. Vasodilation of the tail is an important thermoeffector to reduce Tc during the acute stages of chlorpyrifos exposure. The blockade of the response by scopolamine suggests that the hypothermic and vasodilatory response to chlorpyrifos is mediated via a cholinergic muscarinic pathway in the CNS.
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PMID:Chlorpyrifos-induced hypothermia and vasodilation in the tail of the rat: blockade by scopolamine. 1098 9

The authors investigated the effects of 2,4,6-trihydroxy-alpha-p-methoxyphenylacetophenone (compound D-58), a potent inhibitor of protein tyrosine kinases SYK and Bruton's tyrosine kinase (BTK), on IgE receptor/FcepsilonRI-triggered mast cell-mediated acute allergic responses in vitro and in vivo. Compound D-58 abrogated IgE receptor/FcepsilonRI-mediated SYK and BTK activation as well as calcium mobilization in mast cells. Mast-cell degranulation and leukotriene (LT) C(4) release was inhibited by compound D-58 in a concentration-dependent fashion. Notably, compound D-58 prevented the mast cell mediator-induced vascular hyperpermeability in an in vivo murine model of passive cutaneous anaphylaxis as measured by the prevention of extravasation of systemically administered Evans blue dye. The results uniquely indicate that compound D-58 has potent antiallergic properties. Therefore, further development of compound D-58 may provide the basis for new and effective treatment programs for severe allergic disorders.
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PMID:2,4,6-Trihydroxy-alpha-p-methoxyphenylacetophenone (Compound D-58) is a potent inhibitor of allergic reactions. 1170 80


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