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

---

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

The effects of a range of different analogs of nicotinamide and benzamide on the X ray response of the EMT-6 tumor in vivo was investigated. Using an in vivo/in vitro survival assay, sensitization was seen at a dose of 2 mmole/kg for all but one of the analogs tested. The enhancement ratios (ER's) ranged from 1.0 to 1.5. Of particular interest were nicotinamide and SR-4350 which gave large ER's (1.5 and 1.4 respectively) at doses which were only about 12% of the LD50 values. In one normal tissue studied (skin reaction) a large single dose of nicotinamide (8 mmole/kg) only gave an ER of 1.1. These results will be discussed with reference to the mechanisms involved and the clinical implications.
...
PMID:Preferential tumor radiosensitization by analogs of nicotinamide and benzamide. 294 59

Previous studies have implicated ADP-ribosylation in the mechanism of TNF cytotoxicity. In short-term 51Cr-release assays with several mouse and human tumor cell lines, the inhibitors aminobenzamide (ABA) and nicotinamide (NA) of ADP-ribosylation sensitized HER-2/neu-nonoverexpressing cells (CaOV-3 and MCF-7) but not HER-2/neu-overexpressing cells (SKOV-3 and SKBR-3) to TNF. However, both inhibitors alone or in combination with either TNF and/or actinomycin D (AD) caused similar effects on ADP-ribosylation rates of CaOV-3 and SKOV-3 cells after 4 h of treatment. This result suggests that ADP-ribosylation may not be involved in sensitizing these human tumor cells to TNF. Both ABA and NA decreased the TNF sensitivity of L929 cells and either increased or decreased TNF sensitivity of EMT-6 cells in the absence or presence of actinomycin D, respectively. Again, there was no correlation between ADP-ribosylation and TNF cytotoxicity in these mouse cell lines. Thus, modulation of TNF sensitivity by these inhibitors might be linked to a compromised repair mechanism distinct from the effects on ADP-ribosylation alone.
...
PMID:TNF cytotoxicity: effects of HER-2/neu expression and inhibitors of ADP-ribosylation. 791 50

Rodent tumour models have been the 'workhorse' for tumour oxygenation research and for investigating radiobiological hypoxic fraction. Because of the intertumour heterogeneity of blood flow and related parameters, most studies have pooled information derived from several different tumours to establish the statistical significance of specific measurements. But it is the oxygenation status of and its modulation in individual tumours that has important prognostic significance. In that regard, the bioreducible hypoxic marker technique was tested for its potential to quantify oxygenation changes within individual tumours. Beta-D-iodinated azomycin galactoside (IAZG) and beta-D-iodinated azomycin xylopyranoside (IAZXP) were each radiolabelled with Iodine-125 and iodine-131 for measurements of animal tumour oxygenation. The tumour-blood (T/B) ratio of marker radioactivity in mice after the renal excretion of unbound marker (at 3 h and longer times) had been shown to be proportional to radiobiological hypoxic fraction. When markers labelled with both radioisotopes were administered simultaneously to EMT-6 tumour-bearing scid mice, T/B ratios were found to vary by up to 300% between different tumours, with an average intratumour variation of only approximately 4%. When the markers were administered 2.5-3.0 h apart, changes in T/B ratios of 8-25% were observed in 10 out of 28 (36%) tumours. Changes to both higher and lower hypoxic fraction were observed, suggestive of acute or cycling hypoxia. When 0.8 mg g(-1) nicotinamide plus carbogen was administered to increase tumour oxygenation, reductions in T/B ratios (mean deltaT/B approximately 38%) were observed in all tumours. Similar results were obtained with Dunning rat prostate carcinomas growing in Fischer x Copenhagen rats whose T/B ratios of IAZG and radiobiological hypoxic fractions are significantly lower. These studies suggest that fluctuating hypoxia can account for at least 25% of the total hypoxic fraction in some tumours and that correlations between bioreducible marker avidity and related tumour properties will be optimal when the independent assays are performed over the same time period. This dual hypoxic marker technique should prove useful for investigating both spontaneous and induced oxygenation changes within individual rodent tumours.
...
PMID:A dual hypoxic marker technique for measuring oxygenation change within individual tumors. 968 88

The aminoguanide, methylglyoxal bis(guanylhydrazone) (MGBG), was shown to stimulate phosphorylation of RR-SRC, a synthetic protein tyrosine kinase (PTK) substrate, and different levels of tyrosyl phosphorylation of endogenous proteins in a sea urchin egg membrane-cortex preparation. Stimulating protein tyrosine kinase activity in the sea urchin egg stimulated intracellular Ca2+ release, because microinjection of 1-5 mM of MGBG into unfertilized eggs triggered a transient rise in intracellular Ca2+ activity ([Ca2+]i) after a brief latent period. Pretreating eggs with PTK-specific inhibitors, genistein or tyrphostin B42, significantly inhibited the MGBG-induced rise in [Ca2+]i. Methylglyoxal bis(guanylhydrazone) stimulation of PTK activities in the unfertilized sea urchin egg appeared to trigger Ca2+ release through phospholipase C (PLC)-dependent inositol 1,4,5-trisphosphate (InsP3) production. The MGBG-induced Ca2+ response could be suppressed in eggs preloaded with the InsP3 receptor antagonist, heparin, and was reduced in eggs pretreated with U73122, a PLC inhibitor. However, the response was unchanged in eggs treated with nicotinamide, an inhibitor of ADP-ribosyl cyclase, or nifedipine, an inhibitor of nicotinic acid adenine dinucleotide phosphate activity. These results suggest that MGBG may be useful as a chemical agonist of PTK in sea urchin eggs and allow direct testing of the PTK requirement for the transient rise in [Ca2+]i in sea urchin eggs during fertilization. Although genistein was observed to significantly delay the onset, the sperm-induced Ca2+ response in PTK inhibitor-loaded eggs otherwise appeared normal. Therefore, it was concluded that sea urchin eggs contain a PTK-dependent pathway that can mediate intracellular Ca2+ release, but PTK activity does not appear to be required for the fertilization response.
...
PMID:Protein tyrosine kinase-dependent release of intracellular calcium in the sea urchin egg. 1040 Mar 96

In the present paper we show that transendothelial migration of a subset of CD14(+) circulating leukocytes, coexpressing the CD34 precursor marker, leads to protection from the apoptosis that follows growth factor(s) withdrawal. The resistance of this cell subset to starvation-induced programmed cell death, lasting from 48 to 96 hours, is accompanied by a rise of mitochondrial adenosine triphosphate (ATP), a high nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, and by the up-regulation of expression of the antiapoptotic proteins Bcl-2 and Bcl-X, together with an increase in the cytoplasmic, inactive, form of Bax. This suggests that protection from apoptosis is due to the preservation of mitochondrial function(s). Interestingly, ligation of the platelet endothelial cell adhesion molecule-1 (PECAM-1), which drives CD14(+)CD34(+) transendothelial migration, leads to an increase in Bcl-2 A1 and Bcl-X intracellular content, and to protection from starvation-induced apoptosis. This event is dependent on the engagement of phosphatidylinositol-3 kinase and activation of Akt/PKB that is known to contribute to Bcl-2 and Bcl-X induction. These data point to a critical role of endothelium in preventing the apoptotic program triggered by starvation, possibly inducing a prolonged survival of antigen presenting cell precursors, in order to allow recirculation of these cells and localization to the site of priming of T lymphocytes.
...
PMID:Transendothelial migration leads to protection from starvation-induced apoptosis in CD34+CD14+ circulating precursors: evidence for PECAM-1 involvement through Akt/PKB activation. 1239 47

There is increased interest in accurately assessing the total dietary intake of vitamins from all sources, including foods and dietary supplements. Consequently, a Dietary Supplement Ingredient Database (DSID), based upon analytical values, is being established by USDA with support of the Office of Dietary Supplements (ODS), NIH. The DSID necessitated the development of a new SRM, 3280--Multivitamin/Multimineral Tablets, by the National Institute of Standards and Technology (NIST), with support from the ODS. As a continuation of a long-term project to develop and validate new methods of determining water-soluble B vitamins in foods and dietary supplements, and as part of a collaborative effort with NIST to characterize SRM 3280, values for the vitamin contents of SRM 3280 have been generated by a liquid chromatographic isotope dilution mass spectrometric (LC/IDMS) method. Isotope-labeled ((13)C and/or (2)H) B vitamins (B1-thiamine, B6-pyridoxine, B3-nicotinamide, and B5-pantothenic acid) were obtained from commercial sources, with the support of the ODS/NIH. Our LC/IDMS method uses a C18 reversed phase column, an Agilent 1100 HPLC system, and a Quattro Micro triple-quad mass spectrometer (MS). B vitamin determination was achieved using a gradient LC profile combined with MS/MS detection in multiple reaction monitoring mode. Stock solutions of the isotope-labeled vitamins were calibrated against USP standard solutions. The SRM tablets, with added amounts of the four isotope-labeled B vitamins, were extracted and the vitamins simultaneously determined in a single LC run, in contrast with the single-component determinations performed via IDMS. Unknown vitamin concentrations were calculated by comparing the ratios of the integrated LC peaks at the different masses of the unlabeled and labeled vitamins.
...
PMID:Contents of selected B vitamins in NIST SRM 3280 multivitamin/multielement tablets by liquid chromatography isotope dilution mass spectrometry. 1764 73

The Src family of non-receptor protein tyrosine kinases plays a critical role in the progression of human cancers so that the development of its specific inhibitors is important as a therapeutic tool. We previously reported that cysteine residues in the cysteine-cluster (CC) motif of v-Src were critical for the kinase inactivation by the SH-alkylating agents such as N-(9-acridinyl) maleimide (NAM), whereas other cysteine residues were dispensable. We found similar CC-motifs in other Src-family kinases and a non-Src-family kinase, FAK. In this study, we explored the function of the CC-motif in Yes, Lyn and FAK. While Src has four cysteines in the CC-motif, c-Yes and Lyn have three and two of the four cysteines, respectively. Two conserved cysteines of the Src family kinases, corresponding to Cys487 and Cys498 of Src, were essential for the resistance to the inactivation of the kinase activity by NAM, whereas the first cysteine of c-Yes, which is absent in Lyn, was less important. FAK has similar CC-motifs with two cysteines and both cysteines were again essential for the resistance to the inactivation of the kinase activity by NAM. Taken together, modification of cysteine residues of the CC-motif causes a repressor effect on the catalytic activity of the Src family kinases and FAK.
...
PMID:The cysteine-cluster motif of c-Yes, Lyn and FAK as a suppressive module for the kinases. 1835 84

We evaluated the cardioprotection against myocardial ischemia-reperfusion injury induced by sevoflurane postconditioning (SpostC) in chronically-infarcted rat hearts, and investigated the roles of phosphoinositide 3-kinase (PI3K)-protein kinase B/Akt (PKB/Akt), mitogen-activated extracellular regulated kinase 1/2 (MEK 1/2)-extracellular regulated kinase 1/2 (ERK 1/2), and mitochondrial permeability transition pore (mPTP). Left anterior descending (LAD) coronary artery was ligated to induce myocardial infarction in rats. Six weeks later, chronically-infarcted hearts were isolated and subjected to 30 min of global ischemia, followed by 1 h of reperfusion with Krebs-Henseleit (K-H) buffer. SpostC was administered by perfusing the hearts with K-H buffer saturated with 3% sevoflurane during the first 15 min of reperfusion. To evaluate the role of PI3K-PKB/Akt and MEK 1/2-ERK 1/2 in SpostC, PI3K inhibitor LY294002 (15 microM) and MEK 1/2 inhibitor PD98059 (20 microM) were administered alone or together with sevoflurane during the first 15 min of reperfusion. We found that exposure of 3% sevoflurane during early reperfusion significantly improved functional recovery (improved left ventricular developed pressure (LVDP), +/-dp/dt, CF, HR and reduced left ventricular end-diastolic pressure (LVEDP)), decreased myocardial infarct size and reduced LDH and CK-MB release, when compared with unprotected hearts. However, these protective effects were abolished in the presence of either LY294002 or PD98059, which was accompanied by the prevention of PKB/Akt and ERK 1/2 phosphorylation, and reduction of myocardial nicotinamide adenine dinucleotide (NAD+) content. These findings suggest that sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by inhibiting mPTP opening via recruitment of PKB/Akt and ERK 1/2.
...
PMID:Sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by activation of pro-survival kinases and inhibition of mitochondrial permeability transition pore opening upon reperfusion. 1988 Dec 97

Transient reactive oxygen species (ROS) production is currently proving to be an important mechanism in the regulation of intracellular signalling, but reports showing the involvement of ROS in important biological processes, such as cell differentiation, are scarce. In this study, we show for the first time that ROS production is required for megakaryocytic differentiation in K562 and HEL cell lines and also in human CD34(+) cells. ROS production is transiently activated during megakaryocytic differentiation, and such production is abolished by the addition of different antioxidants (such as N-acetyl cysteine, trolox, quercetin) or the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium. The inhibition of ROS formation hinders differentiation. RNA interference experiments have shown that a p22(phox)-dependent NADPH oxidase activity is responsible for ROS production. In addition, the activation of ERK, AKT and JAK2 is required for differentiation, but the activation of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase seems to be less important. When ROS production is prevented, the activation of these signalling pathways is partly inhibited. Taken together, these results show that NADPH oxidase ROS production is essential for complete activation of the main signalling pathways involved in megakaryocytopoiesis to occur. We suggest that this might also be important for in vivo megakaryocytopoiesis.
...
PMID:p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation. 2052 55

In the classic view interleukin-13 (IL-13) binds to a heterodimer protein complex of the IL-13Ralpha1 and IL-4Ralpha chains and signals through a Janus kinase 1 (JAK1)-signal transducer and activator of transcription 6 (STAT6) mechanism. We recently reported that IL-13 also signals through the IL-13Ralpha2 chain initiating all three mitogen activated protein kinase (MAPK) pathways, and the relative expression of IL-13Ralpha1 and IL-13Ralpha2 modulates one another's transduction pathway. Therefore we investigated whether generation of reactive oxygen species (ROS) as second messengers may serve as a common nexus between these two pathways emanating from the individual IL-13 receptor chains in intestinal epithelial cells (IEC). IL-13 stimulates intracellular ROS synthesis within 5min via IL-13Ralpha1-JAK1-STAT6- and IL-13Ralpha2-MEK1/2-ERK1/2-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 (NOX-1). IL-13-induced ROS generation in turn positively regulates phosphorylation of ERK1/2 and STAT6, yielding a feed forward amplification loop. IL-13 also stimulates the stable, long-term gene expression of two other NADPH oxidases, NOX-4 and DUOX-2, which along with constitutive NOX-1, might facilitate elevated, continuous production of ROS in IL-13-activated IEC. The contribution of each signal transduction pathway initiated by IL-13 engagement to such biological functions as wound healing, inflammation, and apoptosis was mapped for representative, responsive genes. Distinct usage patterns were observed, demonstrating not only that IL-13 signal transduction through STAT6, MAPK, and ROS is regulated in both an antagonistic and cyclic fashion, but also that each pathway plays a specific role in modulating the wound healing and anti-apoptotic capabilities of the intestinal epithelium.
...
PMID:REDOX regulation of IL-13 signaling in intestinal epithelial cells: usage of alternate pathways mediates distinct gene expression patterns. 2057 Jul 27


1 2 3 4 Next >>

---