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)

We used cDNA microarray hybridization technology to monitor the transcriptional response of Human Umbilical Vein Endothelial (HUVEC) cells to x-rays doses ranging from 2 to 200 cGy. An early time window from irradiation (4h) was selected in order to minimize the effects of the cell cycle blockage eventually induced at high doses of irradiation. Three different gene-clustering algorithms have been used to group the 4134 monitored ORF based on their transcriptional response in function of the irradiation dose. The results show that while few genes exhibit a typical dose-dependent modulation with a variable threshold, most of them have a different modulation pattern, peaking at the two intermediate doses. Strikingly even the lowest dose used (2 cGy) seems to be very effective in transcriptional modulation. These results confirm the physiological relevance of sublethal-dose exposures of endothelial cells and strengthens the hypothesis that alternative dose-specific pathways of radioadaptive response exist in the mammalian cells. 111 genes were found to be modulated at all doses of irradiation. These genes were functionally classified by cellular process or by molecular function. Genes involved in coagulation and peroxidase activity and structural constituent of ribosomes were over-represented among the up-regulated genes as compared with their expected statistical occurrence. Three genes coding for regulatory kinase activities (CDK6; PRCKB1 and TIE) are found down-regulated at all doses of irradiation.
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PMID:Transcriptional response of human umbilical vein endothelial cells to low doses of ionizing radiation. 1598 46

Interactions between the CXCR4 chemokine receptor in breast cancer cells and the ligand CXCL12/SDF-1alpha are thought to play an important role in breast cancer metastases. In this pilot study, CXCR4 expression along with other biomarkers including HER2-neu and EGFR, were measured in primary tumor samples of patients with operable breast cancer to test whether any of these biomarkers alone and in combination could indicate breast cancer with high likelihood of metastasizing to bone marrow. Cytokeratin (CK) positive cells in bone marrow were identified by flow-cytometry following enrichment with CK 7/8 antibody-coupled magnetic beads. Primary tumors (n = 18) were stained with specific antibodies for CXCR4, HER2-neu, EGFR, and PCNA using an indirect avidin-biotin horseradish peroxidase method. The majority of the patients had T2/T3 tumors (72%), or lymph node involvement (67%) as pathologic characteristics that were more indicative of high-risk breast cancer. High CXCR4 cytoplasmic expression was found in 7 of 18 patients (39%), whereas 6 of 18 patients (33%) were found to have CK positivity in bone marrow. The median number of CK(+) cells was 236 (range, 20-847) per 5 x 10(4) enriched BM cells. The presence of CK(+) cells in bone marrow was found to be associated with increased expression of CXCR4 alone or in addition to EGFR and/or HER2-neu expression (P = 0.013, P = 0.005, and P = 0.025, respectively) in primary tumors. Furthermore, three patients with high CK positivity (>236 CK(+) per 5 x 10(4) enriched bone marrow cells) in bone marrow exclusively expressed high levels of CXCR4 with EGFR/HER2-neu (P = 0.001). Our data suggest that high CXCR4 expression in breast cancer may be a potential marker in predicting isolated tumor cells in bone marrow. CXCR4 coexpression with EGFR/HER2-neu might further predict a particular subset of patients with high CK positivity in bone marrow.
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PMID:Chemokine receptor CXCR4 expression in breast cancer as a potential predictive marker of isolated tumor cells in bone marrow. 1613 77

The aim of this study was to examine the effects of timolol in an experimental model of elevated intraocular pressure (IOP). Three episcleral veins of rats with normal IOP were cauterized. Three months later we examined the effects on anterograde axonal transport from the retinal ganglion cells (RGCs) to the superior colliculus (SC) as well as on the number of neurons in the retinal ganglion layer (RGL). These parameters were also studied in a group of rats submitted to treatment with timolol after confirming that their IOP was still raised after two weeks. After the surgical procedure, the mean IOP of the experimental eyes increased to 33.5+/-1.06 mmHg (1.25 fold compared to the control group) and three months later the IOP remained significantly elevated; however, after a long period of treatment with timolol the IOP was 14.05+/-0.81 mmHg, similar to that of the control group. In the group with normal IOP, labelling with horseradish rabbit peroxidase (HRP) at 120 minutes and 24 hours postinjection showed continuous staining from the retina to the SC. In the experimental group the optic nerve head (ONH) was completely negative, although in the group treated with timolol there was partial block of axonal transport in the ONH, in which the staining was slightly more intense. The number of neurons in the RGL, counted by immunohistochemical labelling with Neu-N, showed that in eyes with normal and elevated IOP there were 423+/-11 neurons/mm(2) and 283+/-10 neurons/mm(2), respectively. After treatment with timolol the number of neurons (331+/-10 cells/mm(2) increased compared with elevated IOP eyes, although the number did not reach that of the control group. These results indicate that treatment with timolol, started two weeks after the surgical procedure, was partially neuroprotective because the loss of neurons in the RGL was lower than in untreated animals, though not sufficient to re-establish normal axonal transport.
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PMID:Effects of a non-selective beta-blocker on adult rat anterograde axonal transport and retinal ganglion layer after increased intraocular pressure. 1613 90

Gastrointestinal mesenchymal tumors (GIMTs) are the most common mesenchymal tumors of the gastrointestinal tract. RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is a cancer cell-surface antigen and has been identified as a prognostic factor in several cancer types. It is thought that tumor cells escape immune attack by expressing RCAS1, which induces apoptosis in receptor-positive immune cells. The current study was designed to elucidate the histogenesis of these tumors by using various immunohistochemical markers, and identify parameters that will help to establish the criteria of malignancy in the GIMT. We also discuss the clinicopathological significance of RCAS1 expression in the diagnosis and prognosis of GIMTs. A total of 70 cases of GIMTs were reviewed. Immunohistochemistry was performed between 1990 and 2000, with the avidin-biotin-peroxidase complex method on 3 microm-thick sections of formalin-fixed paraffin-embedded specimens of GIMTs. Antibodies to the following antigens were used: KIT (CD117), CD34 alpha-SMA, Desmin, cytokeratin, S-100 protein, p53, and RCAS1. Recurrence-free survival analysis was done with Stat View-J 5.0 statistical packages. Univariate analysis for a recurrence-free prognosis demonstrated that antibody detection of p53 expression (p=0.0333) and expression of RCAS1 (p=0.0008) is correlated with a significantly higher potential of recurrence. On multivariate analysis, tumor size and RCAS1 expression were independently and inversely correlated with recurrence-free survival. The expression of RCAS1 has not previously been reported in GIMT; indeed, our study suggests that the expression of RCAS1 is correlated with recurrence not only in carcinomas, but also in mesenchymal tumors.
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PMID:A clinical and immunohistochemical study on gastrointestinal mesenchymal tumor (GIMT): RCAS1 as a predictor for recurrence of GIMT. 1621 Dec 75

Benzo(a)pyrene (BaP) is a known human carcinogen and a suspected breast cancer complete carcinogen. BaP is metabolized by several metabolic pathways, some having bioactivation and others detoxification properties. BaP-quinones (BPQs) are formed via cytochrome P450 and peroxidase dependent pathways. Previous studies by our laboratory have shown that BPQs have significant growth promoting and anti-apoptotic activities in human MCF-10A mammary epithelial cells examined in vitro. Previous results suggest that BPQs act via redox-cycling and oxidative stress. However, because two specific BPQs (1,6-BPQ and 3,6-BPQ) differed in their ability to produce reactive oxygen species (ROS) and yet both had strong proliferative and EGF receptor activating activity, we utilized mRNA expression arrays and qRT-PCR to determine potential pathways and mechanisms of gene activation. The results of the present studies demonstrated that 1,6-BPQ and 3,6-BPQ activate dioxin response elements (DRE, also known as xenobiotic response elements, XRE) and anti-oxidant response elements (ARE, also known as electrophile response elements, EpRE). 3,6-BPQ had greater DRE activity than 1,6-BPQ, whereas the opposite was true for the activation of ARE. Both 3,6-BPQ and 1,6-BPQ induced oxidative stress-associated genes (HMOX1, GCLC, GCLM, and SLC7A11), phase 2 enzyme genes (NQO1, NQO2, ALDH3A1), PAH metabolizing genes (CYP1B1, EPHX1, AKR1C1), and certain EGF receptor-associated genes (EGFR, IER3, ING1, SQSTM1 and TRIM16). The results of these studies demonstrate that BPQs activate numerous pathways in human mammary epithelial cells associated with increased cell growth and survival that may play important roles in tumor promotion.
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PMID:Activation of dioxin response element (DRE)-associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-quinone in MCF-10A human mammary epithelial cells. 1746 51

We report a binary targeted enzymatic system that is composed of two covalent monoclonal antibody conjugates for specific labeling of cellular targets in vivo. The system utilizes low-molecular weight peroxidase-reducing substrates synthesized by linking 5-hydroxytryptamine (serotonin) with DTPA (5HT-DTPA) for magnetic resonance and radionuclide imaging or with Cy5.5 for near-infrared optical imaging. Initially, the conjugation reaction conditions were optimized to achieve a low level of antiepidermal growth factor receptor (EGFR) antibody (EMD 72000) modification with the N-hydroxysuccinimide ester of 4-hydrazinonicotinate acetone hydrazone (SANH), yielding mAb-HNH conjugate. The resultant modified antibodies were incubated with the periodate-oxidized peroxidase (HRP) or 4-formylbenzoyl-conjugated glucose oxidase (GO), followed by the purification of the resultant mAb-enzyme conjugates by size-exclusion HPLC. The conjugates were further characterized by electrophoresis and were tested by cross-titration on A431 EGFR+ squamous carcinoma or SW620 adenocarcinoma cells (negative control). The conjugates at the optimized concentration ratios were further tested using near-infrared fluorescence microscopy in the presence of Cy5.5 monocarboxy-5-hydroxytryptamide. Further in vitro experiments demonstrated that (1) antibody binding was specific and could be inhibited by free antibody; (2) both antibody conjugates exhibited high enzymatic activity after the binding to the cells; (3) 111In-labeled 5-HT-DTPA was avidly binding to EGFR-positive cells only if both HRP- and GO-conjugates were bound to the cells. The conjugates were tested in vivo using a SPECT imaging experiment, which demonstrated the accumulation of 111In-labeled 5-HT-DTPA substrate at the site containing both conjugates.
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PMID:Synthesis and testing of a binary catalytic system for imaging of signal amplification in vivo. 1750 10

In this study we demonstrate the possibility to prepare highly sensitive nanostructured electrochemical immunosensors by immobilizing biorecognition elements on nanoelectrode ensembles (NEEs) prepared in track-etch polycarbonate membranes. The gold nanodisk electrodes act as electrochemical transducers while the surrounding polycarbonate binds the antibody-based biorecognition layer. The interaction between target protein and antibody is detected by suitable secondary antibodies labelled with a redox enzyme. A redox mediator, added to the sample solution, shuttles electrons from the nanoelectrodes to the biorecognition layer, so generating an electrocatalytic signal. This allows one to fully exploit the highly improved signal-to-background current ratio, typical of NEEs. In particular, the receptor protein HER2 was studied as the target analyte. HER2 detection allows the identification of breast cancer that can be treated with the monoclonal antibody trastuzumab. NEEs were functionalized with trastuzumab which interacts specifically with HER2. The biorecognition process was completed by adding a primary antibody and a secondary antibody labelled with horseradish peroxidase. Hydrogen peroxide was added to modulate the label electroactivity; methylene blue was the redox mediator generating voltammetric signals. NEEs functionalized with trastuzumab were tested to detect small amounts of HER2 in diluted cell lysates and tumour lysates.
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PMID:Nanoelectrode ensembles as recognition platform for electrochemical immunosensors. 1840 87

Prdx6 (peroxiredoxin 6), a bifunctional protein with both GSH peroxidase and PLA(2) (phospholipase A(2)) [aiPLA(2) (acidic calcium-independent PLA(2))] activities, is responsible for the metabolism of lung surfactant phospholipids. We propose that the aiPLA(2) activity of the enzyme is regulated through phosphorylation. Incubation of isolated rat alveolar type II cells (AECII) with PMA, a PKC (protein kinase C) agonist, had no effect on Prdx6 expression but led to approximately 75% increase in aiPLA(2) activity that was abolished by pretreatment of cells with the MAPK (mitogen-activated protein kinase) inhibitors, SB202190 or PD98059. Prdx6 phosphorylation after incubation of AECII with PMA was demonstrated by autoradiography after immunoprecipitation with either anti-phosphothreonine o-phosphoserine antibodies. in vitro, several active isoforms of ERK (extracellular-signal-regulated kinase) and p38 phosphorylated Prdx6, resulting in an 11-fold increase in aiPLA(2) activity. The increased activity was calcium-independent and was abolished by the aiPLA(2) inhibitors, surfactant protein A and hexadecyl-3-trifluorethylglycero-sn-2-phospho-methanol (MJ33). The peroxidase activity of Prdx6 was unaffected by phosphorylation. Mass spectroscopic analysis of in vitro phosphorylated Prdx6 showed a unique phosphorylation site at Thr-177 and mutation of this residue abolished protein phosphorylation and the increase in MAPK-mediated activity. These results show that the MAPKs can mediate phosphorylation of Prdx6 at Thr-177 with a consequent marked increase in its aiPLA(2) activity.
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PMID:Mitogen-activated protein kinase-mediated phosphorylation of peroxiredoxin 6 regulates its phospholipase A(2) activity. 1914 Aug 3

In the present study, the chemopreventive effect of topical application of perillyl alcohol (POH) on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis and its possible mechanisms of action in Swiss albino mice were investigated. We evaluated the effect of pretreatment of POH (6 and 12 mg/kg body weight) on TPA (2 microg/200 microl of acetone)-induced skin edema, hyperplasia, peroxidase damage and modulation in activities of catalase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione contents. Application of POH 30 min prior to TPA treatment, showed a protective effect in almost all the investigated parameters. Additionally, pretreatment with POH showed a significant inhibition of ornithine decarboxylase (ODC) activity and [(3)H] thymidine incorporation into epidermal DNA. In promotion phase, a significant reduction was found in tumor incidence and tumor burden in mice pretreated with POH (12 mg/kg body weight) with extension of the latency period from 4 to 8 weeks as compared to those treated with TPA alone. POH significantly suppressed the Ras/Raf/ERK pathway and induced apoptosis in Swiss albino mice skin. Our findings suggested that the chemopreventive efficacy of POH is probably due to the inhibition of oxidative stress responses, inhibition of the Ras cell proliferation pathway and induction of apoptosis in murine skin tumor promotion phase.
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PMID:Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis. 1916 93

Trastuzumab, a humanized monoclonal antibody, is used for the treatment of breast cancer patients who overexpress the HER2 receptor. To optimize therapy, pharmacokinetic studies are necessary. The aim of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for trastuzumab to support these pharmacokinetic studies. For this immunoassay, we raised anti-idiotype antibodies in rabbits. After purification of the rabbit material, the anti-idiotype antibodies are used as capturing antibodies on the ELISA plate. After trastuzumab has bound to the catcher antibody, a sandwich ELISA procedure is followed whereby biotinylated anti-idiotype antibodies can bind to trastuzumab. Detection is performed by streptavidin-polyHRP (poly-horseradish peroxidase) conjugate and (3,5,3',5')-tetramethylbenzidine (TMB) substrate. The reaction is stopped using sulfuric acid, and the absorbance is measured at 450 nm. The calibration range of the assay is 0.039 to 5 ng/ml in well. Because samples are analyzed in multiple dilutions, the validated range corresponds to 1.6 to 1600 ng/ml in undiluted serum. Samples above the upper limit of quantification (ULOQ) can be diluted before transfer to the assay plates. Validation results demonstrate that trastuzumab can be accurately and precisely quantified in human serum and plasma. The assay is now used to support pharmacokinetic studies with trastuzumab in human serum and plasma.
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PMID:Development and validation of an enzyme-linked immunosorbent assay for the quantification of trastuzumab in human serum and plasma. 1946 94


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