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)

RNA polymerase III (RNA pol III) transcribes many small structural RNA molecules involved in RNA processing and translation, and thus regulates the growth rate of a cell. Accurate initiation by RNA pol III requires the initiation factor TFIIIB. TFIIIB has been demonstrated to be regulated by tumor suppressors, including ARF, p53, RB, and the RB-related pocket proteins, and is a target of the oncogene c-myc and the mitogen-activated protein kinase ERK. EGCG has been demonstrated to inhibit the growth of a variety of cancer cells, induce apoptosis and regulate the expression of p53, myc, and ERK. Thus, we hypothesized that EGCG may regulate RNA pol III transcription in cells. Here, we report that EGCG (1) inhibits RNA pol III transcription from gene internal and gene external promoters (2) EGCG inhibits protein expression of the TFIIIB subunits Brf1 and Brf2, and (3) EGCG inhibits Brf2 promoter activity in cervical carcinoma cells.
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PMID:The green tea component EGCG inhibits RNA polymerase III transcription. 1762 4

The aim of this study is to target the interference therapy of signal transduction which is a novel therapeutic strategy in laryngeal squamous cell carcinoma (LSCC). We successfully constructed recombinant adenoviruses Ad-p14ARF, and Ad-antisense EGFR using AdEasy-1 vector System. Clonogenic cell assay, western blotting assay, 3'(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometer (FCM) assay, and immunocytochemical technique were designed to examine the inhibition of proliferation, protein expression of p14ARF and EGFR and induction of differentiation, respectively. Furthermore the synergistic effect of Ad-p14ARF and Ad-antisense EGFR on Hep-2 cell was examined. We successfully used AdEasy-1 vector system to construct recombinant adenoviruses Ad-p14ARF and Ad-antisense EGFR. The activity of proliferation of Hep-2 cells was inhibited markedly by infecting Ad-p14ARF or Ad-antisense EGFR by comparing Ad-sense EGFR (P=0.005) with vector control (Ad-Ctrl) (P=0.005) and with PBS (P=0.003). This effect, combining Ad-antisense-EGFR with Ad-p14ARF became more noticeable than alone (P=0.01, P=0.02, respectively). P14 ARF protein overexpression, EGFR protein down expression, and inhibition of proliferation were observed in Hep-2 cells infected by either Ad-p14ARF or Ad-antisense EGFR. FCM revealed that the proportion of apoptosis cells transfected by Ad-p14ARF and Ad-antisense EGFR increased more obviously than the control. The proportion of (Hep-2 cells in) G0/G1 phases was increased by up to 78.5, 77.7, and 86.9% in Ad-antisense EGFR, Ad-p14ARF, and Ad-antisense EGFR+Ad-p14ARF, respectively. Our findings demonstrated that not only EGFR but p14ARF also plays a major role on the genesis and in modulating the cell growth and differentiation of human laryngocarcinoma. They efficaciously blocked the signal transduction of human laryngocarcinoma cell, and may therefore, be an effective potential target of gene therapy to prevent human laryngocarcinoma cell proliferation.
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PMID:Signal transduction-related gene transfer leads to inhibition of proliferation and induction of differentiation in laryngeal squamous cell carcinoma in vitro. 1762 21

The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented.
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PMID:The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. 1763 7

We developed an improved solution for hypothermic storage (0-4 degrees C) of kidneys. The cold storage solution (HBS) was composed of macromolecules, high-energy cellular substrates, and a mixture of antiproteolytic amino acids, antioxidants, and anti-inflammatory compounds. The objectives in developing this solution were to achieve superior metabolic support of the kidney during cold storage and to protect against ischemic injury. Inbred Brown Norway rats, weighing 225-250 g, were subjected to orthotopic ultrarapid technique for kidney isotransplantation to minimize warm ischemia and to test the preservation process. The kidney was transplanted after 12 h of preservation. The animals were divided into three groups based upon the preservation solution utilized: HBS solution, HTK solution (Custodiol), and UW solution (UWS)(ViaSpan). Among the recipients, each group had two subsets. The first subset of animals was used to assess survival at 7 days as well as the reperfusion damage index (RDI) based on the macroscopic physical characteristics of the kidney at the time of transplantation. The second subset in each group was utilized to measure serum creatinine and blood urea nitrogen at 4 and 7 days, and histology at death or sacrifice. Mean +/- standard deviation (M +/- SD) was used for all parameters studied. The HBS solution showed significantly better protection at 12 h when compared to HTK and UW solutions. The reperfusion damage index (RDI) showed excellent preservation in the HBS (14 +/- 1), good preservation in UWS (13 +/- 1.5), and moderate preservation in the HTK (11 +/- 2) group. Histology was in concordance with the RDI, showing better histological findings with HBS and UW solutions than with the HTK group. Serum creatinine was significantly better in the HBS group when compared to HTK and UWS. Survival was statistically different, with 80% survival at 7 days in the HBS group, 20% survival in the HTK group, and 50% survival in the UWS group (p < .05). The HBS solution offered a new alternative for kidney cold storage with significantly better results when compared to the current gold standards of HTK and UW solutions in Brown Norway rats. This solution warrants further testing in other mammals.
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PMID:Evaluation of a novel cold storage solution (HBs) in a rat kidney transplant model. 1771 Jun 7

The aim of this study was to test the ability of poly(ethylene oxide)-b-poly (epsilon-caprolactone) (PEO-b-PCL) micelles to reduce the renal uptake and nephrotoxicity of Cyclosporine A (CyA) after multiple dose administration. Sprague-Dawley rats received CyA i.v. at a dose of 20 mg/kg/day delivered as the commercial formulation (Sandimmune) or polymeric micellar formulation (PM-CyA). Cremophor EL (the solubilizing agent in Sandimmune), unloaded PEO-b-PCL micelles, or normal saline were also administered i.v. to control rats. After 7 days, kidney function was assessed through measurement of creatinine (CLcr) and urea clearances, as well as electrolyte concentrations in plasma. Blood and kidney were collected and assayed for CyA. Sandimmune administration led to decreased CLcr, and increased urea and potassium levels in plasma. In contrast, functional nephrotoxicity with the PM-CyA was not apparent, as the CLcr did not change significantly. The rate of increase in body weight in control rats was 3.1-3.4% per day. Weight gains (1.8% per day) were also noted in the rats given PM-CyA, although the body weight of animals receiving Sandimmune remained constant. Compared to Sandimmune, polymeric micelles reduced kidney uptake of CyA by 2.6-fold, and increased CyA levels in blood by 2.1-fold. The results show a potential for PEO-b-PCL micelles in restricting the nephrotoxicity of CyA.
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PMID:Polymeric micellar delivery reduces kidney distribution and nephrotoxic effects of Cyclosporine A after multiple dosing. 1778 48

Malignant melanomas make up a heterogeneous group of tumors characterized by particular genetic aberrations depending on their anatomic localization and UV exposure. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway is found in the majority of melanomas, with either somatic missense mutations of BRAF or, considerably more rarely, mutations of N-RAS. The loss of both products of the CDKN2A gene, proteins p16(ARF) and p14(INK4a), or amplification of microphthalmia-associated transcriptional factor (MITF) are also predisposing factors in the development of melanoma. BRAF mutations are observed mainly in melanomas on skin liable to intermittent UV exposure. Acral and mucosal melanomas, and also melanomas on skin damaged by chronic exposure to the sun are characterized by distinct patterns of chromosomal aberrations with frequent amplifications and alterations of the KIT gene, while BRAF mutations are rarely found in these sites. Uveal melanomas show recurrent chromosomal losses (1p, 3, 6q) and gains (6p, 8q), but mutations of BRAF are hardly ever found. So far, ancillary molecular studies are not regularly applied in the routine diagnostic procedures performed when malignant melanoma is suspected. In the future, however, the development of targeted molecular therapies will require that molecular pathological techniques are used to identify the melanoma patients who will most probably benefit from a particular therapy.
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PMID:[Molecular heterogeneity of malignant melanomas]. 1788 57

Malignant melanoma originates in melanocytes, the pigment-producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS-RAF-MEK-ERK pathway (through mutation of BRAF, NRAS or KIT), the p16 INK4A-CDK4-RB pathway (through mutation of INK4A or CDK4) and the ARF-p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K-AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well-characterized genetic events leading to activation of proto-oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high-resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate.
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PMID:The genome and epigenome of malignant melanoma. 1804 49

A series of urea analogues related to SA6817 and a GSK phosphonic acid with reported ACE inhibitory activity were prepared and tested for dual ACE and ECE activities. Although excellent ACE and NEP inhibition was achieved, only modest ECE inhibition was observed with one analogue.
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PMID:Targeting ACE and ECE with dual acting inhibitors. 1816 Feb 83

Segmented poly(urethane urea)s (PUUs) with hard segments derived only from methyl 2,6-diisocyantohexanoate (LDI) without the use of a chain extender have previously been described. These materials, which contain hard segments with multiple urea linkages, show exceptionally high strain capability (1600-4700%). In the study reported here, the rate and effect of hydrolysis of these materials were determined for gamma-sterilized and nonsterilized samples. Materials investigated contained PCL, PTMC, P(TMC-co-CL), P(CL-co-DLLA), or P(TMC-co-DLLA) as soft segments and, as well as their mechanical properties, changes in mass, inherent viscosity (I.V.), and thermal properties were studied over 20 weeks. Results showed that the degradation rate was dependant on the soft segment structure, with a higher rate of degradation for the polyester-dominating PUUs exhibiting a substantial loss in I.V. A tendency of reduction of tensile strength and strain hardening was seen for all samples. Also, loss in elongation at break was detected, for PUU-P(CL-DLLA) it went from 1600% to 830% in 10 weeks. Gamma radiation caused an initial loss in I.V. and induced more rapid hydrolysis compared with nonsterilized samples, except for PUU-PTMC. A cytotoxicity test using human fibroblasts demonstrated that the material supports cell viability. In addition, an in vivo biocompatibility study showed a typical foreign body reaction after 1 and 6 weeks.
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PMID:In vitro degradation and in vivo biocompatibility study of a new linear poly(urethane urea). 1816 2

Raf proteins are key components in the signal transduction of the Ras/Raf/MEK/ERK pathway, which is pivotal in oncogenesis, tumor cell malignancy, viral infection, neuronal degeneration, and lymphocyte activation. A number of gain-of-function mutations of Raf genes have been detected in various cancer cells. Consequently, Raf as an anticancer target has been intensively investigated. Numerous small-molecule Raf-inhibiting compounds have been reported in the literature and in patent applications. One of such compounds, the urea derivative Bay 43-9006, has been subjected to the most extensive clinical trials on cancer, including phase III trials, and results to date indicate that this agent can provide clinical benefit without obvious toxicity. Small-molecule Raf inhibitors have also been evaluated preclinically for treatment of viral infection, neuronal degeneration, and inflammatory disease. Thus, small molecule inhibitors of Raf may have broad applications in addition to cancer therapy.
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PMID:Development of small-molecule inhibitors of Raf. 1822 Nov 49


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