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)

Granular cell astrocytomas (GCA) are an uncommon morphologic variant of infiltrative glioma that contains a prominent population of atypical granular cells. As a rule, they are biologically aggressive compared to similar tumors without granular features. We sought to determine whether GCAs possess distinct genotypic alterations that might reflect their unique morphology or clinical behavior. Eleven GCAs occurring in 7 men and 4 women ranging in age from 46 to 75 years were investigated for genetic alterations of known significance in glial tumorigenesis, including LOH at 1p, 9p, 10q, 17p, and 19q, point mutations of TP53, deletions of p16(CDKN2A) and p14ARF, as well as EGFR amplifications. Tumors included had an infiltrative growth pattern and consisted of large, round cells packed with eosinophilic, PAS-positive granules that varied in quantity, ranging from 30 to 100% of tumor cells. Three tumors were of WHO grade II, one was grade III, and 7 were grade IV lesions. Overall, the tumors showed higher frequencies of LOH at 1p, 9p, 10q, 17p, and 19q than typical infiltrating astrocytomas of similar grades. Losses on 9p and 10q occurred in nearly all cases, including low grade lesions. TP53 mutations were identified in 2 grade IV GCAs, while combined p14ARF and p16(CDKN2A) homozygous deletions were noted in only one grade IV lesion. None showed EGFR amplification. We found no genetic alterations specific for GCA. Instead, it appears that granular cell change occurs across genetic subsets. The high frequency of allelic loss, especially on 9p and 10q, may confer aggressive growth potential and be related to their rapid clinical progression.
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PMID:Granular cell astrocytomas show a high frequency of allelic loss but are not a genetically defined subset. 1274 72

Recent advances in cytogenetic and molecular methodologies have elucidated certain principal characteristics of oncogenesis in glioblastoma multiforme. The earliest clues implicate gene sequence alterations, such as gene amplification and numerical gain or loss of function in specific chromosomes. Genetic classification and expression patterns have thus been constructed, conferring the likelihood of two types of glioblastoma, primary (de novo) as opposed to secondary (evolving from a pre-existing low-grade glioma). The former group of tumors exhibits more frequent occurrences of EGFR gene amplification, whereas the latter group relies strongly on TP53 gene inactivation. Many other tumor suppressor genes and oncogenes have been discovered. Most gene alterations induce cell cycle dysfunction on a complex molecular level. Further insight into tumor genesis by means of genomic assays may aid in predicting the clinical behavior of glioblastoma and in providing individualized potential targets for therapeutic agents.
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PMID:Classification of glioblastoma multiforme in adults by molecular genetics. 1278 73

Effects of ginsenosides on nitric oxide (NO) production induced by lipopolysaccharide plus TNF-alpha (LNT) were examined in C6 rat glioma cells. Among several ginsenosides, ginsenoside Rd showed a complete inhibition against LNT-induced NO production. Ginsenoside Rd attenuated LNT-induced increased phosphorylation of ERK. Among several immediate early gene products, only Jun B and Fra-1 protein levels were increased by LNT, and ginsenoside Rd attenuated Jun B and Fra-1 protein levels induced by LNT. Furthermore, LNT increased AP-1 DNA binding activities, which were partially inhibited by ginsenoside Rd. Our results suggest that ginsenoside Rd exerts an inhibitory action against NO production via blocking phosphorylation of ERK, in turn, suppressing immediate early gene products such as Jun B and Fra-1 in C6 glioma cells.
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PMID:Effect of ginsenoside Rd on nitric oxide system induced by lipopolysaccharide plus TNF-alpha in C6 rat glioma cells. 1278 33

Gliomas are characterized by a deregulation of growth factor production and growth factor receptors expression, e.g. overproduction of the cytokine transforming growth factor-beta (TGF-beta) and overexpression/constitutive activation of receptors for the epidermal growth factor (EGF). Potential interactions of such growth factors and their signaling cascades could enhance the malignancy of these tumors. Therefore, we investigated the effects of TGF-beta and EGF alone and in combination on the proliferation of glioma cells cultivated from eight solid human WHO grade IV gliomas and one glioma cell line, analyzed the expression and intactness of the TGF-beta-signaling molecules Samd-4 and -2, and the phosphorylation of the EGF-signaling kinases ERK 1/2. The effects were divergent and complex: Whereas EGF mostly stimulated glioma cell proliferation, TGF-beta either enhanced, inhibited or had no significant effect on proliferation. In combination, co-stimulation and inhibition of the EGF-induced mitogenic activity could be observed. Smad-4/-2 were expressed in all glioma cells, one point mutation at base 1595 in Smad-4 did not affect its protein sequence. In part of the glioma cells, reduced phosphorylation of ERK 1/2 and expression of cyclin-dependent kinase inhibitor 1 or p21 was observed in co-stimulation experiments. These experiments show that TGF-beta can inhibit EGF-mediated effects only in some gliomas, whereas it enhances it in others. The interaction of both factors is very complex and varies between different gliomas.
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PMID:Interaction of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) in human glioma cells. 1282 16

Liposomes are, when coupled to receptor ligands, candidates for receptor mediated delivery of boron for tumour therapy since they have capacity to deliver large amounts of boron per receptor interaction. With EGF-liposomes we present a pegylated ligand liposome delivery vehicle, containing water soluble boronated phenanthridine, WSP1, or water soluble boronated acridine, WSA1, for EGFR targeting. In the case of WSA1 a ligand dependent uptake was obtained and the boron uptake was as good as if free WSA1 was given. No ligand dependent boron uptake was seen for WSP1 containing liposomes. Thus, WSA1 is a candidate for further studies. Approximately 10(5) boron atoms were in each liposome. A critical assessment indicates that after optimization up to 10(6) boron atoms can be loaded. Since it is known that, for therapeutic effect, approximately 10(8)-10(9) boron atoms are needed in a single tumour cell it is realized that 10(2)-10(3) receptor interactions are needed to meet the demand. Tests applying cultured glioma cells indicate, without optimization of the delivery conditions, a boron uptake in the ppm range, which is necessary for successful BNCT. Thus, it seems possible to kill micro-invasive tumour cells with targeted liposomes if the delivery conditions are optimal.
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PMID:Introductory experiments on ligand liposomes as delivery agents for boron neutron capture therapy. 1285 96

Pilocytic astrocytomas are the most common childhood glioma. Most children with pilocytic astrocytomas survive many years with their tumor, but alternative treatment approaches are needed for those with refractory or metastatic disease. Signaling by the platelet-derived growth factor tyrosine kinase receptor pathways have been postulated to contribute to the development of gliomas. The authors treated a single patient with refractory, metastatic pilocytic astrocytoma with the tyrosine kinase inhibitor imatinib mesylate and observed marked, transient regression of tumor during treatment. Immunohistochemistry was used to assess expression of reported target genes of imatinib mesylate in this patient's tumor tissue and of the PDGFR in pilocytic astrocytomas from 19 other patients. Immunohistochemistry showed that the patient's tumor cells did not express any of the reported target molecules inhibited by imatinib mesylate. PDGFR expression was detected in tumor vasculative in the panel of 20 tumors, and not in the tumor cells. The authors suggest that the PDGFR-signaling pathway postulated to contribute to the development of gliomas in adults might not contribute to pilocytic astrocytomas in children, and that treatment with imatinib mesylate should be considered in patients with refractory pilocytic astrocytoma.
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PMID:Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI-571, Gleevec): a case report and laboratory investigation. 1290 20

The constitutively active, truncated epidermal growth factor receptor EGFRvIII lacks the ability of EGF binding due to a deletion of the NH(2)-terminal domain. EGFRvIII confers increased tumorigenicity, is coexpressed with EGFR wild type (wt) in human carcinoma and malignant glioma cells when grown as xenografts, but is not expressed in vitro. The effects of EGFRvIII expression on cellular radiation responses were studied in Chinese hamster ovary (CHO) cells transfected with plasmids expressing EGFRvIII (CHO.EGFRvIII) or EGFRwt (CHO.EGFRwt). CHO cells expressing similar levels of either receptor were employed to define their roles in response to EGF and ionizing radiation. EGF activated EGFRwt with no effect on EGFRvIII. In contrast, a single radiation exposure of 2 Gy resulted in a 2.8- and 4.3-fold increase in Tyr phosphorylation of EGFRwt and EGFRvIII, respectively. Downstream consequences of this radiation-induced activation were examined by inhibiting EGFRwt and EGFRvIII with AG1478 (kinase inhibitor). The radiation-induced 8.5-fold activation of the pro-proliferative mitogen-activated protein kinase and the 3.2-fold stimulation of the antiapoptotic AKT/phosphatidylinositol-3-kinase pathways by EGFRvIII far exceeded that in CHO.EGFR wt cells. Thus, based on colony formation and apoptosis assays, EGFRvIII expression conferred a stronger cytoprotective response to radiation than EGFRwt, resulting in relative radioresistance. Therefore, disabling EGFRvIII in addition to EGFRwt needs to be considered in any therapeutic approach aimed at targeting EGFR for tumor cell radiosensitization.
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PMID:EGFRvIII-mediated radioresistance through a strong cytoprotective response. 1294 1

Ionizing radiation induces in autocrine growth-regulated carcinoma and malignant glioma cells powerful cytoprotective responses that confer relative resistance to consecutive radiation exposures. Understanding the mechanisms of these responses should provide new molecular targets for tumor radiosensitization. ERBB and other receptor Tyr kinases have been identified as immediate early response gene products that are activated by radiation within minutes, as by their physiological growth factor ligands, and induce secondary stimulation of cytoplasmic protein kinase cascades. The simultaneous activation of all receptor Tyr kinases and nonreceptor Tyr kinases leads to complex cytoprotective responses including increased cell proliferation, reduced apoptosis and enhanced DNA repair. Since these responses contribute to cellular radioresistance, ERBB1, the most extensively studied ERBB receptor, is examined as a target for tumor cell radiosensitization. The three methods of ERBB1 inhibition include blockade of growth factor binding by monoclonal antibody against the ligand-binding domain, inhibition of the receptor Tyr kinase-mediating receptor activation, and overexpression of a dominant-negative epidermal growth factor receptor-CD533 that lacks the COOH-terminal 533 amino acids and forms nonfunctional heterodimeric complexes with wild-type receptors. All the three approaches enhance radiation toxicity in vitro and in vivo. The different mechanisms of inhibition have contributed to the understanding of cellular responses to radiation, vary in relative effectiveness and pose different challenges for translation.
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PMID:ERBB receptor tyrosine kinases and cellular radiation responses. 1294 92

The overexpression of epidermal growth factor receptors, EGFR, in glioblastomas is well documented. Hence, the EGFR can be used as target structure for a specific targeting of glioblastomas. Both radiolabeled anti-EGFR antibodies and the natural ligand EGF are candidate agents for targeting. However, EGF, which has a rather low molecular weight (6 kDa), might have better tissue penetration properties through both normal tissue and tumors in comparison with anti-EGF antibodies and their fragments. The aim of this study was to prepare and evaluate in vitro an EGF-based antiglioma conjugate with residualizing label. Human recombinant EGF (hEGF) was coupled to isothiocyanate-benzyl-DTPA. The conjugate was purified from unreacted chelator using solid-phase extraction and labeled with (111)In. The labeling yield was 87% +/- 7%. The label was reasonably stable; the transchelation of (111)In to serum proteins was about 5% after incubation at 37 degrees C during 24 hours. The obtained [(111)In]benzyl-DTPA-hEGF conjugate was characterized in vitro using the EGFR expressing glioma cell line U343MGaCl2:6. The binding affinity, internalization, and retention of the conjugate were studied. The conjugate had receptor specific binding and the radioactivity was quickly internalized. The intracellular retention of radioactivity after interrupted incubation with conjugate was 71% +/- 1% and 59% +/- 1.5% at 24 and 45 hours, respectively. The dissociation constant was estimated to 2.0 nM. The results indicate that [(111)In]benzyl-DTPA-hEGF is a potential candidate for targeting glioblastoma cells, possibly using locoregional injection.
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PMID:[(111)In]Bz-DTPA-hEGF: Preparation and in vitro characterization of a potential anti-glioblastoma targeting agent. 1450 60

Despite therapeutic interventions including surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. MDA-7 (IL-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound anti-proliferative and cytotoxic effects in a variety of tumor cells, but not in non-transformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cells. Ad.mda-7 reduced the proliferation of rodent and human glioma cells in MTT assays and in colony formation assays. The anti-proliferative effects of Admda-7 were enhanced by radiation in a greater than additive fashion. In vitro, this cellular change correlated with enhanced cell numbers in G1/G0 and G2/M phases of the cell cycle, implying Ad.mda-7 radiosensitizes tumor cells in a cell cycle-independent manner. The radiosensitizing effects were not observed in cultures of non-transformed primary astrocytes. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. Ad.mda-7 enhanced p38 and ERK1/2 activity but did not alter JNK or Akt activity. Irradiation of cells expressing MDA-7 suppressed ERK1/2 activity and dramatically enhanced JNK1/2 activity without altering either Akt or p38 activity. Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad.mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.
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PMID:mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling. 1450 3


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