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)

The expression of the receptor-like tyrosine kinase RET is associated with tumors, tissues or cell lines of neural crest origin. In addition RET products (Ret) are involved in determining cell fate during the differentiation of the enteric nervous system and during renal organogenesis. However, as yet, no direct evidence exists to indicate that the Ret kinase activity might interfere in a specific way with cellular differentiation, or proliferation, of a neural crest derived cell line. By using two constitutively activated forms of RET (RET/PTC1 and RET/PTC3) in transient transfection experiments, we have obtained evidence that active RET could reprogramme the gene expression pattern in the rat pheochromocytoma PC12 cell line. Transcription driven by gene promoters, such as NGFI-A and vgf, which belong, respectively, to primary and delayed response genes to nerve growth factor (NGF), and by the neuron-specific enolase (NSE) promoter, is rapidly induced by the expression of activated RET oncogenes. This induction is not elicited in other non neural derived cell types tested. We also demonstrate that endogenous ras activity is required for RET induction of these neural markers. Finally, in the RET/PTC transfected PC12 cells, NGF is unable to induce further their transcription. This suggests that RET/PTC could share an intracellular signalling pathway with the NGF-receptor.
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PMID:Activated RET/PTC oncogene elicits immediate early and delayed response genes in PC12 cells. 762 17

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are homophilic binding molecules that stimulate axonal growth. We have postulated that the above CAMs can stimulate this response by activating the fibroblast growth factor receptor (FGFR) in neurons. In the present study, we demonstrate that activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant negative form of FGFR1 is expressed in PC12 cells. In addition, we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM, N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite outgrowth stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this response.
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PMID:Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. 905 94

The histological, immunohistochemical and electron microscopic features of a rare malignant granular cell tumor (GCT) arising in the left radial nerve of a 54-year-old man are reported. Despite a lack of local recurrence following extirpation, the tumor metastasized to the skull five years later. Light-microscopically, both primary and metastatic tumors consisted of markedly atypical or pleomorphic neoplastic cells with abundant cytoplasm containing diastase-resistant periodic acid Schiff reaction-positive granules. These tumor cells were arranged in a sheet-like pattern with mitotic figures including atypical ones, and were frequently immunopositive for proliferating cell nuclear antigen and c-MET, the c-met proto-oncogene product. These findings reflect high-grade malignancy of the present tumor. In addition, the tumor cells were positive for S-100 protein and neuron-specific enolase. Ultrastructurally, a large number of intracytoplasmic granules featuring secondary lysosomes as well as long interdigitating cytoplasmic processes, intercellular intermediate junctions, discontinuous basal lamina-like structures, and stromal long-spacing collagen were observed. These findings indicated schwannian differentiation of the present tumor. In addition, based on a review of previously reported cases, the overall clinicopathological characteristics of malignant GCT were summarized.
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PMID:Malignant granular cell tumor: report of a case and review of the literature. 972 67

Two human cancer cell lines were established from metastatic lesions of an adenocarcinoma (RAL) and a squamous cell (CAEP) carcinoma of the lung. The clinical histories of the patients from whom the cell lines were derived are reported. The lines were maintained in continuous culture with doubling times of 65 (RAL) and 50 (CAEP) hours. The RAL and CAEP cell lines, whose morphology and ultrastructural features are presented, showed extensively rearranged karyotypes with modal number of 85 (RAL) and 98 (CAEP). In particular, chromosome 2 pentasomy and several clonal markers were evident in the RAL cells, whereas a telomeric deletion of chromosome 1, del (1)(q32), was observed in the CAEP cells. The morphologic data were confirmed by high expression of specific antigens for each histotype. A marked positivity of the neuron-specific enolase (NSE) levels was evident by immunoenzymatic assays in the cell lines cytosol with respect to those present in the respective patient's sera. No amplification or rearrangements were evident in the CMYC, LMYC, NMYC, INT-2, ERBB2, HRAS, KRAS, MOS, HST-1 genes by Southern blotting analysis in each cell line. Point mutations in exon 1 of KRAS and in exon 7 of TP53 were evident by polymerase chain reaction (PCR)-DNA sequencing in the RAL cell line, whereas no alterations were present in the HRAS and RB genes. The four genes studied did not show point mutations in the CAEP cell line. The RAL cell line was resistant to all the drugs tested, whereas the CAEP cells were sensitive to vinblastine. These cell lines may represent useful experimental models to investigate lung cancer biology and anticancer drug response.
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PMID:Molecular and biological features of two new human squamous and adenocarcinoma of the lung cell lines. 980 28

Several studies have suggested that biochemical or molecular markers examined in non-small cell lung cancer carry prognostic or treatment response information. Non-small cell lung cancer patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of HER2 (c-erbB-2), a membrane-bound receptor with tyrosine kinase activity, has been associated with shortened survival. The Cancer and Leukemia Group B (CALGB) performed a study of patients with stage IIIA (N2 nodes positive) non-small cell lung cancer in which patients received initial chemotherapy followed by surgery, then post-operative therapy consisting of sequential chemotherapy and radiation therapy. Since all patients underwent mediastinoscopy, this provided an opportunity to compare pre- and post-chemotherapy tumor specimens to test the hypothesis that these proteins would predict treatment response. In particular, we hypothesized that the post-chemotherapy specimens would be enriched for NE marker negative cells because of the increased sensitivity of NE positive cells to chemotherapy. We performed immunohistochemical analysis for a panel of NE markers [neuron-specific enolase (NSE), Leu-7, chromogranin A (ChrA), synaptophysin (Syn)], HER2 and CEA to determine if there was an effect of therapy on the percentage of cells expressing these markers. Secondary endpoints were a correlation with chemotherapy response and survival. Slides were scored for intensity (0-4) and percentage of cells positive (0-4). Of 61 eligible patients, there were 38 with both pre- and post-chemotherapy specimens. When both intensity of staining and percentage of positive cells were considered, post-chemotherapy specimens had a higher percentage of positive NE markers compared with pre-chemotherapy. In addition, there was no correlation between NE marker, HER2 or CEA expression (prior to or post treatment) and response to chemotherapy or survival. These data do not support the hypothesis that NE positive tumor cells are preferentially killed by chemotherapy in patients with stage IIIA non-small cell lung cancer.
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PMID:Analysis of neuroendocrine markers, HER2 and CEA before and after chemotherapy in patients with stage IIIA non-small cell lung cancer: a Cancer and Leukemia Group B study. 985 98

Neurons synthesise and secrete many growth and survival factors but it is not usually clear whether they are released locally at the cell body or further afield from axons or axon terminals. Without this information, we cannot predict the site(s) of action or the biological functions of many neuron-derived factors. For example, can neuronal platelet-derived growth factor (PDGF) be secreted from axons and reach glial cells in nerve-fibre (white-matter) tracts? To address this question, we expressed PDGF-A in retinal ganglion neurons in transgenic mice and tested for release of PDGF from cell bodies in the retina and from axons in the optic nerve. In both the retina and optic nerve, there are glial cells that express PDGF receptor alpha (PDGFR alpha) [1] and divide in response to PDGF [2-5], so we could detect functional PDGF indirectly through the mitogenic response of glia at both locations. Expressing PDGF-A in neurons under the control of the neuron-specific enolase promoter (NSE-PDGF-A) resulted in a striking hyperplasia of retinal astrocytes, demonstrating that PDGF is secreted from the cell bodies of neurons in the retina [4]. In contrast, glial proliferation in the optic nerve was unaffected, indicating that PDGF is not released from axons. When PDGF was expressed directly in the optic nerve under the control of an astrocyte-specific promoter (GFAP-PDGF-A), oligodendrocyte progenitors hyperproliferated, resulting in a hypertrophic optic nerve. We conclude that PDGF is constitutively secreted from neuronal cell bodies in vivo, but not from axons in white-matter tracts.
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PMID:Platelet-derived growth factor is constitutively secreted from neuronal cell bodies but not from axons. 1106 9

Small-cell lung cancer (SCLC) carries a bad prognosis despite good initial response to chemotherapy. It is therefore important to identify molecular markers that influence survival as potential new therapeutic targets. In our study, expression of the tyrosine kinase c-erbB-2 (HER2/neu) receptor in tumor tissues of 107 consecutive newly diagnosed patients with primary SCLC was quantified using a monoclonal antibody directed against the c-terminal domain of c-erbB-2. A clear-cut positive expression of c-erbB-2 was observed in 13% of patients. Surprisingly, c-erbB-2 was an independent prognostic factor (RR = 2.16; p = 0.014) when a proportional-hazard model was adjusted to stage (limited vs. extensive disease) and performance status (WHO I-IV), the most relevant clinical parameters. Similarly, a significant association between c-erbB-2 and survival was obtained if a larger number of clinical parameters were included into the analysis, namely response to chemotherapy, TNM stage, lactate dehydrogenase (LDH), neuron-specific enolase (NSE), gender and age (p = 0.033). Interestingly, c-erbB-2 expression was more relevant for patients with advanced tumors. In the subgroup of patients with bad performance status (WHO II-IV), median survival of patients with undetectable c-erbB-2 expression was 274 days compared with only 23 days for patients with clear-cut positive c-erbB-2 immunohistochemistry (p = 0.0031; log-rank test). Similar results were obtained for patients with extensive disease (p = 0.028) and high TNM stages (T>2 or N>1 or M1; p < 0.068, all comparisons). In contrast, c-erbB-2 expression was not associated with survival in patients with limited disease (p = 0.97), low TNM stages (p > 0.56, all comparisons) and good performance status (p = 0.97). In conclusion, c-erbB-2 is expressed in more than 10% of SCLC. Expression of c-erbB-2 is an independent prognostic factor of survival. The effect of c-erbB-2 expression seems to become more important in advanced stages of the disease. Since c-erbB-2 is a therapeutical target in other types of cancer, further studies to identify the role of c-erbB-2 in SCLC are clearly warranted.
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PMID:c-erbB-2 expression in small-cell lung cancer is associated with poor prognosis. 1130 79

Several studies have suggested that non-small cell lung cancer (NSCLC) patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of p53 and HER2 may confer relative chemotherapy resistance and shortened survival. The Cancer and Leukemia Group B performed a series of studies involving sequential chemotherapy followed by radiation for patients with unresectable stage III NSCLC. The objectives of this study were to analyze pathological specimens using immunohistochemistry for NE markers, p53 and HER2 to determine if there was a correlation between marker expression and response or survival. Of 160 eligible patients, 28 (18%) were not evaluable because of inadequate material. The percentage of specimens positive for markers was as follows: neuron-specific enolase 38%, Leu-7 2%, chromogranin A 0%, synaptophysin 5%, > or =2+NE markers 3%, p53 61%, and HER2 65%. There was no statistically significant correlation between any individual marker and response to induction chemotherapy or response to combined chemotherapy/radiation except for synaptophysin. Six of 6 (100%) synaptophysin positive tumors responded by the completion of all therapy compared with 69/125 (55%) synaptophysin negative tumors (P=0.04). None of the individual markers had a significant effect on survival in univariate analysis. Neuron-specific enolase was marginally significant in multivariate analysis (P=0.08). In conclusion, this study did not demonstrate that expression of NE markers, p53 and HER2 were predictive of response to chemotherapy, combined chemotherapy/radiation or for survival in this group of patients with stage III NSCLC. Future studies must employ either different markers or be performed on more adequate surgical specimens.
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PMID:Use of neuroendocrine markers, p53, and HER2 to predict response to chemotherapy in patients with stage III non-small cell lung cancer: a Cancer and Leukemia Group B study. 1155 6

The neuroendocrine (NE) cells represent the third cell population in the normal prostate. Results of several clinical studies strongly indicate that the NE cell population is greatly increased in prostate carcinomas during androgen ablation therapy that correlates with hormone-refractory growth and poor prognosis. However, the mechanism of NE cell enrichment in prostate carcinoma remains an enigma. We investigated the molecular mechanism by which androgen-sensitive C-33 LNCaP human prostate cancer cells become NE-like cells in an androgen-reduced environment, mimicking clinical phenomenon. In the androgen-depleted condition, androgen-sensitive C-33 LNCaP cells gradually acquired the NE-like morphology and expressed an increased level of neuron-specific enolase (NSE), a classical marker of neuronal cells. Several NE-like subclone cells were established. Biochemical characterizations of these subclone cells showed that receptor-type protein-tyrosine phosphatase alpha (RPTPalpha) is elevated and ERK is constitutively activated, several folds higher than that in parental cells. In androgen-depleted condition, PD98059, an MEK inhibitor, could efficiently block not only the activation of ERK, but also the acquisition of the NE-like morphology and the elevation of NSE in C-33 LNCaP cells. In RPTPalpha cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE was elevated. In those cells in the presence of PD98059, the ERK activation and NSE elevation were abolished, following a dose-response fashion. Additionally, in constitutively active MEK mutant cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE level was elevated, and cells obtained the NE-like phenotype. Our data collectively indicated that RPTPalpha signaling via ERK is involved in the NE transdifferentiation of androgen-sensitive C-33 LNCaP human prostate cancer cells in the androgen-depleted condition.
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PMID:Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. 1455 84

Mutations in the APP gene lead to enhanced cleavage by the beta- and gamma-secretase, and increased Abeta formation, which are tightly associated with Alzheimer's disease (AD)-like neuropathological changes. To examine whether depositions of Abeta by APP mutations are increased, and if this is associated with potential pathogenic phenotypes, the APPsw was expressed in a transgenic line under the control of the neuron-specific enolase (NSE) promoter. A behavioral dysfunction was shown at 12 months, and intensive staining bands, with APP and Abeta-42 antibodies, were visible in the brains of transgenic mice. Of the MAPK family, both JNK and p38 were activated in the brains of transgenic mice, whereas there was no significant activation of the ERK. In parallel, tau phosphorylation was also enhanced in the transgenic relative to the control mice. Moreover, the Cox-2 levels, from Western blot and immunostaining, were increased in the brains of the transgenic line. Furthermore, there were significant caspase-3- and TUNEL-stained nuclei in the transgenic line compared to the age-matched control mice. Thus, these results suggest that NSE-controlled APPsw transgenic mice appear to be a more relevant model in neuropathological phenotypes of AD, and thus could be useful in developing new therapeutic treatments for targeting the aberrant phenotypes that appear in these mice.
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PMID:Aberrant expressions of pathogenic phenotype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw. 1498 Aug 7


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