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)

Brain-derived neurotrophic factor (BDNF) promotes neuronal survival and protection against neuronal damage. We addressed whether BDNF might promote survival and chemoprotection in neuroblastoma (NB) using a drug-sensitive human NB cell line. All-trans-retinoic acid (ATRA) induces a striking phenotypic differentiation of NB1643 cells, and exogenous BDNF treatment promotes survival of these differentiated cells. ATRA induces TRKB expression, and exogenous BDNF stimulates both autophosphorylation of TRKB and induction of the immediate early gene, FOS, in these cells. BDNF mRNA is expressed in NB1643 cells. Because the time course of TRKB induction closely parallels phenotypic differentiation of these cells, it seems probable that ATRA induces differentiation of NB1643 cells by establishing an autocrine loop involving BDNF and TRKB. Exogenous BDNF treatment resulted in a further increase in neurite outgrowth, which again suggests that an autocrine loop is involved in differentiation of NB1643 cells in response to ATRA. We then tested whether BDNF might afford drug resistance in NB and found that BDNF does indeed protect in this NB model against cisplatin, a DNA-damaging agent actually used in the treatment of NB.
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PMID:Brain-derived neurotrophic factor promotes survival and chemoprotection of human neuroblastoma cells. 1034 7

Intracellular protozoan parasites of the genus Leishmania antagonize host defense mechanisms by interfering with cell signaling in macrophages. In this report, the impact of Leishmania donovani on mitogen-activated protein (MAP) kinases and nitric oxide synthase (NOS) expression in the macrophage cell line RAW 264 was investigated. Overnight infection of cells with leishmania led to a significant decrease in phorbol-12-myristate-13-acetate (PMA)-stimulated MAP kinase activity and inhibited PMA-induced phosphorylation of the MAP kinase substrate and transcription factor Elk-1. Simultaneously, leishmania infection markedly attenuated the induction of c-FOS and inducible nitric oxide synthase (iNOS) expression in response to PMA and gamma interferon (IFN-gamma), respectively. These effects correlated with decreased phosphorylation of p44 and p42 MAP kinases on tyrosine residues. Consistent with the latter finding, lysates prepared from leishmania-infected cells contained an activity that dephosphorylated MAP kinase in vitro, suggesting the possibility of a phosphatase acting in vivo. Attenuation of both MAP kinase activity and c-FOS and iNOS expression was reversed by treatment of macrophages with sodium orthovanadate prior to infection. It was also found that the specific activity of the Src homology 2 domain containing tyrosine phosphatase (SHP-1) toward MAP kinase was markedly increased in leishmania-infected cells. These findings indicate that infection with L. donovani attenuates MAP kinase signaling and c-FOS and iNOS expression in macrophages by activating cellular phosphotyrosine phosphatases. This may represent a novel mechanism of macrophage deactivation during intracellular infection.
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PMID:Activation of phosphotyrosine phosphatase activity attenuates mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression in macrophages infected with Leishmania donovani. 1041 74

The aim of this study was to evaluate the expression profile of proteins involved in growing of human non-small cell lung cancer (NSCLC) in athymic nude mice. The expressions of 20 gene products in primary NSCLC of 170 patients were analyzed and the proteins were correlated with the transplantability of the carcinomas in nude mice. There was no relationship between xenotransplantability of human non-small cell lung cancer in nude mice and histology, stage or lymph node involvement. Of the analyzed proliferative factors PCNA, cyclin A, cyclin D, cdk2, cdk4 and cell cycle phases only cyclin D, cdk4 and the cell cycle phases were up-regulated in growing carcinomas. There was also a correlation between the apoptotic indices and the take rate in nude mice. Concerning microvessel density and angiogenic factors only VEGF showed a relation to xenotransplantability. Of the proto-oncogenes and suppressor gene products N-RAS, P53, FOS and JUN revealed a relationship to the take rate of NSCLC, while such a relationship was not found with MYC, ERBB-1 and ERBB-2. In a second step, a hierarchical cluster analysis was carried out. The resulting clusters were correlated with the take rate of the carcinomas in nude mice. The expression of JUN, N-RAS, FOS, cyclin D, and cdk4 were significantly different in both groups with non- overlapping confidence intervals. Thus, the up-regulation of the proteins JUN, N-RAS, FOS, cyclin D and cdk4 predicts the growth of NSCLC in nude mice.
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PMID:Expression profile of proteins involved in the xenotransplantability of non-small cell lung cancers into athymic nude mice. 1178 7

Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro. The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-pi, metallothionein, O6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).
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PMID:Protein expression profiles indicative for drug resistance of non-small cell lung cancer. 1217 90

Herceptin is a humanized monoclonal antibody targeted against the extracellular domain of the HER2 oncogene, which is amplified and overexpressed in 10-34% of breast cancers. Herceptin therapy provides effective treatment in HER2-positive metastatic breast cancer, although a favorable treatment response is not achieved in all cases. Here, we show that Herceptin treatment induces a dose-dependent growth reduction in breast cancer cell lines with HER2 amplification, whereas nonamplified cell lines are practically resistant. Time-course analysis of global gene expression patterns in amplified and nonamplified cell lines indicated a major change in transcript levels between 24 and 48 h of Herceptin treatment. A step-wise gene selection algorithm revealed a set of 439 genes whose temporal expression profiles differed most between the amplified and nonamplified cell lines. The discriminatory power of these genes was confirmed by both hierarchical clustering and self-organizing map analyses. In the amplified cell lines, the Herceptin treatment induced the expression of several genes involved in RNA processing and DNA repair, while cell adhesion mediators and known oncogenes, such as c-FOS and c-KIT, were downregulated. These results provide additional clues to the downstream effects of blocking the HER2 pathway in breast cancer and may provide new targets for more effective treatment.
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PMID:Effects of Herceptin treatment on global gene expression patterns in HER2-amplified and nonamplified breast cancer cell lines. 1464 48

Aplidin is an antitumor drug that induces apoptosis and activates EGFR, Src, JNK and p38MAPK. Here, we show that Aplidin induces c-JUN, JUN B, JUN D, c-FOS, FRA-1 and FOS B genes of the activator-protein (AP)-1 family, and also p65/RELA, a major component of nuclear factor-kappa B (NF-kappaB). Concordantly, Aplidin increases AP-1 and NF-kappaB activity. c-FOS induction depends on EGFR, Src and JNK/p38MAPK. In contrast, induction of c-JUN does not require EGFR activity and p65/RELA induction is only partially dependent on these kinases. We used several genetically deficient cells to identify the critical target of Aplidin. Mouse embryo fibroblasts (MEFs) deficient for src, yes and fyn, and those lacking all p38MAPK isoforms displayed normal Aplidin sensitivity (IC50=12 nM). In contrast, MEFs lacking jnk1 and jnk2, which do not express any JNK isoform, were much less sensitive (IC50>500 nM). Furthermore, cells lacking c-jun or expressing a c-Jun protein in which JNK targets Ser(63/73) were mutated (c-JunAA) showed intermediate sensitivity (IC50=60 nM). Additionally, Aplidin has higher cytotoxic activity against proliferating than quiescent cells, which is reflected in higher JNK activation. We conclude that phosphorylation by JNK of c-Jun and additional substrate(s) is crucial for Aplidin activity.
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PMID:JNK activation is critical for Aplidin-induced apoptosis. 1512 39

To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from COPD and control smokers. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.5-fold up- or down-regulated). Microarray analysis using the same RNA source detected 261 transcripts that were differentially expressed to a significant degree between GOLD-2 and GOLD-0 smokers. We confirmed the altered expression of a select number of genes by using real-time quantitative RT-PCR. These genes encode for transcription factors (EGR1 and FOS), growth factors or related proteins (CTGF, CYR61, CX3CL1, TGFB1, and PDGFRA), and extracellular matrix protein (COL1A1). Immunofluorescence studies on the same lung specimens localized the expression of Egr-1, CTGF, and Cyr61 to alveolar epithelial cells, airway epithelial cells, and stromal and inflammatory cells of GOLD-2 smokers. Cigarette smoke extract induced Egr-1 protein expression and increased Egr-1 DNA-binding activity in human lung fibroblast cells. Cytomix (tumor necrosis factor alpha, IL-1beta, and IFN-gamma) treatment showed that the activity of matrix metalloproteinase-2 (MMP-2) was increased in lung fibroblasts from EGR1 control (+/+) mice but not detected in that of EGR1 null (-/-) mice, whereas MMP-9 was regulated by EGR1 in a reverse manner. Our study represents the first comprehensive analysis of gene expression on GOLD-2 versus GOLD-0 smokers and reveals previously unreported candidate genes that may serve as potential molecular targets in COPD.
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PMID:Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. 1546 29

We have established a method for using a cDNA array platform in combination with degenerate oligonucleotide primer polymerase chain reaction (DOP-PCR) and taramide signal amplification (TSA) to identify DNA copy number abnormalities (CNA) in cancer cell lines and cancer cells procured with laser-based microdissection. To determine the sensitivity and specificity for detecting single-copy gain and loss, receiver-operator curve analysis was performed on hybridization signal ratios generated from non-DOP and DOP amplified female and male DNA using a 10,816-element cDNA microarray. A cutoff value of 1.12 and 1.07 average signal ratio for X-chromosomal genes versus autosomal genes provided a sensitivity and specificity of 50 and 79%, respectively, for non-DOP amplified DNA and a sensitivity and specificity of 50 and 72%, respectively, for DOP amplified DNA. We used this approach to identify DNA copy number abnormalities in the ovarian cancer cell line OVCA633, which has previously been shown to have 12p amplification. Transcription profiling of OVCA633 was also performed. Two amplified and overexpressed genes located on 12p11, KRAS2 and LRMP, were identified; these were validated with quantitative real-time PCR. Subsequently, the same approach was used to identify CNAs and gene expression alterations in 11 microdissected serous ovarian adenocarcinoma cases. Validated data revealed amplification and overexpression of ERBB3 and FOS and deletion and underexpression of KRT6 and APXL in more than 50% of the tissue samples. These results show the feasibility of using the cDNA array platform to identify changes in DNA and mRNA copy number simultaneously in microdissected tumor tissues.
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PMID:Identification of DNA copy number changes in microdissected serous ovarian cancer tissue using a cDNA microarray platform. 1557 95

Previously we have demonstrated that both plasminogen (Plg) and plasmin (Pla) regulate the expression of the transcription factors c-FOS and EGR-1 [L.P. De Sousa, B.S. Brasil, B.M. Silva, M.H. Freitas, S.V. Nogueira, P.C. Ferreira, E.G. Kroon, C.A. Bonjardim, Plasminogen/plasmin regulates c-fos and egr-1 expression via the MEK/ERK pathway, Biochem. Biophys. Res. Commun. 329 (2005) 237-245]. Here we show that Plg activates the mitogen-activated protein kinases MEK and ERK which leads to alpha-enolase (alpha-ENO) gene expression not only in fibroblasts, but also in peripheral blood mononuclear cells. The alpha-ENO mRNA accumulation was apparent three hours post-Plg treatment and remained elevated out to 28h, a process that seems to require both de novo protein synthesis and active gene transcription. Pla mimics Plg-stimulated alpha-ENO expression through its serine protease activity, suggesting that conversion of Plg to active Pla is required. Pharmacological and genetic blockade of MEK caused inhibition of alpha-ENO mRNA accumulation, implicating MEK/ERK as the transduction pathway that leads to alpha-ENO expression upon Plg stimulation. Furthermore, Plg stimulated DNA binding activity of the transcription factors activator-protein 1 and early growth response gene-1 to their cognate regulatory sequences at alpha-ENO promoter. Altogether, our data show that Plg/Pla regulates alpha-ENO expression through the MEK/ERK pathway.
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PMID:Plasminogen/plasmin regulates alpha-enolase expression through the MEK/ERK pathway. 1622 43

Higher soy food intake has been hypothesized to be a major factor explaining the decreased breast cancer risk in Asian countries, compared to those regions of the world consuming predominantly Western-style diets. Consumption of soy isoflavones, particularly genistein, has received considerable attention as the soy component largely responsible for the protective effects hypothesized to result from soy food consumption. However, the impact of adult consumption of soy foods on breast cancer risk in pre-menopausal and menopausal women is not consistent. There are recent epidemiological reports that consumption of soy foods can most effectively reduce breast cancer risk when consumed early in life during the pre-pubertal or adolescent periods. The aim of the present study was to evaluate the effects of physiologically-relevant levels of genistein (0.5 microM and 1 microM), concentrations achievable in the plasma following soy food consumption, on proliferation and expression of select genes in the human breast epithelial cell model. Treatment of the non-neoplastic, immortalized human breast epithelial MCF-10F cells with these low concentrations of genistein was associated with decreased cell proliferation, down-regulation of the protooncogene MET, up-regulation of the breast tumor suppressor gene EGR-1, and up-regulation of the immediate-early response genes FOS and JUN. In addition, genistein treatment was associated with a significant increase in Egr-1 binding to the transcription factor Sp1. Taken together, these genistein-induced changes in gene expressions provide insights into potential mechanisms by which this isoflavone may protect human breast cells against neoplastic transformation.
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PMID:Genistein suppresses proliferation and MET oncogene expression and induces EGR-1 tumor suppressor expression in immortalized human breast epithelial cells. 1661 4


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