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)

More than 60% of anaplastic large-cell lymphomas (Ki-1 lymphoma) are associated with a t(2;5)(p23;q35) translocation that produces an 80 kDa hyperphosphorylated chimeric protein (p80) derived from the fusion of the anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM). The NPM-ALK chimeric gene is an activated tyrosine kinase that has been shown to be a potent oncogene. We have developed a cellular model for the study of p80 action in rat 1a fibroblasts. Expression of cDNA's encoding NPM-ALK (p80) in rat 1a fibroblasts induces anchorage-independent growth in soft agar and promotes foci formation in culture. Cells expressing exogenous p80 showed significantly increased proliferation characterized by accelerated cell cycle entry into S-phase. Consistent with increased G0/G1 to S-phase transition, there is also marked up-regulation of cyclin A and cyclin D1 expression. In addition, p80 transformed cells showed elevated expression of several immediate early genes involved in cellular proliferation, including fos, jun, and c-myc. DNA binding analysis of nuclear extracts prepared from p80 transformed cells reveal marked up-regulation of AP-1 DNA binding activity. Functional AP-1-specific transfection assays also show up-regulation of AP-1-dependent transcriptional activation. These finding demonstrate that p80 transformed rat 1a fibroblast can be a highly useful model system for the molecular and biochemical characterization of the mechanisms of action of this interesting new oncogene.
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PMID:The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up-regulation in rat 1a fibroblasts. 933 49

The effects of EGF and TGF beta 1 on onco gene expressions was studied by RT-PCR technique in an ovarian cancer cell line HO-8910. The results showed that TGF beta 1 could inhibit mRNA expression of TGF beta 1 gene and that of c-myc, EGFR and c-erbB2 genes in HO-8910 cells in vitro. However, EGF could enhance the mRNA expressions of c-myc, c-erbB2 and EGFR to various extents, but inhibit that of TGF beta 1 gene.
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PMID:[The effects of growth factors on gene expressions in human ovarian cancer cell line HO-8910]. 938 73

This paper summarizes the current knowledge on the role of genetic factors in the development of thyroid neoplasms. The introduction of the methods and concepts of molecular genetics (as, e.g. recombinant DNA technology) have elucidated etiopathogenesis of the majority of thyroid tumours and, in the future, can make the diagnosis easier. Mutations of genes involved in the control of cellular growth and/or differentiation (ras, c-myc, RET, met) affect the development of thyroid neoplasms. Loss of heterozygosity (LOH) may suggest the presence of tumor suppressor genes and has been reported in thyroid follicular carcinomas. Activation of tyrosine kinase, whether by specific oncogene amplification or by rearrangement, appears to be highly specific for the transformation of thyroid follicular cells into papillary tumours. Cytogenetic studies have shown frequent clonal abnormalities in thyroid follicular adenomas and carcinomas.
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PMID:[The role of genetic factors in the pathogenesis of thyroid neoplasms]. 944

In situ duct carcinoma (DCIS) is a heterogeneous group of lesions which has recently been subdivided into three types: well-differentiated (type I), intermediately differentiated (type II) and poorly differentiated (type III) DCIS. Fourteen cases of DCIS and 11 of DCIS with minimal invasion were analysed for mRNA levels of beta-actin, EGFR, c-cerbB2, MTS1, k-ras, RB, BRCA1, cyclin E, and c-myc genes. A microdissection technique was used on paraffin-embedded tissue. A statistically significantly higher expression of cyclin E oncogene and MTS1 tumor suppressor gene was seen in type III DCIS than in the other types, while no significant differences in the mRNA expression patterns of the other genes were observed. These data are consistent with the fact that poorly differentiated DCIS is a readily recognizable class of tumours that have a particularly aggressive behaviour and probably unique histogenesis.
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PMID:Molecular characterization of intraductal breast carcinomas. 950 54

We studied early changes in gene expression during fibroblast contraction of stressed collagen matrices. The level of c-fos mRNA increased dramatically and peaked 50 to 60 min after matrix contraction was initiated. This response did not require serum and could not be accounted for simply by disruption of the actin cytoskeleton. Increased c-fos mRNA levels required Ca2+ influx but not the cyclic AMP or extracellular signal-regulated kinase (ERK 1/2) signaling pathways, both of which are activated when fibroblasts contract stressed collagen matrices. The levels of two other immediate-early genes, fosb and c-jun, also increased transiently after fibroblast contraction, whereas the levels of fra-1, fra-2, c-myc, and the transcription factor NF-kappaB remained the same, indicating that fibroblast contraction caused changes in a selective group of genes. The increase in c-fos mRNA during contraction of stressed collagen matrices may reflect a unique role for c-fos in mechanoregulated events at the end of wound repair.
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PMID:Increased c-fos mRNA expression by human fibroblasts contracting stressed collagen matrices. 956 85

Lipid metabolism can play an important role in the development and progression of human cancers. We have used Syrian hamster embryo (SHE) fibroblasts as a model system to study how lipid metabolites can alter cell proliferation and apoptosis. For example, the linoleic acid metabolite 13(S)-HpODE enhances EGF-dependent growth by inhibiting de-phosphorylation of the EGFR which leads to activation of the MAP kinase pathway. In contrast, the arachidonic acid metabolite, PGE2, inhibits EGF-dependent mitogenesis and the expression of the proto-oncogenes c-myc, c-jun, and jun-B. In this study, we have investigated the mechanism by which PGE2 attenuates these responses by studying the EGF signaling cascade in SHE cells. PGE2 pretreatment caused a concentration-dependent decrease in EGF-dependent phosphorylation of MAP kinase and a corresponding inhibition of EGF-stimulated MAP kinase activity. Pretreatment of the SHE cells with PGE2 had little effect on the magnitude of EGF-dependent receptor auto-phosphorylation and the phosphorylation of GAP suggesting a down-stream target. Treatment of cells with forskolin and EGF causes similar inhibition of MAP kinase phosphorylation as observed with PGE2 and EGF. Since PGE2 elevates cAMP in these cells, it may act by altering cAMP accumulation. Raf-1 activity can be inhibited by a cAMP-dependent process. Raf-1 activity, measured by phosphorylation of Mek-1, was attenuated by the addition of PGE2. To determine if inhibition of Raf-1 activity causes inhibition of the MAP kinase pathway, cells were concomitantly incubated with PGE2 and EGF. Inhibition of MAP kinase phosphorylation was observed. From these data, we propose that in SHE cells PGE2 increases cAMP levels, which in turn causes inhibition of Raf-1 activity. The MAP kinase pathway is thus downregulated which decreases mitogenesis and proto-oncogene expression. This study demonstrates that an arachidonic acid metabolite can modulate phosphorylation and activity of key signal transduction proteins in a growth factor mitogenic pathway.
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PMID:Inhibition of EGF-dependent mitogenesis by prostaglandin E2 in Syrian hamster embryo fibroblasts. 965

We have used FISH to determine the level of synchronisation in replication timing of four pairs of alleles, unrelated to chromosome 21 (p53, HER2, RB1, and c-myc), in foetal (amniotic fluid) cell samples of Down syndrome and in normal foetuses. All samples derived from the Down syndrome subjects showed large temporal differences in replication timing, in contrast to the high level of synchrony shown in all samples of normal individuals. Thus, as judged by four independent loci which are not associated with chromosome 21, the additional chromosome in the Down syndrome genome induces changes in the replication pattern of an allelic pair: from a synchronous pattern characteristic to concomitantly expressed alleles to an unsynchronised one shown by alleles displaying an allele-specific mode of expression.
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PMID:Asynchronous replication of allelic loci in Down syndrome. 978 Oct 44

A key regulatory step in translation is initiation, or the recruitment of the translational machinery to the 5' end of mRNA. The 5' terminus of most mRNAs is demarcated by a m7GpppN cap (where m is a methyl group, and N is any nucleotide). The m7 cap is essential for the translation of most mRNAs, as it directs the translational machinery to the 5' end of the mRNA via its interaction with the cap binding protein, the eukaryotic translation initiation factor 4E (eIF4E). eIF4E is the limiting initiation factor in most cells. Thus, eIF4E activity plays a principal role in determining global translation rates. Consistent with this role, eIF4E is required for cell cycle progression, exhibits anti-apoptotic activity, and, when overexpressed, transforms cells. This review focuses upon the various mechanisms utilized in the regulation of eIF4E activity. (1) eIF4E is regulated transcriptionally; it is one of the few identified transcriptional targets of c-myc. (2) eIF4E is phosphorylated following activation of the MNK1 kinase, a substrate of the ERK and p38 MAPKs. The recent determination of the three-dimensional structure of eIF4E bound to a m7 cap analog has provided insight into the mechanisms involved in the regulation of the eIF4E-cap and eIF4E-mRNA interactions. As suggested by the crystal structure, phosphorylation of eIF4E may enhance its affinity for mRNA. (3) eIF4E is also regulated through binding to a family of translational repressor proteins. Interaction with the 4E-BPs prevents the incorporation of eIF4E into an active translation initiation complex, and thus, inhibits cap-dependent translation. This inhibitory interaction is relieved following phosphorylation of the 4E-BPs by a PI3K-dependent pathway, involving signalling by the anti-apoptotic kinase Akt/PKB, as well as FRAP/mTOR.
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PMID:eIF4E activity is regulated at multiple levels. 1021 43

Although the kidney represents a target for the accumulation and toxicity of arsenic, little is known about the molecular targets of arsenic in this organ. Therefore, these studies were designed to examine the molecular impact of arsenite [As(III)] and arsenate [As(V)] at low (nanomolar) concentrations. Precision-cut rabbit renal cortical slices were challenged with As(III) or As(V) for up to 8 h. Neither form of the metal induced overt cytotoxicity as assessed by intracellular K+ levels over this time period at concentrations from 0.01-10 microM. In addition, no alterations in the expression of Hsp 60, 70, or 90 were observed. However, induction of heme oxygenase-1 (Hsp 32) was seen following a 4-h challenge with As(III), but not with As(V). As(III) and As(V) induced DNA binding of AP-1 at 2- and 4-h exposure; following a 6-h exposure there was no difference. Although no alteration in the DNA binding activity of ATF-2 was induced by As(III) or As(V), both forms enhanced the DNA binding activity of Elk-1. Enhanced DNA binding activity of AP-1 and Elk-1 correlated with increased gene expression of c-fos, but not c-jun, at 2 h. c-myc gene expression was also induced by As(III) and As(V), albeit at a later time point (6 h). These results suggest that acute arsenic challenge, by either As(III) or As(V), is associated with discrete alterations in the activity of signaling pathways and gene expression in renal tissue.
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PMID:Enhanced transcription factor DNA binding and gene expression induced by arsenite or arsenate in renal slices. 1044 58

The kidneys are the primary organ for the accumulation and toxicity of inorganic mercury. In these studies the molecular response of precision-cut rabbit renal cortical slices to low levels of inorganic mercury was examined. Cortical slices (275 microm) were obtained from 1.0 kg NZW rabbits and exposed to mercuric chloride [Hg(II)] at concentrations of 0.01-10 microM for 2-8 h. Overt cytotoxicity, as assessed by intracellular K(+) levels, was not observed following exposure to these concentrations of Hg(II). However, an induction of heme-oxygenase-1 (Hsp32) was seen following a 2-h challenge to Hg(II). A dose-dependent induction of the DNA binding activity of the AP-1 transcription factor after 4 h of Hg(II) exposure correlated with a dose-dependent enhancement of c-jun gene expression following 2 h of Hg(II) exposure. Additionally, an increase in phosphorylated c-Jun NH(2)-terminal protein kinase (JNK) was observed following 2 h of Hg(II) exposure. These results suggest activation of the mitogen-activated protein (MAP) signal transduction pathway, specifically the c-Jun NH(2)-terminal protein kinase (JNK) pathway. No changes were observed, however, in the DNA binding activity of ATF2 and Elk-1, transcription factors involved in both the JNK and p38 pathways of MAP signal transduction, nor in the gene expression of c-myc. This selectivity of alterations in molecular signaling suggests an acute response in signal transduction, specifically activation of the JNK pathway in renal tissue following exposure to nanomolar concentrations of Hg(II).
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PMID:Selective activation in the MAPK pathway by Hg(II) in precision-cut rabbit renal cortical slices. 1054 60


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