Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our group reported that inhibiting DNA methylation in human T cells increases DNA methyltransferase expression and activity, and suggested that this may represent a response to DNA hypomethylation. The increase correlates with increases in Ha-ras and c-jun, suggesting that increased signaling through the ras-MAPK pathway, due to overexpression of some elements, may be responsible. However, whether human DNA MTase is regulated by the ras-MAPK pathway, and whether overexpression of elements in this pathway will increase DNA MTase, is unknown. We report that treating cells with a DNA methylation inhibitor increases transcription regulated by a putative DNA MTase promoter, and that this increase requires AP-1 sites. Additional studies demonstrate that overexpression of an unmutated Ha-ras causes an increase in DNA MTase, and that human T cell DNA MTase can be decreased by inhibiting signaling through the ras-MAPK pathway. Together, these studies suggest that human T cell DNA MTase is regulated through the ras-MAPK pathway, and that overexpression of Ha-ras is sufficient to increase DNA MTase expression. These results thus provide a mechanism for the increase in DNA MTase observed after inducing DNA hypomethylation, a response which may have relevance to some disease states.
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PMID:Role of the ras-MAPK signaling pathway in the DNA methyltransferase response to DNA hypomethylation. 979 44

The apoptosis-promoting protein Par-4 has been shown to be down-regulated in Ras-transformed NIH 3T3 fibroblasts through the Raf/MEK/ERK MAPK pathway. Because mutations of the ras gene are most often found in tumors of epithelial origin, we explored the signaling pathways utilized by oncogenic Ras to down-regulate Par-4 in RIE-1 and rat ovarian surface epithelial (ROSE) cells. We determined that constitutive activation of the Raf, phosphatidylinositol 3-kinase, or Ral guanine nucleotide exchange factor effector pathway alone was not sufficient to down-regulate Par-4 in RIE-1 or ROSE cells. However, treatment of Ras-transformed RIE-1 or ROSE cells with the MEK inhibitors U0126 and PD98059 increased Par-4 protein expression. Thus, although oncogenic Ras utilizes the Raf/MEK/ERK pathway to down-regulate Par-4 in both fibroblasts and epithelial cells, Ras activation of an additional signaling pathway(s) is required to achieve the same outcome in epithelial cells. Methylation-specific PCR showed that the par-4 promoter is methylated in Ras-transformed cells through a MEK-dependent pathway and that treatment with the DNA methyltransferase inhibitor azadeoxycytidine restored Par-4 mRNA transcript and protein levels, suggesting that the mechanism for Ras-mediated down-regulation of Par-4 is by promoter methylation. Support for this possibility is provided by our observation that Ras transformation was associated with up-regulation of Dnmt1 and Dnmt3 DNA methyltransferase expression. Finally, ectopic Par-4 expression significantly reduced Ras-mediated growth in soft agar, but not morphological transformation, highlighting the importance of Par-4 down-regulation in specific aspects of Ras-mediated transformation of epithelial cells.
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PMID:Ras-mediated loss of the pro-apoptotic response protein Par-4 is mediated by DNA hypermethylation through Raf-independent and Raf-dependent signaling cascades in epithelial cells. 1583 92

EBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH(2)-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IkappaB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor-associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor kappaB and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1.
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PMID:Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. 1717 61

A clear understanding is developing concerning the importance of epigenetic-related molecular mechanisms in transcription-dependent long-term memory formation. Chromatin modification, in particular histone acetylation, is associated with transcriptional activation, and acetylation of histone 3 (H3) occurs in Area CA1 of the hippocampus following contextual fear conditioning training. Conversely, DNA methylation is associated with transcriptional repression, but is also dynamically regulated in Area CA1 following training. We recently reported that inhibition of the enzyme responsible for DNA methylation, DNA methyltransferase (DNMT), in the adult rat hippocampus blocks behavioral memory formation. Here, we report that DNMT inhibition also blocks the concomitant memory-associated H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular signal-regulated kinase (ERK). Interestingly, the DNMT inhibitor-induced deficit in memory consolidation, along with deficits in long-term potentiation, can be rescued by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition. These observations suggest that DNMT activity is not only necessary for memory and plasticity, but that DNA methylation may work in concert with histone modifications to regulate plasticity and memory formation in the adult rat hippocampus.
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PMID:DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. 1788 Dec 51

Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, we characterized gene expression profiles from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin-labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips, and pathway analysis was conducted with DAVID (NIH), Ingenuity Systems and MetaCore's GeneGo. Differential expression of several key genes was verified through qPCR. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol and insulin signaling pathways. Approximately 20 genes exhibited a dose response, including several genes known to be associated with carcinogenesis or tumor progression including cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers.
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PMID:Dose response evaluation of gene expression profiles in the skin of K6/ODC mice exposed to sodium arsenite. 1819 Nov 66

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against a host of nuclear antigens. The pathogenesis of lupus is incompletely understood. Environmental factors may play a role via altering DNA methylation, a mechanism regulating gene expression. In lupus, genes including CD11a and CD70 are overexpressed in T cells as a result of promoter hypomethylation. T-cell DNA methyltransferase expression is regulated in part by the extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we investigate the effects of decreased ERK pathway signaling in T cells using transgenic animals. We generated a transgenic mouse that inducibly expresses a dominant-negative MEK in T cells in the presence of doxycycline. We show that decreased ERK pathway signaling in T cells results in decreased expression of DNA methyltransferase 1 and overexpression of the methylation-sensitive genes CD11a and CD70, similar to T cells in human lupus. Our transgenic animal model also develops anti-dsDNA antibodies. Interestingly, microarray expression assays revealed overexpression of several interferon-regulated genes in the spleen similar to peripheral blood cells of lupus patients. This model supports the contention that ERK pathway signaling defects in T cells contribute to the development of autoimmunity.
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PMID:Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients. 1852 34

At 2 and 4 weeks following treatment with phenobarbital (PB), the classical nongenotoxic rodent liver carcinogen, we elucidated unique gene expression changes (both induction and repression) in liver tumor-susceptible B6C3F1 mice, as compared with the relatively resistant C57BL/6. Based on their cancer-related roles, we believe that altered expression of at least some of these genes might underlie PB-induced liver tumorigenesis. Putative constitutive active/androstane (CAR) response elements (CAREs), a subset of PB response elements, were present within multiple genes whose expression was uniquely altered in the B6C3F1 mice, suggesting a role for CAR in their regulation. Additionally, three DNA methyltransferase genes (Dnmt1, Dnmt3a, and Dnmt3b) were repressed uniquely in the tumor-prone B6C3F1 mice, and all possess putative CAREs, providing a potential direct link between PB and expression of key genes that regulate DNA methylation status. Previously, we demonstrated that PB-elicited unique regions of altered methylation (RAMs) in B6C3F1 mice, as compared with the relatively resistant C57BL/6, at 2 and 4 weeks, and annotation of the regions harboring these changes revealed 51 genes. This is extended by the current study, which employed RNA isolated from the same liver tissue used in the earlier investigations. Genes elucidated from both the methylation and expression analyses are involved in identical processes/pathways (e.g., cell cycle, apoptosis, angiogenesis, epithelial-mesenchymal cell transition, invasion/metastasis, and mitogen-activated protein kinase, transforming growth factor-beta, and Wnt signaling). Therefore, these changes might represent very early events that directly contribute to PB-induced tumorigenesis. It is instructive to consider the possibility that, in a hypothesis-driven fashion, these genes are initial candidates that could be utilized to develop a biomarker "fingerprint" of early exposure to PB and PB-like compounds.
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PMID:Phenobarbital elicits unique, early changes in the expression of hepatic genes that affect critical pathways in tumor-prone B6C3F1 mice. 1927 15

Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to successful development of several biological agents that substantially improve survival and quality of life for some patients. There is now a rich pipeline of novel anticancer agents in early phase clinical trials. The specific tumor and stromal aberrancies targeted can be conceptualized as membrane-bound receptor kinases (HGF/c-Met, human epidermal growth factor receptor and insulin growth factor receptor pathways), intracellular signaling kinases (Src, PI3k/Akt/mTOR, and mitogen-activated protein kinase pathways), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, HIF, endothelium, integrins). Several technologies are available to target these abnormalities. Of these, monoclonal antibodies and small-molecule inhibitors have been the more successful, and often complementary, approaches so far in clinical settings. The success of this target-based cancer drug development approach is discussed with examples of recently approved agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. This review also highlights the pipeline of rationally designed drugs in clinical development that have the potential to impact clinical care in the near future.
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PMID:Novel agents on the horizon for cancer therapy. 1927 61

Detoxification mechanisms can play a pivotal role in determining tumor cell responses to platinum-based chemotherapy. Glutathione S-transferase-pi (GSTP1) belongs to a supergene family of detoxifying enzymes involved in the prevention of DNA damage and subsequent platinum resistance in numerous cancers. The role of GSTP1 in gastric cancer sensitivity to chemotherapy is, however, not known. In this study, we found that the human gastric cancer cell line MGC803 was significantly more sensitive to cis-platinum (CDDP) than the other gastric cancer lines examined (BGC823 and SGC7901). To explore the potential role of GSTP1 in drug resistance, we measured GSTP1 expression in these cells. GSTP1 mRNA and protein were not detectable in MGC803 cells; both were present in BGC823 and SGC7901 cells. GSTP1 CpG island DNA methylation was examined. We report that promoter hypermethylation was associated with the absence of GSTP1 expression in MGC803 cells. Treatment of these cells with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, restored GSTP1 expression and suppressed sensitivity to CDDP. The selective mitogen-activated protein kinase/extracellular regulated kinase (ERK) pathway inhibitor PD98059 decreased GSTP1 expression in 5-aza-2'-deoxycytidine-treated cells. A similar decrease was observed in the BGC823 and SGC7901 cell lines, suggesting that mitogen-activated protein kinase/ERK signaling stimulates GSTP1 expression. CDDP sensitivity was also enhanced by PD98059. These observations indicate that somatic promoter hypermethylation and impaired ERK signaling are associated with decreased GSTP1 expression and CDDP sensitivity in gastric cancer cell lines. Evaluation of promoter methylation and ERK activity may be useful for predicting tumor sensitivity to platinum-based chemotherapeutics.
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PMID:GSTP1 determines cis-platinum cytotoxicity in gastric adenocarcinoma MGC803 cells: regulation by promoter methylation and extracellular regulated kinase signaling. 1939 19

We have recently reported that the mitogen-activated protein kinase/ERK kinase (MEK) inhibitor AZD6244 (ARRY-142886) strikingly potentiated the effects of histone deacetylase inhibitor to induce growth arrest and apoptosis of acute myelogeneous leukemia (AML) cells in association with enhanced upregulation of p21(waf1). This study examined the effects of the MEK inhibitor on the action of DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-AzadC), another epigenetic agent in AML cells. AZD6244 significantly potentiated the ability of 5-AzadC to induce growth arrest and apoptosis of NB4, and freshly isolated AML cells. In parallel, 5-AzadC induced expression of p21(waf1) in AML cells, which was potently enhanced in the presence of AZD6244. Further studies explored the molecular mechanisms by which 5-AzadC induced expression of p21(waf1) and found that a low dose of 5-AzadC (1 microM) induced acetylation of histone H3 on the p21(waf1) gene promoter; however, higher dose of this compound (3 or 5 microM) potently induced DNA damage as assessed by expression of gammaH2AX, in NB4 cells. These effects were strikingly enhanced by concomitant blockade of MEK signaling. Furthermore, knock-down of p21(waf1) by the siRNA rescued NB4 cells from 5-AzadC-mediated growth inhibition. Taken together, combination of 5-AzadC and the MEK inhibitor may be useful for treatment of individuals with a subset of AML.
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PMID:Blockade of MEK signaling potentiates 5-Aza-2'-deoxycytidine-induced apoptosis and upregulation of p21(waf1) in acute myelogenous leukemia cells. 1942 44


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