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)

ERK and p38 MAP kinases, acting through the downstream mitogen- and stress-activated kinase 1/2 (MSK1/2), elicit histone H3 phosphorylation on a subfraction of nucleosomes--including those at Fos and Jun--concomitant with gene induction. S10 and S28 on the H3 tail have both been shown to be phospho-acceptors in vivo. Both phospho-epitopes appear with similar time-courses and both occur on H3 tails that are highly sensitive to TSA-induced hyperacetylation, similarities which might suggest that MSK1/2 phosphorylates both sites on the same H3 tails. Indeed, on recombinant histone octamers in vitro, MSK1 efficiently phosphorylates both sites on the same H3 tail. However, sequential immunoprecipitation studies show that antibodies against phosphorylated S10-H3 recover virtually all this epitope without depletion of phosphorylated S28-H3, and vice versa, indicating that the two phospho-epitopes are not located on the same H3 tail in vivo. Confocal immunocytochemistry confirms the clear physical separation of the two phospho-epitopes in the intact mouse nucleus. Finally, we used transfection-based experiments to test models that might explain such differential targeting. Overexpression and delocalisation of MSK1 does not result in the breakdown of targeting in vivo despite the fact that the ectopic kinase is fully activated by external stimuli. These studies reveal a remarkable level of targeting of S10 and S28 phosphorylation to distinct H3 tails within chromatin in the interphase mouse nucleus. Possible models for such exquisite targeting are discussed.
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PMID:MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2. 1587 Jan 5

We have previously demonstrated that macrophages stimulated in the presence of immune complexes produce high levels of IL-10. We now examine the mechanism of IL-10 superinduction. We report that the enhanced production of IL-10 correlates with a rapid and enhanced activation of two MAPKs, ERK and p38. The inhibition of either ERK or p38 prevented IL-10 induction, indicating that both MAPKs were required for IL-10 synthesis. By chromatin immunoprecipitation assay, we demonstrate that activation of ERK leads to the phosphorylation of serine 10 on histone H3 at the il-10 gene, making the promoter more accessible to transcription factors generated in response to p38 activation. Inhibition of ERK activation prevented histone modifications, and decreased the binding of Sp1 and STAT3 to the IL-10 promoter. We conclude that the activation of ERK following FcgammaR ligation leads to a remodeling of the chromatin at the il-10 locus, making it more accessible to transcription factors. The rapid and transient regulation of transcription factor accessibility to the IL-10 promoter by MAPK activation represents a novel way that the production of this cytokine is regulated.
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PMID:ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. 1597 81

The myelodysplastic syndromes (MDS) are receiving unusual attention recently as great strides have been made in understanding the biology. Recognition that excessive cytokine-induced apoptosis plays a significant role in the cytopenias of the majority of patients opened the doors to anti-cytokine therapy, with thalidomide being used with success in approximately 20% patients. Other therapies that have emerged include the thalidomide analog lenalidomide which is particularly beneficial for 5q- patients as well as a subset of non-5q- patients with low or intermediate-1 risk MDS. Other targeted therapies include vitamins, agents that are cytoprotective, differentiation inducers, anti-angiogenic, or immune modulatory. In addition, inhibitors of proteasome, methylation, histone deacetylation, farnesylation, receptor tyrosine kinases, topoisomerase, and matrix mettaloproteinases have yielded encouraging responses in subsets of patients. Specific therapies have also been developed for genetic abnormalities that lead to fusion genes (TEL-PDGFR-beta, or FIP1L1-PDGFR-alpha), or abnormal proteins due to mutations/functional inactivation (FLT3), dysregulated expression (EVI-1). In a short span of ten years, the field has evolved from having no effective therapy to offer the majority of MDS patients save chemotherapy, to having one FDA approved drug, several on the way to approval, and a number of novel agents producing exciting clinical results. This chapter summarizes the novel targets and targeted therapies in the rapidly evolving therapeutic landscape of MDS.
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PMID:Translational research in myelodysplastic syndromes. 1602

Ethanol treatment increases gene expression in the liver through mechanisms that are not clearly understood. Histone acetylation has been shown to induce transcriptional activation. We have investigated the characteristics and mechanisms of ethanol-induced histone H3 acetylation in rat hepatocytes. Immunocytochemical and immunoblot analysis revealed that ethanol treatment significantly increased H3 acetylation at Lys9 with negligible effects at Lys14, -18, and -23. Acute in vivo administration of alcohol in rats produced the same results as in vitro observations. Nuclear extracts from ethanol-treated hepatocytes increased acetylation in H3 peptide to a greater extent than extracts from untreated cells, suggesting that ethanol either increased the expression level or the specific activity of histone acetyltransferases (HAT). Use of different H3 peptides indicated that ethanol selectively modulated HAT(s) targeting H3-Lys9. Treatment with acetate, an ethanol metabolite, also increased acetylation of H3-Lys9 and modulated HAT(s) in the same manner as ethanol, suggesting that acetate mediates the ethanol-induced effect on HAT. Inhibitors of MEK (U0126) and JNK (SP600125), but not p38 MAPK inhibitor (SB203580), suppressed ethanol-induced H3 acetylation. However, U0126 and SP600125 did not significantly affect ethanol-induced effect on HAT, suggesting that ERK and JNK regulate histone acetylation through a separate pathway(s) that does not involve modulation of HAT. Chromatin immunoprecipitation assay demonstrated that ethanol treatment increased the association of the class I alcohol dehydrogenase (ADH I) gene with acetylated H3-Lys9. These data provide first evidence that ethanol increases acetylation of H3-Lys9 through modulation of HAT(s) and that histone acetylation may underlie the mechanism for ethanol-induced ADH I gene expression.
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PMID:Involvement of histone acetyltransferase (HAT) in ethanol-induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression. 1608 63

Reduction of prefrontal cortex glutamic acid decarboxylase (GAD67) and reelin (mRNAs and proteins) expression is the most consistent finding reported by several studies of postmortem schizophrenia (SZ) brains. Converging evidence suggests that the reduced GAD67 and reelin expression in cortical GABAergic interneurons of SZ brains is the consequence of an epigenetic hypermethylation of RELN and GAD67 promoters very likely mediated by the overexpression of DNA methyltransferase 1 in cortical GABAergic interneurons. Studies of the molecular mechanisms (DNA methylation plus related chromatin remodeling factors) that cause the down-regulation of reelin and GAD67 in SZ brains have important implications not only to understand the disease pathogenesis but also to improve present pharmacological interventions to treat SZ. The mouse treated with l-methionine models some of the molecular neuropathologies detected in SZ, including the hypermethylation of RELN promoter CpG islands and the down-regulation of reelin and GAD67 expression. We now report that in these mice, RELN and GAD67 promoters express an increased recruitment of methyl-CpG binding domain proteins. In these mice the histone deacetylase inhibitor valproate, which increases acetylated histone content in cortical GABAergic interneurons, also prevents MET-induced RELN promoter hypermethylation and reduces the methyl-CpG binding domain protein binding to RELN and GAD67 promoters. These findings suggest that DNA hypermethylation and the associated chromatin remodeling may be critically important in mediating the epigenetic down-regulation of reelin and GAD67 expression detected in cortical GABAergic interneurons of SZ patients.
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PMID:Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. 1611 80

RET gene expression is characterized by high tissue and stage specificity during the development of neural crest derivatives and in the pathogenesis of inherited cancer syndromes and Hirschsprung disease. Identifying all elements contributing to its transcriptional regulation might provide new clues to clarify both developmental and pathogenic mechanisms. We previously demonstrated that chromatin acetylation affects RET transcription; therefore, we have set up a strategy based on analysis of sequences conserved among species at the RET locus, combined with the characterization of their chromatin structure, to identify new potential regulatory elements. The histone acetylation level was evaluated by the chromatin immunoprecipitation method applied to cells displaying different degrees of endogenous RET expression. Real-time quantitative PCR of immunoprecipitated DNA-protein complexes and transfection experiments, with constructs expressing a reporter gene in which the putative regulatory regions are inserted, indicate a correlation between histone acetylation and endogenous RET expression and highlight conserved sequences with potential regulatory roles. This paper presents a reliable screening procedure to unearth elements able to affect gene regulation at the transcriptional level in a large genomic region.
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PMID:Comparative genomic sequence analysis coupled to chromatin immunoprecipitation: a screening procedure applied to search for regulatory elements at the RET locus. 1614 62

Estrogen is well-established as a mitogenic factor implicated in the tumorigenesis and progression of breast cancer via its binding to the estrogen receptor alpha (ERalpha). Recent data indicate that chromatin inactivation mediated by histone deacetylation (HDAC) and DNA methylation is a critical component of ERalpha silencing in human breast cancer cells. The aim of this study was to determine the expression of the HDAC1 gene in malignant human breast tissue and to correlate our observations with available clinical information. In the present study, the level of expression of HDAC1 mRNA was assessed by LightCycler-based quantitative real-time reverse transcriptase (RT)-PCR analysis in 162 cases of invasive carcinoma of the breast. Associations between HDAC1 mRNA expression and different clinicopathological factors were sought. It was found that HDAC1 mRNA was expressed at significantly higher levels in tumors from patients over 50 years of age and in those tumors without axillary lymph node involvement, that are less than 2 cm, that are of a non-high histological grade, that are HER2 negative and that are ERalpha/PgR positive. Patients with tumors displaying high levels of HDAC1 mRNA expression tended to have a better prognosis in terms of both disease-free and overall survival. However, univariate and multivariate analysis did not show HDAC1 mRNA expression level to be an independent prognostic factor for either disease-free or overall survival. These results imply that HDAC1 mRNA expression could have potential as an endocrine response marker and may have prognostic implications for breast cancer progression.
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PMID:Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*. 1617 92

Isothiocyanates (ITCs) are potentially important cancer chemopreventive compounds found in cruciferous vegetables. In this study, three ITCs: allyl ITC, benzyl ITC and phenylethyl ITC, induced DNA cell-cycle changes and cell death in undifferentiated Caco-2 cells and their roles in PI3K/Akt and MEK/ERK signaling pathways have been investigated. Flow cytometric analysis was used to measure cell-cycle distribution, expression of mitotic marker (phosphorylated H3 histone), mitochondrial transmembrane potential for the determination of ITC-induced apoptosis measured by Annexin V-FITC staining and metabolic conversion of fluorescein diacetate, and quantification of sub-G1 population. Cellular MAPK and phosphorylated MAPK were measured using western blot analysis. All ITCs tested induced G2/M cell-cycle arrest after 24-h treatment, a time- and concentration-dependent activation of ERK1/2, dissipation of mitochondrial transmembrane potential and apoptosis. Both PI3K/Akt and MEK/ERK inhibitors, LY294002 and PD98059, attenuated the extent of BITC-induced cell death. Pretreatment of cells with either the PD98059 or LY294002 inhibitor, caused a dose-dependent inhibition of histone H3 (p-H3) phosphorylation. Despite the LY294002 inhibitor having no effect on the proportion of ITC-induced G2/M arrested cells, a significant decrease of p-H3/(G2/M) ratio in both PD98059- and LY294002-treated cells was observed. We suggest that the decrease of mitotic cells was compensated for by an increase of cells in G2 phase. LY294002 and PD98059 affect cell transition from G2 to M phase and from S to G2 phase respectively. These results indicate that isothiocyanates can induce cell cycle-change through multiple signaling pathways and more detailed study is merited to further unravel the chemopreventive and chemotherapeutic mechanisms of ITCs.
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PMID:Effects of MEK1 and PI3K inhibitors on allyl-, benzyl- and phenylethyl-isothiocyanate-induced G2/M arrest and cell death in Caco-2 cells. 1621 Dec 42

An RTK-Ras-mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in vulval induction in Caenorhabditis elegans. We have previously carried out screens for suppressors of activated Ras to identify factors that play critical roles in the regulation of the pathway. ku258 was isolated as a semidominant allele that suppresses the Multivulva phenotype caused by activated let-60 ras. Our genetic and molecular analyses indicate that ku258 is a gain-of-function allele resulting from two point mutations in the C. elegans homolog of the transcriptional coactivator p300/CBP, cbp-1. Genetic data also suggest that cbp-1 may act downstream of the Ras signaling pathway, but not primarily downstream of the Wnt signaling pathway, to negatively regulate vulval cell fate specification. cbp-1 may function in concert with LIN-1, an Ets transcription factor family member that is one of the targets of MAPK. In vitro histone acetylation assays have revealed that together, the two point mutations cause a sevenfold increase in the histone acetyltransferase (HAT) activity of recombinant CBP-1. To our knowledge, this is the only such HAT activity mutation isolated in a CBP/p300 family protein, and this mutation may define a negative role of the HAT activity in antagonizing Ras function in a specific developmental event.
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PMID:A gain-of-function allele of cbp-1, the Caenorhabditis elegans ortholog of the mammalian CBP/p300 gene, causes an increase in histone acetyltransferase activity and antagonism of activated Ras. 1622 93

Leukemias are differentially sensitive to histone deacytelase inhibitor (HDI)-induced apoptosis, but molecular reasons for this remain unclear. We here show that BCR/ABL-, but not FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-transformed 32D cells or primary acute myeloid leukemia (AML) blasts undergo apoptosis after treatment with the HDI valproic acid (VPA) plus all-trans retinoic acid (VPA/ATRA). A particular VPA/ATRA responsiveness of Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) was confirmed in a therapy-refractory patient in vivo. HDI-stimulated apoptosis in Ph+ cells was caspase dependent, but independent from Akt pathway inhibition. Conversely, separate blockage of the Akt/mTor-signaling pathway was a prerequisite for overcoming apoptosis resistance to VPA/ATRA in FLT3-ITD cells, and primary AML blasts (n = 9). In conclusion, constitutive Akt activation causes apoptosis resistance to VPA/ATRA in AML, but not in Ph+ leukemia. This warrants the application of HDI-based therapies in poor-risk Ph+ ALL, and the use of Akt/mTor inhibitors to overcome HDI resistance in AML.
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PMID:FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment. 1630 46


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