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)

HA(306-318) is an immunodominant peptide of the hemagglutinin of influenza virus that binds to most human leukocyte antigen (HLA-DR) alleles, while p18(73-85) is a HIV peptide characterized as a DR101 binding peptide. Our results demonstrate that crystal relaxation leads to the loss of a hydrogen bond between the beta81 histidine and the HA(306-318) peptide. This histidine is also involved in the binding of superantigens like SEA via a coordination of a zinc atom. To monitor the interaction of these peptides with this histidine of HLA-DR molecules, chemical modification, peptide binding on HLA-DR101 wild type and mutated molecules, and proliferation experiments were conducted, together with molecular simulation of HLA-DR/peptide molecular complexes. Our data suggest a different binding peptide pattern, depending of whether the peptide is HLA-DR101 allele specific or a shared one. Furthermore, tyrosine substitution at position beta81 does not affect either peptide binding or HA(306-318) clone-specific T-cell proliferation. On the contrary, the alanine substitution at position HLA-DR101 beta81 abrogated both peptide binding and T-cell proliferation. These results suggest that the histidine 81 on the DRbeta chain plays an important role in the HLA-DR peptide binding, more likely by polar interactions of the amino acid side chain ring with the peptide.
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PMID:Influence of histidine beta81 of HLA-DR101 on peptide binding and presentation to T-cell receptor. 1203 21

In Caenorhabditis elegans, Ras/ERK and Wnt/beta-catenin signaling pathways cooperate to induce P12 and vulval cell fates in a Hox-dependent manner. Here we describe eor-1 and eor-2, two new positively acting nuclear components of the Ras and Wnt pathways. eor-1 and eor-2 act downstream or in parallel to ERK and function redundantly with the Mediator complex gene sur-2 and the functionally related gene lin-25, such that removal of both eor-1/eor-2 and sur-2/lin-25 mimics the removal of a main Ras pathway component. Furthermore, the eor-1 and eor-2 mutant backgrounds reveal an essential role for the Elk1-related gene lin-1. eor-1 and eor-2 also act downstream or in parallel to pry-1 Axin and therefore act at the convergence of the Ras and Wnt pathways. eor-1 encodes the ortholog of human PLZF, a BTB/zinc-finger transcription factor that is fused to RARalpha in acute promyelocytic leukemia. eor-2 encodes a novel protein. EOR-1/PLZF and EOR-2 appear to function closely together and cooperate with Hox genes to promote the expression of Ras- and Wnt-responsive genes. Further studies of eor-1 and eor-2 may provide insight into the roles of PLZF in normal development and leukemogenesis.
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PMID:C. elegans EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component. 1213 May 41

Early growth response gene 1 (Egr1) codes for a transcriptional regulator that contains a zinc-finger DNA binding domain. Egr1 expression is induced by a variety of extracellular stimuli including TCR-ligand interactions. Its pattern of expression in the thymus and dependence on ERK activation have led to speculation that it has a role in T cell development, but the exact nature of this role has been undefined. To more clearly define the role of Egr1 in thymocyte development, we have analyzed thymocytes from Egr1-deficient mice. We find that thymuses from Egr1-deficient mice contain twice as many cells as age-matched controls, and the increase in thymocyte number is apparent at the early CD4/CD8 double negative stage of development. Subsequent maturation to the CD4/CD8 double positive stage and survival of the double positive cells both appear normal in Egr1-deficient animals. We also find that Egr1 promotes positive selection of both CD4 and CD8 single positive cells without playing a major role in negative selection. Egr1 influences positive selection by enhancing expression of the helix-loop-helix inhibitor Id3 and the anti-apoptosis molecule bcl-2. Thus, Egr1 translates developmental signals into appropriate changes in gene expression at multiple stages of thymocyte development.
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PMID:Thymocyte development in early growth response gene 1-deficient mice. 1216 91

Zinc is an important trace element in the body and is involved in both the proliferation and growth arrest of many kinds of cells including colorectal epithelial cells. The aim of this study was to identify the molecular mechanism of the growth regulation of colorectal cancer cells by extracellular zinc. Zinc-stimulated activation of the mitogen-activated protein kinase (MAPK) cascade was measured by immunoblotting and Elk-1 dependent trans-reporter gene expression, and zinc-stimulated p21(Cip/WAF1) activation by immunoblotting, Northern blot analysis and immunochemistry. Cell proliferation was measured by thymidine and bromodeoxyuridine (BrdU) incorporation. By treating colorectal cancer cells with 100 microM ZnCl2, MAPKs were activated in two different phases, the initial weak activation occurred within 5 min and this was followed by a stronger and more prolonged activation. Zinc concomitantly activated Raf-1-MEK-MAPK kinases, and induced Elk-1 dependent trans-reporter gene expression. Prolonged activation of MAPKs by 100 microM of ZnCl2 resulted in the induction and nuclear localization of p21(Cip/WAF1) and was related to the inhibition of both thymidine and BrdU incorporations. These results not only suggest the presence of a mechanism for p21(Cip/WAF1) dependent negative regulation of colorectal cancer cell growth by zinc but also suggest potential usage of zinc to control the growth of colorectal cancer cells.
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PMID:Extracellular zinc stimulates ERK-dependent activation of p21(Cip/WAF1) and inhibits proliferation of colorectal cancer cells. 1238 73

Cyclin D1 is essential for Neu-induced cell growth and is induced by growth factors through Ras-dependent and Ras-independent signaling pathways (1). Because flavopiridol, a novel flavanoid cyclin-cyclin-dependent kinase inhibitor, may function through Ras-dependent and/or -independent pathways, we hypothesized that treatment of breast cancer cells with inhibitors of Neu signaling and flavopiridol might synergize to inhibit proliferation. Human breast cancer cell lines, which express high levels of endogenous Neu receptor, were treated with the anti-Neu antibody, trastuzumab, together with flavopiridol and subject to MTT assay. Cell lines were assayed for alterations in cell cycle by fluorescence-activated cell sorter and signaling proteins by Western blot. Flavopiridol and trastuzumab synergistically inhibited DNA synthesis, cellular proliferation, and contact-dependent growth. Cytotoxic synergy was observed independent of the sequence of addition of the two drugs to cultured cells. In SKBR3 cells, a combination of trastuzumab and flavopiridol inhibited the Ras-MAPK-Akt pathway, decreased cyclin D1 abundance, and kinase activity to a greater extent than either drug alone. Compared with single-agent treatment, combination treatment selectively inhibited Akt and pRB phosphorylation. Cytotoxic synergy was observed with flavopiridol plus LY294002 (selective phosphatidylinositol 3-kinase inhibitor) but not with PD98059 (selective mitogen-activated protein kinase kinase 1 inhibitor) suggesting that Akt inhibition may be important in synergy. Zinc-induced overexpression of cyclin D1 in T-47D deltaMTcycD1 cells were more resistant to drug-induced cell death when compared with vector-transfected T-47D deltaMT cells. Cyclin D1 overexpression reverses drug treatment induced cell cycle arrest in SKBR3 cells. Flavopiridol and trastuzumab yield cytotoxic synergy in human breast cancer cells overexpressing Neu. Cyclin D1 overexpression results in combination drug resistance. In addition, inhibition of Akt may prove to be a useful therapeutic strategy in combination with flavopiridol.
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PMID:Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways. 1247 66

The single known epidermal growth factor-like growth factor and single epidermal growth factor receptor in Caenorhabditis elegans mediate two types of processes, each via a distinct signal transduction pathway. Several instances of cell fate specification during organogenesis require the RAS-MAP kinase pathway, as well as multiple nuclear factors. By contrast, appropriate myoepithelial contractions during ovulation involve IP3-mediated signal transduction. Positive modulators of the RAS pathway include KSR, SUR-8, phosphatase PP2A, and a zinc cation diffusion facilitator. Negative regulators of the RAS pathway include homologs of CBL, GAP-1, ACK, and MAP kinase phosphatase, while negative regulators of the IP3 pathway are enzymes that modify IP3. In addition to its stimulation of RAS activity, the GRB2 homolog SEM-5 acts negatively on both signaling pathways, as does the Ack-related kinase ARK-1.
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PMID:The epidermal growth factor system in Caenorhabditis elegans. 1264 74

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism, which leads to the generation of carbon monoxide (CO), biliverdin, and free iron. One of 3 mammalian HO isoforms, HO-1, is a stress-responsive protein and known to modulate such cellular functions as cytokine production, cell proliferation, and apoptosis to protect organs and tissues from acute injury. Although nitric oxide (NO)-mediated cytoprotective effects against cytotoxicity induced by glucose deprivation have been well recognized, the underlying mechanisms remain to be elucidated. Thus, we investigate the involvement of HO-1 in the cytoprotective effects of NO. Deprivation of glucose markedly reduced the viability of BNL CL.2 cells and primary rat hepatocytes. Pretreatment with NO donor, sodium nitroprusside (SNP), protected hepatocytes from glucose deprivation-induced cytotoxicity; zinc protoporphyrin (ZnPP) IX, an inhibitor of HO, was found to block the SNP-induced cytoprotection. SNP increased the induction of HO-1 protein as well as its activity in hepatocytes. A cytoprotective effect comparable to SNP was observed when the cells were transfected with HO-1 gene or preincubated with another HO-1 inducer, hemin. Additional experiments revealed the involvement of CO in the cytoprotective effect of SNP/HO-1 in BNL CL.2 cells. CO mediated cytoprotective effect through suppression of ERK MAPK activation. In conclusion, our results show that SNP protects hepatocytes from glucose deprivation-induced cytotoxicity through up-regulation of HO-1. Thus, HO-1 might be an important cellular target of NO donor with clinical implications for the prevention of acute liver injury in several pathological conditions.
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PMID:Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of heme oxygenase-1. 1266 64

The von Hippel-Lindau tumor suppressor (pVHL) is a component of an E3 ubiquitin ligase and targets hypoxia-inducible factor-1alpha (HIF-1alpha) for ubiquitylation and degradation under normoxic conditions. pVHL also directly inhibits HIF-1alpha transactivation by recruiting histone deacetylases. Here, we report a novel pVHL-interacting protein that functions as a negative regulator of HIF-1alpha transactivation. This protein, generated from the ZnF197 locus by alternative splicing, contains a Kruppel-associated box (KRAB)-A domain and a SCAN domain, but lacks the 22 C2H2-type zinc fingers present in ZnF197. Therefore, we named this protein pVHL-associated KRAB-A domain-containing protein (VHLaK). We demonstrate that the KRAB-A domain in VHLaK mediates pVHL binding and functions as a transcriptional repression module. The SCAN domain mediates VHLaK homo-oligomerization, which enhances VHLaK repressive activity. pVHL can recruit VHLaK to repress HIF-1alpha transcriptional activity and HIF-1alpha-induced VEGF expression. Finally, we demonstrate that pVHL, VHLaK and KAP1/TIF-1beta can be recruited into a single complex, indicating that KAP1/TIF-1beta may participate in pVHL-mediated transcriptional repression of HIF-1alpha. Our findings provide a novel mechanism for the modulation of HIF-1alpha transactivation by pVHL.
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PMID:The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity. 1268 18

In order to determine the interrelationship between dietary iron and zinc levels, the effects of dietary iron levels (2, 10, 20, and 40 microg/g) on changes in iron and zinc status and zinc enzyme activities (aminolevulinic acid dehydratase ALA-D EC 4.2.1.24 and alkaline phosphatase ALK-P EC 3.1.3.1) in male Wistar rats were investigated using adequate and marginally deficient zinc diets (25 and 5 microg/g). When rats were fed 5 microg Zn/g diets, body weight gain and food intake remained unchanged at a Fe diet intake of 20 microg/g or greater. Similar tendencies were obtained for hemoglobin, hematocrit, plasma iron, and transferrin saturation. In contrast, liver, spleen, and femur iron concentrations increased gradually with increased iron intake. Feeding diets containing 25 microg Zn/g did not alter these parameters. The percentages of apparent iron absorption in both dietary zinc groups tended to increase with decreasing dietary iron and attained maximum levels at an Fe intake of 10 microg/g. However, In the case of rats fed Fe at concentrations of 2 microg/g Iron absorption decreased. Regardless of the dietary zinc level, rats fed diets with an Fe concentration of 2 microg/g had decreased zinc absorption and plasma ALK-P activity. However, ALA-D activity was not influenced by dietary iron.
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PMID:The effect of dietary iron levels on changes in iron status and zinc-dependent enzyme activities in rats fed two levels of dietary zinc. 1277 12

A highly specific t(8;13)(p11;q12) translocation has been consistently identified in bone marrow cells from patients with an atypical myeloproliferative disease that is associated with peripheral blood eosinophila and T- or B-cell leukemias. In all patients analysed to date, the translocation event results in a chimeric gene in which the atypical zinc-finger domain of ZNF198 is fused to the N-terminal end of the catalytic domain of the FGFR1 receptor tyrosine kinase. To understand more about the consequences of this rearrangement we have investigated the normal function of the ZNF198 gene. Using yeast two-hybrid analysis we identified HHR6 as a protein binding partner and confirmed this using immunoprecipitation studies. The ZNF198/FGFR1 fusion protein also binds to HHR6. We demonstrate here that the human RAD18 is also present in the ZNF198/HHR6 protein complex, although it does not coimmunoprecipitate with the fusion kinase. Cells expressing the fusion kinase gene show a marked increased sensitivity to UVB irradiation, suggesting that it acts in a dominant-negative way to affect DNA repair. These observations support the idea that ZNF198, through its interaction with HHR6 and RAD18, may be involved in the DNA repair process.
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PMID:ZNF198 protein, involved in rearrangement in myeloproliferative disease, forms complexes with the DNA repair-associated HHR6A/6B and RAD18 proteins. 1277 93


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