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)

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

The aim of the present study was to investigate which growth factors, receptors, and growth inhibiting factors are expressed in invasive breast cancer. Five (angiogenic) growth factors and their receptors: platelet-derived growth factor A chain (PDGF-AA) and PDGF receptor alpha (PDGF alpha R), PDGF-BB and PDGF beta receptor, transforming growth factor alpha (TGF alpha) and its receptor epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) and its receptors vascular endothelial growth factor receptor I (Flt-1) and vascular endothelial growth factor receptor II (Flk-1/KDR); two growth inhibiting factors: transforming growth factor-beta-1 (TGF beta 1) and (TGF beta 2) and their receptor couple transforming growth factor beta receptor I (TGF beta R-I) and TGF beta R-II; and basic fibroblast growth factor (bFGF) were stained by standard immunohistochemistry on frozen sections in 45 cases of invasive carcinoma of the breast. Staining was scored as negative or positive in tumour epithelium, stroma, and blood vessels. TGF beta 1 and TGF beta 2 were expressed in the tumour cells in 67 per cent and 76 per cent of cases, respectively, whereas PDG beta R and TGF beta R-II were expressed in 0 per cent and 2 per cent, respectively. The other factors showed variable expression in tumour cells. All factors were expressed in the stroma in most cases, except Flt-1, Flk-1/KDR, TGF beta 2, and TGF beta R-II, which showed variable expression, and EGFR, which showed no expression. The endothelium was in most cases positive for bFGF, PDGF-AA, PDGF-BB, VEGF, PDGF alpha R, PDGF beta R, and TGF beta 1 but TGF beta/ was negative in most cases and TGF alpha, EGFR, Flt-1, Flk-1/KDR, TGF beta R-I, and TGF beta R-II were variably expressed. The most interesting possible auto/paracrine loops, as demonstrated on serial sections and by fluorescence double staining, were the TGF alpha/EGFR, TGF beta s/TGF beta R, VEGF/Flt-1, and the VEGF/Flk-1 combinations. In conclusion, growth factors, growth inhibiting factors, and their receptors are frequently expressed in invasive breast cancer. Indications for some possible auto- and paracrine loops have been found, which should encourage further study on the role of these factors in breast cancer proliferation and angiogenesis.
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PMID:Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: An inventory in search of autocrine and paracrine loops. 958 26

Growth factors may play an important role in tumour growth and angiogenesis by their influence on tumour cell proliferation or their effect on neovascularization. The aim of the present study was to determine which of the growth factors, growth-inhibiting factors, and their receptors investigated in a previous study are correlated with proliferation and angiogenesis in invasive breast cancer, with emphasis on the impact of possible autocrine and paracrine loops. Five growth factors and their receptors: platelet-derived growth factor A chain (PDGF-AA) and PDGF alpha receptor (PDGF alpha R), PDGF-BB and PDGF beta receptor (PDGF beta R), transforming growth factor alpha (TGF alpha) and its receptor epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1/KDR; two growth-inhibiting factors: transforming growth factor beta-1 (TGF beta 1) and TGF beta 2 and their receptor couple TGF beta R-I and TGF beta R-II; and basic fibroblast growth factor (bFGF) were stained in 45 cases of invasive breast cancer by standard immunohistochemistry on frozen sections. Staining in tumour cells, stromal cells, and endothelial cells was scored as negative or positive. Proliferation was determined by assessment of the mitotic activity index (MAI) and the degree of angiogenesis was measure by counting the number of microvessels (microvessel density: MVD) in the most vascularized area of the tumour. bFGF and EGFR showed positive correlations with the MAI, while TGF beta 2 showed a negative correlation. Expression of bFGF, TGF alpha, TGF beta 2, and EGFR correlated positively with the MVD. Co-expression of the TGF alpha/EGFR growth factor/receptor combination showed a stronger correlation with the MAI and the MVD than EGFR or TGF alpha alone, and the TGF beta 2/TGF beta R-I/TGE beta R-II combination showed a positive correlation with the MVD. In conclusion, the expression of several growth factors, growth factor receptors and growth-inhibiting factors showed correlations with the rate of proliferation and the degree of angiogenesis in invasive breast cancer. Some growth factor/receptor combinations showed stronger correlations with proliferation and angiogenesis than the growth factor or receptor alone, pointing to the importance of possible auto- and paracrine loops for stimulation of proliferation and angiogenesis by growth factors and their receptors.
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PMID:Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer. II: Correlations with proliferation and angiogenesis. 958 27

Beta-1 integrins have essential functions in hemopoietic and immune systems by controlling phenomenons such as cell homing and cell activation. The function alpha 4 beta 1 and alpha 5 beta 1 integrins is regulated by divalent cations and, as demonstrated more recently, by mitogenic cytokines which activate them by "inside-out" mechanisms. Using the adhesive interaction of a cytokine-dependent human hemopoietic cell line to immobilized fibronectin, we have analyzed the requirements in divalent cations Mn2+, Mg2+ and Ca2+ for alpha 4 beta 1 and alpha 5 beta 1 activation by "inside-out" mechanisms triggered by cytokines such as granulocyte-macrophage colony stimulating factor or KIT ligand, or by external conformational constraints with the function-activating anti-beta 1 integrin monoclonal antibody 8A2. The intrinsic difference between these two modes of beta 1 integrin activation was revealed by their different requirements in divalent cations. We found that in the absence of any divalent cations, alpha 4 beta 1 and alpha 5 beta 1 were non-functional even after further stimulation by cytokines or 8A2. However, whilst either Ca2+, Mg2+ or Mn2+ were able to restore adhesive functions of alpha 4 beta 1 and alpha 5 beta 1 when activated by 8A2, only Mg2+ and Mn2+ were able to support activation of alpha 4 beta 1 and alpha 5 beta 1 by cytokines. Furthermore, high concentrations of Ca2+ exceeding 20 mM dramatically inhibited cell adhesion to fibronectin induced by Mn2+ and cytokines but not by 8A2. On the contrary, in the presence of both Ca2+ and Mg2+, Mn2+ had an additive effect on the activation of alpha 4 beta 1 and alpha 5 beta 1 by mitogenic cytokines. The presence of the absence of these divalent cations did not inhibit early tyrosine phosphorylation induced by the binding of KIT ligand to its tyrosine-kinase receptor KIT. Therefore, we propose that in hemopoietic cells, Ca2+, Mg2+ and Mn2+ may modulate in vivo alpha 4 beta 1 and alpha 5 beta 1 regulation by mitogenic cytokines, a phenomenon involved in the regulation of hemopoietic progenitor cell homing within the bone marrow.
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PMID:Dual control by divalent cations and mitogenic cytokines of alpha 4 beta 1 and alpha 5 beta 1 integrin avidity expressed by human hemopoietic cells. 978 83

Emerging lines of evidence suggest that in addition to growth factors, the process of colorectal tumorigenesis may also be driven by the upregulation of the inducible form of cyclooxygenase-2 (COX-2), an enzyme responsible for the conversion of arachidonic acid to PGEs. The present study was undertaken to investigate the expression and activation of the HER family members, and to explore the regulation of COX-2 expression by the HER2 pathway in human colorectal cancer cells. Here, we report that human colorectal cancer cell lines express abundant levels of HER2 and HER3 receptors, and are growth-stimulated by recombinant neu-differentiation factor-beta 1 (NDF). NDF-treatment of colorectal cancer cells was accompanied by increased tyrosine phosphorylation and heterodimerization of HER3 with HER2. In addition, we demonstrated that HER2 and HER3 receptors in colorectal cancer cells are constitutively phosphorylated on tyrosine residues and form heterodimeric complexes in the absence of exogenous NDF. Inhibition of HER2/HER3 signaling by an anti-HER3 mAb against the ligand binding site resulted in a decrease in the levels of constitutively activated HER2/ HER3 heterodimers, and the unexpected reduction of COX-2 expression. Activation of the HER2/HER3 pathway by NDF induced the activation of COX-2 promoter, expression of COX-2 mRNA, COX-2 protein and accumulation of prostaglandin E2 in the culture medium. Finally, we demonstrated that NDF promotes the ability of colorectal cancer cells to survive in an extracellular matrix milieu, such as Matrigel, and also to invade through a 8 microm porous membrane. These biological activities of NDF and its stimulation of cell proliferation are blocked by a specific inhibitor of COX-2. Taken together, our findings provide the first biochemical evidence of a possible role of the COX-2 pathway in the mitogenic action of NDF in colorectal cancer cells where it may be constitutively upregulated due to the autocrine/paracrine activation of HER2/ HER3 heterodimers.
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PMID:Regulation of cyclooxygenase-2 pathway by HER2 receptor. 992 87

A lectin was isolated from the mycelium of the stationary growing enthomopathogenic fungus Beauveria bassiana by extraction, chromatography on QAE-Sephadex A-25, salt precipitation, and hydrophobic chromatography on Phenyl-Sepharose 4B. The Beauveria bassiana lectin (BBL) is a 15 kDa glycoprotein rich in hydrophobic amino acids, without detectable amount of methionine. It contains 12.6% of carbohydrates including galactose and mannose. Isoelectric point was found at pH 7.1. The lectin is stable between pH 6 and 11, and at temperature under 50 degrees C. The activity of the lectin was not dependent on with Ca++, Mn++, Mg++ cations and was apparently not blood group ABO specific. The hemagglutination caused by the lectin was inhibited by alpha lactose (Gal beta 1-->4 Glc alpha), but not by beta lactose (Gal beta 1-->4 Glc beta). In direct ELISA the BBL preferentially reacted with some glycoproteins carrying O-linked sugar structure Gal beta 1-->3 GalNAc: strongly with human glycophorin A and weaker with mouse glycophorin, fetuin, IgA, ovine submaxillary mucin. On the other hand BBL did not react in direct ELISA with N-glycoproteins (alpha 1-acid glycoprotein, haptoglobin, fibronectin), however, N-glycoproteins could act as inhibitors of lectin-glycophorin A interaction. We observed also weak interaction with asialo-Tamm-Horsfall N-glycoprotein having unusual large, branched N-glycans with outer GalNAc beta 1-->4Gal sequence. Moreover, the interaction of BBL with highly sialylated preparations of glycoproteins was weaker than with asialo forms. Presented results indicate that BBL exhibits sugar binding specificity towards glycotope corresponding to Thomsen-Friedenreich antigen and its related sequences: Gal beta 1-->3 GalNAc > Neu Ac alpha 2-3 Gal beta 1-->3 (Neu Ac alpha 2-6) GalNAc > Gal beta 1-->4 Glc alpha.
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PMID:Lectin from Beauveria bassiana mycelium recognizes Thomsen-Friedenreich antigen and related structures. 1042 10

Cell-cell and cell-matrix interactions play important regulatory roles in lymphocyte homeostasis. Thrombospondin-1 (TSP1) is a matricellular protein that differentially promotes the adhesion of resting and activated T cells. In this work, we show that adhesion of Jurkat T cells on substrates coated with TSP1 or TSP1-derived peptides is mediated by beta 1 integrins, CD47, and heparan sulfate proteoglycans. Interactions with TSP1 or TSP1 peptides stimulated CD3-induced Ras activation and tyrosine phosphorylation of several T cell proteins. The signals from TSP1 and its derived peptides differentially synergized with activation of the TCR to induce phosphorylation of linker for activation of T cells (LAT) and extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38 kinases. The phosphorylation of ERK in the presence of full-length TSP1 was transient and dependent on a beta 1 integrin receptor. Interestingly, peptides derived from the type 1 repeats of TSP1 and a CD47-binding peptide from the carboxyl-terminal domain of TSP1 also stimulated mitogen-activated protein (MAP) kinase phosphorylation. Moreover, the TSP1 heparin-binding peptide synergized with Ab-ligated TCR to transduce signals to the nucleus, detected by activation of AP-1- and Elk-dependent transcription. This TSP1 peptide-dependent activation of AP-1 was inhibited by both heparin and the MAP/ERK kinase inhibitor PD98059, providing a functional link between adhesion molecule interaction and nuclear transactivation events via the MAP kinase pathways. These findings have implications for the role of extracellular TSP1 and TSP1 fragments in the regulation of T cell function during hemostasis, wound repair, and other inflammatory responses.
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PMID:Beta 1 integrin- and proteoglycan-mediated stimulation of T lymphoma cell adhesion and mitogen-activated protein kinase signaling by thrombospondin-1 and thrombospondin-1 peptides. 1049 Sep 55

Urokinase plasminogen activator receptor (uPAR) has been identified some 15 years ago and the anticipation was that its presence on the cell surface will provide a focus for anchoring uPA and possibly protect the enzyme from native inhibitors. The studies of the last decade have shown that uPA localized to the surface of cells by uPAR is indeed an important factor in the process of cancer cell invasion and metastasis. We developed a chick embryo model in which we showed that uPAR is crucial in invasion of stroma and in intravasation (breaching of the blood vessels walls). More recently and unexpectedly, uPAR--a protein anchored in the outer leaf-let of the plasma membrane, has been shown to initiate signal transduction events and affect cell migration. We have shown that uPAR co-associates with fibronectin binding integrin, alpha 5 beta 1, activates them and that this interaction leads to a greatly increased level of active ERK. When the association between uPAR and integrin or integrin and fibronectin are interrupted either by reduction of surface uPAR expression, or by other means, human carcinoma cells enter a state of protracted dormancy. We show that very high levels of active ERK are required to keep cancer cells proliferating in vivo.
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PMID:The role of plasminogen activator receptor in cancer invasion and dormancy. 1068 57

We have found using differential display of mRNA that the growth factor heregulin beta 1 (HRG), a combinatorial ligand for human epidermal growth factor receptors (HERs), induced expression of G3BP, the Ras GTPase-activating protein SH3 domain-binding protein, in breast cancer cells. G3BP is a downstream effector protein of Ras signaling with ATP-dependent RNase and helicase activities, which may link Ras signaling with RNA turnover and cell cycle progression. In human breast cancer cells, HRG induced G3BP mRNA and protein expression. Up-regulation of G3BP was found in MCF7 breast cancer cells overexpressing HER2. G3BP was also overexpressed in human breast tumors in parallel with HER2 overexpression and in an estrogen-independent manner, suggesting a role for G3BP in cancer progression. In addition, HRG stimulation of breast cancer cells promoted phosphorylation of G3BP and increased the association of G3BP with GTPase-activating protein, both of which are essential for G3BP activity. G3BP ATPase activity was also significantly increased by HRG treatment. Furthermore, HRG treatment resulted in G3BP translocation to the nucleus and colocalization with acetylated histone H3, a hallmark of active transcription sites. G3BP induction, phosphorylation, ATPase activity, and relocalization after HRG treatment could all be blocked by pretreatment with the anti-receptor HER2 monoclonal antibody Herceptin (trastuzumab), which may suggest additional applications for this therapeutic antibody. These findings demonstrate for the first time the receptor-dependent regulation of G3BP, a downstream effector of Ras signaling, by HRG, a growth factor with diverse functions in breast cancer cells.
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PMID:Heregulin induces expression, ATPase activity, and nuclear localization of G3BP, a Ras signaling component, in human breast tumors. 1188 85

TRs are transcription factors that regulate cell proliferation, differentiation, and apoptosis. They are cellular homologs of the transcriptionally inactive viral oncogene v-erbA. We tested the hypothesis that the functions of TRs could be impaired in cancer tissues as a result of aberrant expression and/or somatic mutations. As a model system, we selected human thyroid papillary cancer, in which the most common abnormalities, RET/papillary thyroid cancer rearrangements (fusion of RET kinase domain to the activating domains of other genes), were found in 40--45% of cases. We found that the mean expression levels of TR beta mRNA and TR alpha mRNA were significantly lower, whereas the protein levels of TR beta 1 and TR alpha 1 were higher in cancer tissues than in healthy thyroid. Sequencing of TR beta 1 and TR alpha 1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such TR beta 1 or TR alpha 1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant negative activity. These findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma.
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PMID:Functionally impaired TR mutants are present in thyroid papillary cancer. 1188 75


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