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)

A recent in vitro study has suggested that overexpression of ERBB2 may mediate breast tumour progression and metastasis by inhibiting the transcription of the E-cadherin (E-CD) gene. To test this hypothesis in human breast cancer in vivo, we studied the relationship between the expression of both molecules in 247 breast carcinomas immunohistochemically. Five ductal carcinomas in situ overexpressed ERBB2 and showed preserved E-CD expression. Forty-four of 226 infiltrating ductal carcinomas (19.47%) showed ERBB2 overexpression, and a statistically significant relationship was found between ERBB2 overexpression and high histological grade. E-CD expression was preserved in 111 cases (49.1%) and correlated with the histological grade. However, no significant relationship was found between ERBB2 and E-CD expression. None of the 16 infiltrating lobular carcinomas expressed ERBB2 or E-CD. These observations in different histological types of breast carcinoma strongly argue against a role for ERBB2 as a transcriptional regulator of E-CD expression in most human breast carcinomas in vivo.
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PMID:Relationship between ERBB2 and E-cadherin expression in human breast cancer. 749 94

Overexpression of the ERBB2 receptor in transfectants of a human mammary epithelial cell line (MTSV1-7) is associated with a reduced ability to undergo morphogenesis in vitro and with a decreased level of expression of the E-cadherin and alpha 2 integrin genes. The inhibition of expression of the adhesion molecules has been shown to be at the level of transcription by using nuclear run-on assays and by following transcription of a reporter gene fused to 5' sequences of the E-cadherin gene. To relate the effects on gene transcription to a functional ERBB2 protein, signaling from the receptor was inhibited by the antibody 4D5, which blocks phosphorylation of ERBB2 on tyrosine residues and association of the protein with the GRB2/Sem5 protein. After treatment with the antibody 4D5, the ERBB2 transfectants regain the ability to form three-dimensional structures in collagen gels and the rates of transcription of the genes encoding the E-cadherin and the alpha 2 integrin subunit are restored to the levels seen in MTSV1-7neo cells. These results demonstrate that the inhibition of morphogenesis and transcription of specific adhesion molecules in human mammary epithelial cells can be affected by signals generated by the ERBB2 receptor and suggest a role for ERBB2 overexpression in tumor progression and metastasis.
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PMID:Overexpression of ERBB2 in human mammary epithelial cells signals inhibition of transcription of the E-cadherin gene. 791 48

Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchymally derived glycoprotein with a strong scattering effect on epithelial cells. A receptor tyrosine kinase encoded by the met proto-oncogene has been identified as the cellular receptor for HGF/SF. Following stimulation with HGF/SF, cell scattering occurs concurrent with decreased cell-cell adhesion and disassembly of junctional components. In culture, junction formation is cell-cell contact dependent and can be regulated by modulating the Ca2+ concentrations of the growth media. Decreasing the Ca2+ concentrations below 50 microM causes rapid disassembly of junctions, whereas increasing the Ca2+ concentrations to 1.8 mM induces cell-cell contact and junction assembly. Although associated with decreased cell-cell adhesion and disassembly of the junctional complex, HGF/SF-induced scattering occurs under high extracellular Ca2+ concentrations. To gain insight into the mechanisms of HGF/SF-induced scattering of epithelial cells, we have studied the effect(s) of HGF/SF on junction assembly by examining the solubility, stability, phosphorylation, and subcellular localization of the major components of the adhering junctions, plakoglobin (Pg) and E-cadherin, in Madin-Darby canine kidney (MDCK) epithelial cells and in a MDCK cell line expressing an exogenous chimeric met receptor (CSF-MET) that scatters in response to colony-stimulating factor 1 (CSF-1). The results have shown that in HGF/SF-stimulated MDCK cells, adhering junctions were not assembled upon induction of cell-cell contact. Immunofluorescence analyses showed that larger amounts of Pg and E-cadherin were Triton X-100 extractable, and more significantly, these proteins were homogeneously distributed along the membrane and were not concentrated at the areas of cell-cell contact. Similar results were obtained for CSF-MET expressing MDCK cells in response to CSF-1. In contrast, none of the above effects were detected in MDCK cells expressing a mutant CSF-MET chimera containing a phenylalanine substitution at tyrosine 1356 in met, which fails to scatter in response to CSF-1. When compared with the unstimulated cells, the inhibition of cell adhesion promoted by HGF/SF correlated with an increased stability of the newly synthesized soluble E-cadherin and Pg and an altered phosphorylation pattern of E-cadherin, as determined by partial proteolytic peptide mapping.
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PMID:Inhibition of junction assembly in cultured epithelial cells by hepatocyte growth factor/scatter factor is concomitant with increased stability and altered phosphorylation of the soluble junctional molecules. 910 Oct 91

The purpose of this study was to determine whether the expression level of several metastasis-regulating genes correlates with the metastatic potential of human prostate cancer cells implanted into the prostate of nude mice. The steady-state mRNA expression levels for epidermal growth factor receptor (EGFR; growth), basic fibroblast growth factor (bFGF) and interleukin (IL)-8 (angiogenesis), 72-kd and 92-kd type IV collagenase (invasion), E-cadherin (adhesion), and multidrug resistance (mdr-1; drug resistance) were measured by Northern blot and colorimetric in situ hybridization techniques in human PC-3M cells and selected cell variants with different metastatic potentials. Highly metastatic cells growing in culture constitutively and uniformly expressed higher levels of bFGF, IL-8, type IV collagenase, and mdr-1 mRNA transcripts than parental PC-3M cells or low metastatic cells, which displayed a heterogeneous pattern of gene expression. Human prostate cancer cells implanted in nude mice at an ectopic site (subcutaneous) expressed lower levels of EGFR, mdr-1, bFGF, IL-8, and collagenase type IV than those implanted in an orthotopic site (prostate), indicating that the expression of these genes was dependent on the organ environment. Highly metastatic cells growing in the prostate expressed higher levels of EGFR, bFGF, type IV collagenase, and mdr-1 mRNA than low metastatic parental cells in the same site. These data demonstrate a direct correlation between the expression of several metastasis-related genes and the metastatic potential of human prostate cancer cells in nude mice and suggest that multiparametric in situ hybridization analyses can be used to identify the metastatic potential of individual patients' prostate cancers.
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PMID:Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. 913 84

Interactions between the ureteric bud (UB) and metanephric mesenchyme are crucial for tubulogenesis during kidney development. Two immortalized cell lines derived from the day 11.5 embryonic kidney, UB cells, which appear to be epithelial (cytokeratin-positive, E-cadherin-positive, and ZO-1-positive by immunostaining) and BSN cells, which are largely mesenchymal (vimentin-positive, but negative for cytokeratin, cell surface E-cadherin, and cell surface ZO-1), were used to establish an in vitro tubulogenesis system. BSN cells expressed hepatocyte growth factor (HGF) and transforming growth factor-beta1 mRNAs, and its conditioned medium (BSN-CM) contained factors capable of activating the epidermal growth factor (EGF) receptor (EGFR). When UB cells were cultured in an extracellular matrix gel in the presence of the embryonic kidney or BSN-CM, the UB cells underwent morphogenetic changes characteristic of early in vitro branching tubulogenesis. These changes were largely inhibited by a combination of neutralizing anti-HGF antibodies and the EGFR inhibitor tyrphostin AG1478, suggesting that EGFR ligands, together with HGF, account for much of this early morphogenetic activity. Nevertheless, there was a significant fraction of tubulogenic activity that could not be inhibited, suggesting the existence of other soluble factors. Whereas HGF, EGF, transforming growth factor alpha, basic fibroblast growth factor (bFGF), and insulin-like growth factor 1 (IGF-1), or a mixture of these growth factors, induced epithelial processes for up to 3 days, only IGF-1, possibly bFGF, and the mixture were able to sustain morphogenesis for longer periods, though not nearly to the same degree as BSN-CM. Moreover, only BSN-CM induced branching tubular structures with clear lumens, consistent with the existence of other soluble factors crucial for the formation and/or maintenance of branching tubular structures with lumens in vitro.
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PMID:An in vitro tubulogenesis system using cell lines derived from the embryonic kidney shows dependence on multiple soluble growth factors. 917 8

Totipotent murine ES cells have an enormous potential for the study of cell specification. Here we demonstrate that ES cells can differentiate to hemopoietic cells through the proximal lateral mesoderm, merely upon culturing in type IV collagen-coated dishes. Separation of the Flk1+ mesoderm from other cell lineages was critical for hemopoietic cell differentiation, whereas formation of the embryoid body was not. Since the two-dimensionally spreading cells can be monitored easily in real time, this culture system will greatly facilitate the study of the mechanisms involved in the cell specification to mesoderm, endothelial, and hemopoietic cells. In the culture of ES cells, however, lineages and stages of differentiating cells can only be defined by their own characteristics. We showed that a combination of monoclonal antibodies against E-cadherin, Flk1/KDR, PDGF receptor(alpha), VE-cadherin, CD45 and Ter119 was sufficient to define most intermediate stages during differentiation of ES cells to blood cells. Using this culture system and surface markers, we determined the following order for blood cell differentiation: ES cell (E-cadherin+Flk1-PDGFRalpha-), proximal lateral mesoderm (E-cadherin-Flk1+VE-cadherin-), progenitor with hemoangiogenic potential (Flk1+VE-cadherin+CD45-), hemopoietic progenitor (CD45+c-Kit+) and mature blood cells (c-Kit-CD45+ or Ter119+), though direct differentiation of blood cells from the Flk1+VE-cadherin- stage cannot be ruled out. Not only the VE-cadherin+CD45- population generated from ES cells but also those directly sorted from the yolk sac of 9.5 dpc embryos have a potential to give rise to hemopoietic cells. Progenitors with hemoangiogenic potential were identified in both the Flk1+VE-cadherin- and Flk1+VE-cadherin+ populations by the single cell deposition experiment. This line of evidence implicates Flk1+VE-cadherin+ cells as a diverging point of hemopoietic and endothelial cell lineages.
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PMID:Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. 952 12

Progress in dendritic cell research has been overwhelming in the past few years. This was made possible by the recent development of simple methods to generate large numbers of dendritic cells. These methods use as starting populations for culture either CD34+ progenitor cells from cord blood or bone marrow, or monocytes from peripheral blood. The latter approach is critically dependent on the combination of GM-CSF and interleukin 4. Such "priming cultures" yield populations of immature dendritic cells (CD83-/CD86 +/- /CD115+/antigen uptake high/antigen processing high/T cell sensitization low). In order to generate mature dendritic cells a subsequent "differentiation culture" has to be added whereby monocyte-conditioned medium appears to be the optimal stimulus for maturation. This results in terminally mature dendritic cells (CD83+/CD86++/CD115-/antigen uptake low/antigen processing low/T cell sensitization high). We investigated the expression of some molecules involved in maturation and migration on human monocyte-derived dendritic cells from blood in comparison with dermal dendritic cells and epidermal Langerhans cells. We present a method to highly enrich epidermal Langerhans cells. Survival of purified Langerhans cells in culture is dependent on the presence of GM-CSF and TNF-alpha. During maturation a substantial part of the Langerhans cells loses expression of the cutaneous lymphocyte antigen (CLA); mature dendritic cells from the dermis are completely devoid of CLA. Similarly, CLA as well as CD15s (Sialyl Lewis x) and CD31 (PECAM-1) that can be readily detected on immature monocyte-derived dendritic cells are down-regulated upon maturation. CD68 expression is very low in cutaneous dendritic cells; in monocyte-derived dendritic cells this molecule is abundantly present. Subsets of monocyte-derived dendritic cells express E-cadherin; CD87 (urokinase plasminogen activator receptor) is weakly expressed on both immature and mature monocyte-derived dendritic cells. Taken together, these data suggest that the phenotype of monocyte-derived dendritic cells (E-cadherin low to negative, CD68++) is not indicative for a cutaneous destiny. Furthermore, the downregulation upon maturation of molecules involved in migration through vessel walls (CD31, CLA, CD15s) indicates that the entry of mature dendritic cells into lymphatic vessels may not be as rigidly regulated by adhesion molecules as the process of extravasation from blood vessels.
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PMID:Expression of maturation-/migration-related molecules on human dendritic cells from blood and skin. 956 74

MCAM/MUC18 is a cell-surface glycoprotein of 113 kDa, originally identified as a melanoma antigen, whose expression is associated with tumor progression and the development of metastatic potential. We have previously shown that enforced expression of MCAM/MUC18 in primary cutaneous melanoma led to increased tumor growth and metastatic potential in nude mice. The mechanism for up-regulation of MCAM/MUC18 during melanoma progression is unknown. Here we show that up-regulation of MCAM/MUC18 expression in highly metastatic cells correlates with loss of expression of the transcription factor AP-2. The MCAM/MUC18 promoter contains four binding sites for AP-2, and electrophoretic mobility shift assay gels demonstrated that the AP-2 protein bound directly to the MCAM/MUC18 promoter. Transfection of AP-2 into highly metastatic A375SM melanoma cells (AP-2-negative and MCAM/MUC18-positive) inhibited MCAM/MUC18 promoter-driven chloramphenicol acetyltransferase reporter gene in a dose-dependent manner. MCAM/MUC18 mRNA and protein expression were down-regulated in AP-2-transfected but not in control cells. In addition, re-expression of AP-2 in A375SM cells inhibited their tumorigenicity and metastatic potential in nude mice. These results indicate that the expression of MCAM/MUC18 is regulated by AP-2 and that enforced AP-2 expression suppresses tumorigenicity and metastatic potential of human melanoma cells, possibly by down-regulating MCAM/MUC18 gene expression. Since AP-2 also regulates other genes that are involved in the progression of human melanoma such as c-KIT, E-cadherin, MMP-2, and p21(WAF-1), we propose that loss of AP-2 is a crucial event in the development of malignant melanoma.
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PMID:Loss of AP-2 results in up-regulation of MCAM/MUC18 and an increase in tumor growth and metastasis of human melanoma cells. 963 18

Embryonic stem cells can differentiate in vitro into hematopoietic cells through two intermediate stages; the first being FLK1(+) E-cadherin- proximal lateral mesoderm and the second being CD45(-) VE-cadherin+ endothelial cells. To further dissect the CD45(-) VE-cadherin+ cells, we have examined distribution of alpha4-integrin on this cell population, because alpha4-integrin is the molecule expressed on hematopoietic stem cells. During culture of FLK1(+) E-cadherin- cells, CD45(-) VE-cadherin+ alpha4-integrin- cells differentiate first, followed by alpha4-integrin+ cells appearing in both CD45(-) VE-cadherin+ and CD45(-) VE-cadherin- cell populations. In the CD45(-) VE-cadherin+ cell population, alpha4-integrin+ subset but not alpha4-integrin- subset had the potential to differentiate to hematopoietic lineage cells, whereas endothelial cell progenitors were present in both subsets. The CD45(-) VE-cadherin- alpha4-integrin+ cells also showed hematopoietic potential. Reverse transcription-polymerase chain reaction analyses showed that differential expression of the Gata2 and Myb genes correlated with the potential of the alpha4-integrin+ cells to give rise to hematopoietic cell differentiation. Hematopoietic CD45(-) VE-cadherin+ alpha4-integrin+ cells were also present in the yolk sac and embryonic body proper of 9.5 day postcoitum mouse embryos. Our results suggest that the expression of alpha4-integrin is a marker of the earliest precursor of hematopoietic cell lineage that was diverged from endothelial progenitors.
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PMID:Expression of alpha4-integrin defines the earliest precursor of hematopoietic cell lineage diverged from endothelial cells. 994 59

HER2 is a ligand-less member of the human epidermal growth factor receptor or ErbB family of tyrosine kinases. In normal biological systems, HER2 functions as a co-receptor for a multitude of epidermal growth factor-like ligands that bind and activate other HER family members. HER2 overexpression is observed in a number of human adenocarcinomas and results in constitutive HER2 activation. Specific targeting of these tumors can be accomplished with antibodies directed against the extracellular domain of the HER2 protein. One of these antibodies, 4D5, has been fully humanized and is termed trastuzumab (Herceptin; Genentech, San Francisco, CA). Treatment of HER2-overexpressing breast cancer cell lines with trastuzumab results in induction of p27KIP1 and the Rb-related protein, p130, which in turn significantly reduces the number of cells undergoing S-phase. A number of other phenotypic changes are observed in vitro as a consequence of trastuzumab binding to HER2-overexpressing cells. These phenotypic changes include downmodulation of the HER2 receptor, inhibition of tumor cell growth, reversed cytokine resistance, restored E-cadherin expression levels, and reduced vascular endothelial growth factor production. Interaction of trastuzumab with the human immune system via its human immunoglobulin G1 Fc domain may potentiate its antitumor activities. In vitro studies demonstrate that trastuzumab is very effective in mediating antibody-dependent cell-mediated cytotoxicity against HER2-overexpressing tumor targets. Trastuzumab treatment of mouse xenograft models results in marked suppression of tumor growth. When given in combination with standard cytotoxic chemotherapeutic agents, trastuzumab treatment generally results in statistically superior antitumor efficacy compared with either agent given alone. Taken together, these studies suggest that the mechanism of action of trastuzumab includes antagonizing the constitutive growth-signaling properties of the HER2 system, enlisting immune cells to attack and kill the tumor target, and augmenting chemotherapy-induced cytotoxicity.
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PMID:Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). 1048 95


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