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)

In 1970, Field and Caspary reported that lymphocytes from patients with malignant disease can be stimulated by a basic protein from human brain (human encephalitogenic protein--HEP). The stimulated lymphocytes are capable of releasing the macrophage-slowing factor, which reduces the electrophoretic mobility of guinea-pig macrophages. In general, this effect was not found with lymphocytes from patients without malignant disease. This paper deals with the application of the MEM test using HEP and HCG as antigen in the diagnosis of trophoblastic disease. We have found cellular sensitization against HCG in all patients with gestational trophoblastic tumours and against HEP in patients with hydatidiform moles of the group II or III as well as choriocarcinoma. Patients with malignant tumours of different localization showed a cellular sensitization against HEP, but only some against HCG. In pregnant women no cellular sensitization against HEP as well as HCG was detected. The results of the MEM test using HEP as antigen in patients with gestational trophoblastic tumours are compared with the clinical findings and the histological diagnosis. By means of this combination a more exact evaluation of the biological activity of the trophoblastic disease was obtained.
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PMID:The macrophage electrophoretic mobility (MEM) test for the diagnosis of hydatidiform mole and choriocarcinoma. Preliminary report. 7 73

Endometrial epithelial cell expression of CSF-1 and FMS antigens was studied in vivo and in vitro in 24 human endometrial carcinoma and 11 benign endometrial biopsy specimens. Twenty-one of 24 adenocarcinomas and 4 of 11 benign lesions stained positively (by IHC) with rabbit anti-human CSF-1 antibodies, while all 24 carcinomas and 3 out of 11 benign lesions (all secretory endometrial specimens) showed significant IHC staining (1+ or greater) of epithelial elements and tissue macrophages with a mouse anti-FMS (CSF-1 receptor) monoclonal antibody. CSF-1 levels in plasma from endometrial carcinoma patients (85 samples, 24 patients) were also found to be markedly elevated (some greater than 100 ng/ml) in patients with active or recurrent disease. In vitro, several endometrial carcinoma cell lines were shown to express FMS complementary transcripts and FMS antigen which were very similar if not identical to those expressed in choriocarcinoma cell line positive controls. Autocrine and paracrine effects mediated by tumor or stromally produced CSF-1 and a tumor epithelial cell CSF-1 receptor may therefore contribute to the biological behavior of endometrial neoplasms in vivo and in vitro.
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PMID:The cytokine CSF-1 (M-CSF) expressed by endometrial carcinomas in vivo and in vitro, may also be a circulating tumor marker of neoplastic disease activity in endometrial carcinoma patients. 214 48

In order to facilitate cloning of genes for cell surface molecules, we cotransfected LTK- mouse fibroblasts with thymidine kinase (TK) genes and total human or mouse DNA. TK+ cells, selected by growth in HAT medium, were stained with fluorochrome conjugated monoclonal antibodies or other fluorescent ligands which bind to one or another membrane differentiation antigen or receptor. We isolated fluorescent transfectants expressing these molecules using a fluorescence activated cell sorter (FACS). For some antigens, spontaneous gene amplification occurred. By repeated cycles of FACS sorting and regrowth we obtained high expressing clones. We then isolated cDNA and genomic clones using selected cDNA probes to screen phage with cDNA inserts. DNA from virtually any tissue source transfected equally well for the various molecules except for DNA from a trophoblast derived choriocarcinoma cell line which did not transfect for Leu-2.
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PMID:Transfection and cloning of genes for membrane antigens using the FACS. 644 77

An in vitro model of placental infection by human immunodeficiency virus type 1 (HIV-1) was established using human choriocarcinoma-derived trophoblast lines exposed to free HIV-1 or HIV-1-infected lymphocytic and monocytic cells. Virus infectivity was evaluated by measuring both the levels of p24 HIV-1 antigen and reverse transcriptase activity either from indicator MT-4 lymphocytes after co-cultivation with infected trophoblasts or directly from trophoblast cultures. None of the tested trophoblast lines were permissive, in a detectable manner, to infection by cell-free virus. Furthermore, there were no signs of infection when trophoblasts were exposed to HIV-1-carrying ACH-2 and U1 cells with impaired adhesion capacity. However, the exposure to MOLT-4/IIIB lymphocytes or U937/YH5 monocytes that adhere to substrate cells resulted invariably in productive infection. The ultrastructure of the trophoblasts suggests endocytosis of HIV-1. It appears that the infection of the host cell results from the escape of virions from degradation in lysosomes. Alternatively, HIV-1 may enter by budding directly from the lymphocyte surface into the cytoplasm of trophoblasts. These results confirm previous studies and suggest that CD4-negative placental trophoblasts--the only foetal cells in direct contact with maternal blood--can be susceptible to HIV-1 infection.
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PMID:Human immunodeficiency virus type 1 infection of choriocarcinoma-derived trophoblasts. 810 49

Early placental development occurs in an environment of relative hypoxia. Hypoxia promotes angiogenesis and up-regulates vascular endothelial growth factor (VEGF) expression while it down-regulates placenta growth factor (PIGF) that possess 53% homology with VEGF. Morphological studies show poor placental vascular development and an increase in the mitotic index of cytotrophoblasts in intrauterine growth restriction (IUGR). We hypothesized that the reported relatively high oxygen level in the intervillous space in contact with IUGR placental villi will limit angiogenesis by changes in VEGF and PIGF expression and function. Western immunoblot analysis demonstrates a diametric expression of PIGF and VEGF proteins throughout pregnancy with PIGF levels increasing and VEGF levels decreasing, consistent with placental oxygenation. In IUGR placentae, the ratio of PIGF/GAPDH mRNA was increased by 2.3-fold (p < 0.03) and PIGF protein levels were also increased, (p < 0.05) as compared with gestationally-matched normal placentae. PIGF mRNA and protein were localized to the trophoblast bilayer and villous mesenchyme of the human placenta throughout gestation. In vitro studies demonstrated that increasing oxygen tension (hyperoxia) up-regulated PIGF protein in term placental villous explants, whereas hypoxic culture of a term trophoblast choriocarcinoma cell line (BeWo) down-regulated PIGF mRNA and protein and VEGFR-1 (Flt-1) autophosphorylation. The addition of PIGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line stimulated DNA synthesis while PIGF-2 had little effect. VEGF and PIGF exert their biological actions by means of a common receptor VEGFR-1. In the first trimester trophoblast cells, PIGF-1 increased the association of phosphorylated extracellular signal-related kinase (ERK) with VEGFR-1 immunoprecipitates while both PIGF-1 and PIGF-2 also potentiated endogenous VEGF mediated association of phosphorylated extracellular related kinase (ERK) with VEGFR-2 (KDR). More importantly, the addition of PIGF-1 had little effect while PIGF-2 inhibited cell growth in cultured endothelial cells derived from human umbilical vein. Nitric oxide (NO) is reported to promote angiogenesis and PIGF-2 inhibited the basal release of NO from the first trimester trophoblast. The tissue expression and functional studies support the hypothesis of "placental hyperoxia" in early-onset IUGR because hypoxia down-regulates trophoblast PIGF levels, PIGF expression is increased in IUGR, and PIGF-2 inhibits endothelial cell growth. Taken together, these changes provide a cellular explanation for the observed poor angiogenesis in the pathogenesis of IUGR and show that the two PIGF isoforms may modulate trophoblast and endothelial cell function differently, possibly through potentiation of VEGF mediated activation of VEGF-2.
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PMID:Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: molecular evidence for "placental hyperoxia" in intrauterine growth restriction. 1006 4

Although the 100-kDa Ras GTPase-activating protein (p100 RasGAP) has been reported to exist specifically in human placental trophoblasts, the molecular mechanisms responsible for regulating its expression remain unclear. In this study we used okadaic acid, an inhibitor of serine/threonine phosphatase 1 and 2 A, as a probe to explore the signaling pathway regulating the expression of p100 RasGAP in JEG-3 human placental choriocarcinoma cells. Treatment of JEG-3 cells with okadaic acid provoked dose- and time-dependent stimulation of p100 RasGAP expression without marked modification of expression of p120 RasGAP, another isoform of RasGAP. Co-treatment of cells with okadaic acid and the protein kinase C activator, phorbol 12-myristate 13-acetate, exerted an additive effect on p100 RasGAP induction. Moreover, the response of the p100 RasGAP de novo synthesis to okadaic acid was not affected by the selective inhibitor of protein kinase C, GF 109203X. Thus this study identified a novel signaling pathway regulating p100 RasGAP expression, which is independent of protein kinase C. In addition, okadaic acid treatment resulted in the activation of ERK2 (p42 MAP kinase) and the induction of both c-Jun and c-Fos proteins without activating JNK (c-Jun NH2-terminal kinase). Significantly, blockade of c-Jun expression with antisense c-jun oligonucleotides suppressed p100 RasGAP expression. Taken together, it is concluded that okadaic acid induces the expression of p100 RasGAP protein in JEG-3 cells preceded by activation of ERK and AP-1 cascade, and that this okadaic acid-induced p100 RasGAP expression is independent of protein kinase C-mediated pathway but requires c-Jun/AP-1 function.
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PMID:A protein kinase C-independent pathway leading to c-Jun-dependent expression of 100-kDa Ras GTPase-activating protein in JEG-3 human choriocarcinoma cells. 1071 88

Nonseminomatous components within testicular germ cell tumors affect patient prognosis to varying degrees. These components are well known to mimic early embryonic totipotential tissues. Prompted by the recent observation that fibroblast growth factor (FGF) 8, FGF4, and FGF receptor (FGFR) 1 are required for the growth of early postimplantational embryonic tissues, we investigated the expressions of FGF8, FGF4, and FGFRI in surgically resected specimens of primary testicular germ cell tumors using an immunohistochemical method. All cases of embryonal carcinoma (14 cases), yolk sac tumor (3 cases), and choriocarcinoma (3 cases) showed positive immunostaining for FGF8, FGF4, and FGFR1. In contrast, out of 13 cases of seminoma, immunostaining was negative for FGF8, FGF4, and FGFR1 in 8 cases (61.5%), 6 cases (46.1%), and 7 cases (53.8%), respectively. In 7 cases of mature and immature teratoma, most areas showed negative immunostaining. In addition, the Ki-67 labeling index showed extremely high mitogenic activity in embryonal carcinoma, yolk sac tumor, and choriocarcinoma, which are precisely the carcinomas with the highest expressions of FGF8, FGF4, and FGFR1. It is in keeping with the immunohistochemical result that murine teratocarcinoma P19 cells were shown to express FGF8, FGF4, and FGFRI only under undifferentiated growth conditions. Taken together, these findings confirm the involvement of FGF8, FGF4, and FGFR1 in highly proliferative conditions of nonseminomatous germ cell tumors.
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PMID:Predominant expression of fibroblast growth factor (FGF) 8, FGF4, and FGF receptor 1 in nonseminomatous and highly proliferative components of testicular germ cell tumors. 1176 80

Pituitary tumorigenesis is a poorly understood process involving dysregulation of the cell cycle, proliferation, and angiogenesis. The novel securin pituitary tumor transforming gene (PTTG) disrupts cell division and stimulates fibroblast growth factor (FGF)-2-mediated angiogenesis. We investigated expression of the angiogenic vascular endothelial growth factor (VEGF) and its receptor KDR/Flk-1 in 103 human pituitary tumors, and we assessed functional relationships between these genes in vitro. Nonfunctioning tumors (n = 81) demonstrated markedly raised VEGF mRNA (3.2-fold, P < 0.05) and protein concentrations, compared with normal pituitaries (n = 10). KDR was also highly induced in nonfunctioning tumors (14-fold, P < 0.001, n = 78) as well as in the whole cohort of pituitary tumors, compared with normal pituitary samples (14-fold, P < 0.0001, n = 100). In vitro, PTTG induced VEGF, but not KDR, expression in fetal neuronal NT2 cells (2.7-fold, P < 0.001, n = 8), MCF-7 breast carcinoma cells (1.9-fold, P = 0.03, n = 10), and choriocarcinoma JEG-3 cells (P = 0.0002, n = 8). A mutated PTTG construct that cannot be phosphorylated showed identical VEGF up-regulation (2.9-fold, P < 0.001, n = 8) in NT2 cells, compared with wild-type PTTG, but a further mutated construct with abrogation of the key protein:protein interaction domain of PTTG resulted in a significant reduction in VEGF stimulation, compared with wild-type (0.37-fold reduction, P < 0.001, n = 8). FGF-2 findings mirrored those of VEGF, although antibody depletion of secreted FGF-2 in the cell medium failed to influence VEGF up-regulation by PTTG. Overall, our findings implicate altered VEGF and KDR signaling in pituitary tumorigenesis, and we propose that PTTG stimulation of FGF-2 and VEGF expression in the presence of up-regulated growth factor receptors may account for angiogenic growth and progression of human pituitary tumors.
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PMID:Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors. 1221 78

Mammalian pregnancy bears many similarities to transplantation, since the fetus is semi-allogenic to mother. Thus, mammals have developed numerous mechanisms to protect the developing fetus from maternal immunologic recognition and attack. We have previously shown that human choriocarcinoma JAR cells, which resemble first trimester trophoblasts, regulate several important mRNAs in activated peripheral blood mononuclear cells (PBMC). We now provide further evidence that communication between maternal and fetal tissues is bi-directional, and that activation of PBMC leads to activation of specific signaling pathways in JAR cells. Activated PBMC were co-cultured with JAR cells for specific time intervals, after which JAR cells were lysed and subjected to western blotting for activated forms of the JNK, Erk 1-2, and p38 mitogen-activated protein kinases (MAPK). Phosphorylation of Erk 1-2, but not JNK or p38, was induced in co-cultures of PBMC and JAR cells. These results were also obtained when JAR cells were incubated with conditioned medium from activated, but not resting, PBMC. Results were confirmed using specific MAPK reporter constructs, using luciferase activity as a measure of Elk-1 phosphorylation. Erk 1-2 phosphorylation was not required for JAR cells to inhibit IL-2 production in activated PBMC. Addition of the specific MAPK inhibitor UO126 to JAR cells prior to the addition of activated PBMC to the cultures did not abolish the capacity of JAR cells to inhibit IL-2 mRNA expression in PBMC. We conclude that there is likely to be significant bi-directional signaling between leukocytes and trophoblasts at the maternal-fetal interface. We propose the existence of a delicate maternal-fetal immunologic homeostasis based on these experimental results.
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PMID:Activated peripheral blood mononuclear cells induce p44/42 mitogen-activated protein kinase phosphorylation in trophoblast-like JAR cells. 1463 39

During the first trimester of pregnancy, well-differentiated primary cells of the placenta known as trophoblast cells grow in an invasive and destructive fashion similar to malignancies, but limited in space and time. The comparison of trophoblast cells with their malignant counterpart, human choriocarcinoma cells, offers an attractive model to understand the origin or development of malignant growth. Several cytokines and growth factors are known to influence trophoblast migration (e.g. EGF, IGF-2, HGF), proliferation (e.g. leptin, HGF, GM-CSF) and/or invasion (e.g. leukemia inhibitory factor, LIF), each factor utilizing at least one pathway for intracellular signaling in the trophoblast. Two pathways that are crossed especially often mediate the signals of these factors and are simultaneously well established in terms of tumor invasion: the Janus kinase-signal transducers and activators of transcription (Jak-Stat) and receptor-associated tyrosine kinase-mitogen-activated protein kinase (RTK-MAPK) pathways. These two pathways are detrimental for reproduction in general, and in part for placenta development, as a series of knockout experiments demonstrate. Aspects of each pathway are also implicated to be involved in trophoblast invasion, e.g. STAT3 is constitutively activated in invasive first trimester trophoblast cells, and activated ERK is detectable in intermediate trophoblast cells, an invasive phenotype. Interaction at several intersection points between the pathways has been described in several cell systems so that the same would seem to be possible in trophoblast cells. In this review, some of the possible areas of interaction are alluded to.
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PMID:Signal transduction in trophoblast invasion. 1612 46


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