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 putative hypophysiotropic factor pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates glycoprotein hormone alpha-subunit (alpha GSU) gene transcription and secretion in the clonal gonadotroph alpha T3-1 cell line. The specific signalling pathways regulating these actions of PACAP have not been clearly defined. We have examined the possibility that mitogen activated protein kinases (MAPKs) may play a role in mediating the effects of PACAP on alpha T3-1 gonadotrophs. Treatment of alpha T3-1 cells with PACAP (100 nM) or epidermal growth factor (EGF, 10 nM) for 5 min significantly stimulated extracellular signal-regulated kinase activity (ERK, a component of the MAPK pathway) as determined by an immunocomplex assay. Pre-treatment of alpha T3-1 cells with the specific MAPK kinase (MEK) inhibitor, U0126, blocked PACAP and EGF-induced activation of ERK. Transcriptional stimulation of a human alpha GSU-luciferase reporter construct by PACAP was unaffected by U0126 treatment. However, pre-treatment with U0126 significantly inhibited PACAP stimulation of [(3)H]-thymidine incorporation in alpha T3-1 cells. Thus our results suggest that PACAP stimulates ERK activation in alpha T3-1 cells, and that the functional effect of this ERK activation is increased DNA synthesis and cell proliferation rather then transcriptional activation of the alpha GSU gene.
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PMID:Stimulation of extracellular signal-regulated kinase by pituitary adenylate cyclase-activating polypeptide in alpha T3-1 gonadotrophs. 1173 23

Implantation is a complex spatio-temporal interaction between the genotypically different embryo and the mother. Success of this event requires the synchronization of development and effective biochemical communications from both sides. Chorionic gonadotropin (CG), which is a major embryonic signal in the primate, is a glycoprotein hormone synthesized and secreted by the trophoblast. Various isoforms exist in plasma, urine, and blastocyst culture medium, a result of posttranslational modifications. The exponential secretion of CG and its long circulatory half-life extends the life span of corpus luteum to maintain the supply of progesterone during the first 6-8 weeks of pregnancy. To study the direct effects of CG in the uterus, we used the baboon (Papio anubis) as a non-human primate model. In vivo stimulation with CG during the window of uterine receptivity results in further morphologic and biochemical modifications of the receptive endometrium. These are characterized by the plaque reaction in the luminal epithelium, an increase in glycodelin expression and secretion by the glandular epithelium, and the differentiation of subepithelial stromal fibroblasts characterized by expression of the alpha smooth muscle actin (alpha SMA). Pretreatment with progesterone receptor antagonist (PRa) completely or partially inhibits these effects. The signal transduction pathway activated by CG in primate endometrial epithelial cells involves the protein kinase A (PKA)-independent phosphorylation of extracellular signal regulated kinase (ERK 1/2). This alternate signal transduction pathway may prevent CG Receptor (R) downregulation at the implantation site and enhance epithelial cell proliferation and differentiation. Thus, our results suggest that CG plays an important role in implantation in addition to its luteotrophic role.
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PMID:The role of chorionic gonadotropin (CG) in blastocyst implantation. 1175 Jul 40

The role of ERK and Jun N-terminal kinase (JNK) in basal- and GnRH-stimulated LHbeta-promoter activity was examined in the gonadotroph cell line LbetaT-2. GnRH agonist (GnRH-A) stimulates the MAPK cascades ERK, JNK, and p38MAPK, with a peak at 7 min for ERK and at 60 min for JNK and p38MAPK. The rat glycoprotein hormone LHbeta-subunit promoter, linked to the chloramphenicol acetyl transferase (CAT) reporter gene, was used to follow its activation. Addition of GnRH-A (10 nM) to LbetaT-2 cells resulted in a 6-fold increase in LHbeta-CAT activity at 8 h, which was markedly reduced by a GnRH antagonist. The PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA), but not the Ca(2+) ionophore ionomycin, stimulated LHbeta-CAT activity. Addition of GnRH-A and TPA together did not produce an additive response. Down-regulation of PKC, but not removal of Ca(2+), abolished the GnRH-A and the TPA response. Cotransfection of the LHbeta-promoter and the constitutively active form of Raf-1 stimulated basal and GnRH-A-induced LHbeta-CAT activity. The dominant negative forms of the ERK cascade members Ras, Raf-1, and MAPK/ERK kinase (MEK) markedly reduced basal and GnRH-A-induced LHbeta-CAT activity, Similar results were obtained with the MEK inhibitor PD 098059. Cotransfection of the LHbeta-promoter and the constitutively active CDC42 stimulated basal and GnRH-A-induced LHbeta-CAT activity. The dominant negative forms of the JNK cascade members Rac, CDC42, and SEK markedly diminished basal and GnRH-A-induced LHbeta-CAT activity. Interestingly, the constitutively active form of c-Src stimulated the basal and the GnRH-A response, whereas the dominant negative form of c-Src, or the c-Src inhibitor PP1 diminished basal and the GnRH-A response. We conclude that ERK and JNK are involved in basal and GnRH-A stimulation of LHbeta-CAT activity. c-Src participates also in LHbeta-promoter activation by a mechanism which might be linked to ERK and JNK activation.
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PMID:Activation of MAPK cascades by GnRH: ERK and Jun N-terminal kinase are involved in basal and GnRH-stimulated activity of the glycoprotein hormone LHbeta-subunit promoter. 1186 27

Proteolysis-inducing factor (PIF) is a novel sulfated glycoprotein initially identified as a protein capable of triggering muscle proteolysis during the process of cancer cachexia. Only skeletal muscle and liver exhibit substantial binding of PIF in adult tissue. Here, we demonstrate that PIF induces transcriptional regulation in both the liver endothelial cell line SK-HEP-1 and in human umbilical vein endothelial cells (HUVECs) but not in pulmonary artery endothelial cells. PIF differentially induces activation of nuclear factor-kappaB, resulting in the induction of proinflammatory cytokines [interleukin (IL)-8 and IL-6] and increased expression of the cell surface proteins intercellular adhesion molecule-1 and vascular cell adhesion molecule in SK-HEP-1 and HUVECs only. In addition, PIF induces the shedding of syndecans from the cell surface. Syndecans are involved in wound repair, metastasis of cancers, and embryonic development. These results suggest that PIF may play additional roles in the proinflammatory response observed in cancer cachexia but may also have a role without the cachectic process.
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PMID:Proteolysis-inducing factor differentially influences transcriptional regulation in endothelial subtypes. 1188 95

Integrin-mediated interactions with collagen IV and its domains were examined in a human neuroblastoma cell line (SK-N-SH). By adhesion assays we demonstrated that neuroblastoma cells bound to solid-phase intact collagen IV and synthetic cell-binding peptide HEP-III, derived from the collagenous part of the molecule, but not to the main noncollagenous NC1 domain or to the synthetic cell-binding peptide HEP-I, derived from this domain. Monoclonal antibodies against beta1, alpha3, and alpha(v)beta3 integrins resulted in inhibition of cell binding to collagenous substrates by 95, 30, and 35%, respectively. By flow cytometry and immunoblotting it was shown that culture of SK-N-SH cells on collagen IV resulted in alteration in the expression of major neuroblastoma cell integrins. Binding to collagen IV induced the expression and activation of matrix metalloproteinases A and B (MMP-2, MMP-9), with a concomitant increase at the protein level of tissue-specific inhibitors of metalloproteinases (TIMP-1, TIMP-2). Finally, the expression of MMP-2 was significantly up-regulated by anti-alpha3beta1 antibodies, whereas ligation of anti-alpha(v)beta3 antibodies resulted in a modest down-regulation of MMP-2. Our results indicate that the presence of collagen IV modulates the expression of integrins, which are used for binding to this glycoprotein, and MMP-2 secreted by SK-N-SH cells.
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PMID:Effects of collagen IV on neuroblastoma cell matrix-related functions. 1190 Apr 77

The gonadotropic hormones, FSH and LH exert a major effect on ovarian and testicular function through interaction with specific seven-transmembrane domain glycoprotein receptors. Desensitization to the hormones, which can occur both in vivo and in vitro, is essential for prevention of overstimulation of the gonadal cells. The long-term process of desensitization to the gonadotropic hormones is probably mediated, in part, by extensive clustering and internalization of the hormone-receptor complex. Short-term desensitization may occur as a result of phosphorylation of serine or threonine residues on the receptor molecules, although a specific receptor kinase has not yet been identified. Recently, we have discovered a novel mechanism of gonadotropin desensitization, which is exerted by down-regulation of StAR expression and steroidogenesis mediated by MAPK activation as a result of hormone-receptor interaction, cAMP accumulation and PKA activation. Thus, PKA not only mediates gonadotropin-induced steroidogenesis, it also activates the down-regulation mechanism that can silence steroidogenesis under certain conditions. Moreover, our findings raise the possibility that activation or inhibition of ERK by other pathways could be an important mechanism for diminution or amplification of gonadotropin-stimulated steroidogenesis. This could contribute to functional luteolysis, a process in which luteinized granulosa cells show reduced sensitivity to LH despite maintenance of LH receptors, or to up-regulation of the steroidogenic machinery during luteinization of granulosa cells.
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PMID:Mechanisms of gonadotropin desensitization. 1198 13

The extracellularly regulated kinase (ERK), one of the three types of mitogen-activated kinases, was rapidly activated after cutting porcine articular cartilage either when maintained as explants or in situ. Cutting released a soluble ERK-activating factor from the cartilage, which was purified and identified by MS as basic fibroblast growth factor (bFGF). Experiments with neutralizing Abs to bFGF and an FGFR1 tyrosine kinase inhibitor showed that this growth factor was the major ERK-activating factor released after injury. Treating cartilage with the heparin-degrading enzyme heparitinase also caused release of bFGF, suggesting the presence of an extracellular store that is sequestered in the matrix and released upon damage. Basic FGF induced the synthesis of a number of chondrocyte proteins including matrix metalloproteinases 1 and 3, tissue inhibitor of metalloproteinases-1, and glycoprotein 38, which were identified by MS. The strong induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 suggests that bFGF could have a role in remodeling damaged tissue.
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PMID:Basic FGF mediates an immediate response of articular cartilage to mechanical injury. 1203 79

In breast cancer the membrane expression of HER2 receptor protein encoded by the HER2 proto-oncogene seems to have an ever growing clinical significance. In tissue cultures and animal experiments it was shown that the HER2 gene amplification induces malignant transformation and intensifies the aggressiveness of the tumour cells. Correlating with the so called pheno-and genotypic prognostic markers, the overexpression of HER2 in breast cancer predicts also poor prognosis and indicates enhanced potential for metastatisation. In some of the so called precancerous proliferations and "in situ" carcinomas we demonstrated the enhanced membrane staining of the HER2 receptor protein. In these cases we frequently observed DNA aneuploidy,the presence of p53 mutational protein and CD44v6 glycoprotein. The immunohistochemical studies of HER2 protein in invasive carcinomas have revealed, an interrelationship between the grade of differentiation, histological type, aggressiveness and biological behaviour of the "in situ" and invasive carcinomas. In clinical studies trastuzumab, a humanized monoclonal antibody recognizing extracellular domain of HER2 receptor protein, has proved to be effective in HER2 overexpressing metastatic breast cancer either as monotherapy or in combination with chemotherapeutical agents. The DAKO "HercepTest" is a semiquantitative, standardised method for the determination of HER2 overexpression.
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PMID:[Expression of HER2 in breast cancer] 1205 Jul 66

Vascular endothelial growth factor (VEGF) is one of the most important endothelial mitogens involved in the development and differentiation of the vascular system. Vascular endothelial growth factor is a highly conserved, homodimeric glycoprotein with multiple isoforms. The most abundant isoform, VEGF165, binds to vascular endothelial growth factor receptors-1 (Flt-1) and 2 (KDR/Flk-1) with picomolar affinity. Recently, correlation between microvessel density and engineered expression of VEGF in human breast xenografts was observed. A role of VEGF in breast cancer progression is evident from clinical studies showing elevated serum VEGF in invasive breast cancers. Vascular endothelial growth factor in breast tumor cytosols is correlated with microvessel density, and VEGF165 content correlates with disease-free and overall survival in primary breast cancers. Preliminary data indicate a transcriptional upregulation of VEGF in HER2-overexpressing breast cancer cells. We hypothesize that the upregulation of VEGF in HER2-overexpressing breast cancers contributes to the aggressive phenotype observed in HER2-positive cases and that the "angiogenic switch" associated with HER2 can be attenuated by trastuzumab. Although tumor angiogenesis in breast cancer is complex, the VEGF/vascular endothelial growth factor receptor (VEGFR) system provides a useful model for testing new angiogenesis inhibitors that target this pathway. The VEGF/VEGFR system provides a number of opportunities for therapeutic intervention in breast cancer. Understanding the biology of this system is paramount to fully exploiting VEGF as a therapeutic target in breast cancer. We hypothesize that new therapeutic molecules targeting VEGF and/or its receptors, such as recombinant humanized monoclonal anti-VEGF antibody (rhuMAb VEGF), may have unique activity against HER2-overexpressing breast cancers.
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PMID:Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. 1213 95

Transcriptional activation of the human glycoprotein hormone alpha-subunit (alphaGSU) promoter in response to GnRH and phorbol-12-myristate-13-acetate (PMA) has been well characterized in alphaT3-1 gonadotropes but not investigated in the more differentiated LbetaT2 clonal gonadotrope. We have evaluated alphaGSU transcription in the more mature LbetaT2 cell line, using deletion and heterologous constructs of the alphaGSU promoter linked to a luciferase reporter gene. Basal alphaGSU-promoter activity was significantly less in LbetaT2 cells than in alphaT3-1 cells, but stimulation of transfected cells with GnRH and PMA resulted in similar increases in alphaGSU-promoter activity. Deletional analysis of the human alphaGSU promoter in LbetaT2 cells indicated that sequences between -398 and -244 and between -244 and -195 base pairs (bp) were involved in regulating basal alphaGSU-promoter transcription, whereas the region between -244 and -195 bp regulated PMA-stimulated promoter activity. Deletion of this promoter region containing a steroidogenic factor-1 (SF-1) binding site abolished basal and PMA-stimulated transcription. Site-directed mutagenesis of the SF-1 binding site resulted in a significant attenuation of basal and PMA-stimulated alphaGSU transcription. Pretreatment of LbetaT2 cells with a mitogen-activated protein kinase kinase-specific inhibitor, U0126, abolished the PMA-stimulated increase in MAPK activity and significantly reduced basal and PMA-stimulated promoter activity. Electrophoretic mobility shift assays for SF-1 and GATA revealed that PMA failed to affect SF-1 binding but enhanced GATA binding to a consensus GATA oligonucleotide, an effect that was blocked with U0126 pretreatment, suggesting that GATA may mediate ERK activation of alphaGSU transcription. Our data suggests that, in the mature LbetaT2 gonadotrope cell line, two regions of the human alphaGSU promoter regulate basal transcription and that SF-1 is involved in mediating basal and PMA-stimulated promoter activity. Furthermore, PKC-stimulated transcription partially relies on ERK acting on elements downstream of -244 bp of the human alphaGSU promoter.
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PMID:Regulation of human glycoprotein hormone alpha-subunit gene transcription in LbetaT2 gonadotropes by protein kinase C and extracellular signal-regulated kinase 1/2. 1219 78


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