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)

Regulation of nestin gene expression is largely unknown despite that it is widely used as a progenitor cell marker. In this study, we showed that nestin expression is regulated by the thrombin-mediated EGFR transactivation in serum-deprived primary cultures of rat vascular smooth muscle cells (VSMCs). This resulted from the direct binding of thrombin to PAR-1 rather than indirectly affecting through the binding to thrombomodulin, as demonstrated by thrombomodulin RNAi. In this process, the PAR-1-induced c-Src plays a critical role through two routes; one was the direct intracellular phosphorylation of EGFR and the other was the extracellular activation of the MMP-2-mediated shedding of HB-EGF. The transactivated EGFR then led to the downstream Ras-Raf-ERK signaling axis, but not the p38 or JNK pathways. In addition, the EMSA experiment showed that the transcriptional factor Sp1 is critical for the thrombin-induced nestin expression in rat VSMCs. Furthermore, RNAi of nestin attenuated the thrombin-induced cell proliferation, indicating that thrombin-induced nestin expression and cell proliferation share the same EGFR transactivation mechanism. This study also suggested that nestin may play an important role in cell proliferation induced by the thrombin-mediated EGFR transactivation.
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PMID:Thrombin induces nestin expression via the transactivation of EGFR signalings in rat vascular smooth muscle cells. 1924 30

Despite major advances in the management of malignant gliomas of which glioblastomas represent the ultimate grade of malignancy, they remain characterized by dismal prognoses. Glioblastoma patients have a median survival expectancy of only 14 months on the current standard treatment of surgical resection to the extent feasible, followed by adjuvant radiotherapy plus temozolomide, given concomitantly with and after radiotherapy. Malignant gliomas are associated with such dismal prognoses because glioma cells can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Clinical and experimental data have demonstrated that invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) as compared to the highly cellular centre of the tumor, and this may contribute to their resistance to conventional pro-apoptotic chemotherapy and radiotherapy. Resistance to apoptosis results from changes at the genomic, transcriptional and post-transcriptional level of proteins, protein kinases and their transcriptional factor effectors. The PTEN/ PI3K/Akt/mTOR/NF-kappaB and the Ras/Raf/MEK/ERK signaling cascades play critical roles in the regulation of gene expression and prevention of apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer, notably glioblastomas. Monoclonal antibodies and low molecular-weight kinase inhibitors of these pathways are the most common classes of agents in targeted cancer treatment. However, most clinical trials of these agents as monotherapies have failed to demonstrate survival benefit. Despite resistance to apoptosis being closely linked to tumorigenesis, tumor cells can still be induced to die by non-apoptotic mechanisms such as necrosis, senescence, autophagy (type II programmed cell death) and mitotic catastrophe. Temozolomide brings significant therapeutic benefits in glioblastoma treatment. Part of temozolomide cytotoxic activity is exerted through pro-autophagic processes and also through the induction of late apoptosis. Autophagy, type II programmed cell death, represents an alternative mechanism to overcome, at least partly, the dramatic resistance of many cancers to pro-apoptotic-related therapies. Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which then should restore a level of sensitivity to pro-apoptotic drugs. Recent series of studies have supported the concept that malignant gliomas might be seen as an orchestration of cross-talks between cancer cells, microenvironment, vasculature and cancer stem cells. The present chapter focuses on (i) the major signaling pathways making glioblastomas resistant to apoptosis, (ii) the signaling pathways distinctly activated by pro-autophagic drugs as compared to pro-apoptotic ones, (iii) autophagic cell death as an alternative to combat malignant gliomas, (iv) the major scientific data already obtained by researchers to prove that temozolomide is actually a pro-autophagic and pro-apoptotic drug, (v) the molecular and cellular therapies and local drug delivery which could be used to complement conventional treatments, and a review of some of the currently ongoing clinical trials, (vi) the fact that reducing the levels of malignant glioma cell motility can restore pro-apoptotic drug sensitivity, (vii) the observation that inhibiting the sodium pump activity reduces both glioma cell proliferation and migration, (viii) the brain tumor stem cells as a target to complement conventional treatment.
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PMID:Present and potential future adjuvant issues in high-grade astrocytic glioma treatment. 1936 79

Decreased expression levels of EPHB6, a member of the receptor tyrosine kinases (RTKs), are associated with an increased risk of metastasis development in early stage non-small cell lung cancer (NSCLC). However, the signaling properties of the kinase-defective EPHB6 receptor are not well-understood. Here, we show that expression of EPHB6 in A549 lung adenocarcinoma cells led to phosphorylation of the MAP kinase ERK. Conversely, siRNA based knockdown of EPHB6 reversed ERK phosphorylation. Intriguingly, EPHB6-induced phosphorylation of ERK was uncoupled by activation of the Elk-1 transcriptional factor. These analyses suggest that kinase defective EPHB6 can lead to MAPK activation.
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PMID:The kinase defective EPHB6 receptor tyrosine kinase activates MAP kinase signaling in lung adenocarcinoma. 1951 65

Human papillomaviruses (HPV) are the main etiological factor for cervical carcinoma. HPV-16 is the most prevalent high-risk HPV-genotype found in HPV-associated cancers. We studied the effect of HPV-16 E7 oncoprotein on cadherin-mediated cell adhesion. The expression of E7 strongly suppressed the cadherin-mediated cell adhesion in the rat fibroblast cell line 3Y1. This suppression was associated with the decreased expression of N-cadherin at the transcriptional level. The treatment of 3Y1 cells that express E7 (E7-3Y1) with MEK inhibitor recovered the cadherin-mediated cell adhesion together with the accumulation of N-cadherin at the cell-cell contact site. Moreover, the suppression of c-Jun, which is the element of AP-1 transcriptional factor, leads to the recovery of N-cadherin expression and cadherin-mediated cell adhesion in E7-3Y1 cells. Taken together, our results demonstrate that E7 regulates cadherin-mediated cell adhesion through the modulation of cadherin expression via the MEK-ERK and AP-1 signaling pathway.
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PMID:Human papillomavirus type 16 oncoprotein E7 suppresses cadherin-mediated cell adhesion via ERK and AP-1 signaling. 1957 44

In the present study, we found that hyaluronic acid (HA) suppressed the neuronal differentiation mediated by nerve growth factor (NGF). In addition, we examined the mechanism by which HA inhibits the NGF-induced neurite outgrowth of PC12 cells. We elucidated the direct interaction between NGF and HA, and found that HA did not bind to NGF directly using a quartz-crystal microbalance. Western blot analysis revealed that HA suppressed NGF-induced phosphorylation of p38 MAPK, ERKs, and transcriptional factor CREB in PC12 cells. Furthermore, HA inhibited the luciferase activity of pCRE-Luc transfected PC12 cells in the presence of NGF. We confirmed that the p38 MAPK inhibitor SB203580 and ERK inhibitor U0126 suppressed NGF-induced neurite outgrowth of PC12 cells, and found that the inhibitory effects of HA on phosphorylation of ERKs, but not of p38 MAPK, were restored by the anti-RHAMM antibody. The number of PC12 cells with neurites increased remarkably when pre-cultured with the anti-RHAMM antibody, then treated with NGF and HA. Our findings indicate that HA inhibits NGF-induced neuronal differentiation of PC12 cells partially by inhibiting ERK phosphorylation through RHAMM, and suggest that the binding of HA to RHAMM modifies the signaling pathways in PC12 cells treated with NGF.
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PMID:Mechanisms involved in suppression of NGF-induced neuronal differentiation of PC12 cells by hyaluronic acid. 1961 62

Cyclooxygenase (COX) is the rate-limiting enzyme for the conversion of prostaglandins from arachidonic acid. Upregulation of COX-2 has been well documented during tumorigenesis and metastasis of breast cancer. Isoliquiritigenin (ILN), a flavonoid isolated from licorice (the rhizomes of GLYCYRRHIZA GLABRA, a member of the bean plant family), is known to be a potential suppressor of COX-2 expression. This study focuses on phorbol ester-induced COX-2 expression in the non-tumorigenic MCF-10A cells. Real-time PCR and Western blotting indicated that ILN at 5 microM or above significantly inhibited phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in the breast cells. The activated PKC alpha appeared to be not affected, whereas its downstream mitogen-activated protein kinase (MAPK) ERK-1/2 was deactivated. ERK can activate the transcriptional factor binding of AP-1 or CRE, which can be located at the COX-2 promoter region (- 72/- 53). Electrophoretic mobility shift assays illustrated that ILN suppressed DNA binding at this region. The shifted bands could be competed off with consensus sequences of AP-1 and CRE, and the supershift assay demonstrated that CREB-1 instead of c-Jun was responsible for the binding. This study showed that ILN downregulated PMA-induced COX-2 expression by modulating ERK-1/2 signaling, a finding that may be relevant to the disease prevention properties of licorice.
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PMID:The licorice flavonoid isoliquiritigenin suppresses phorbol ester-induced cyclooxygenase-2 expression in the non-tumorigenic MCF-10A breast cell line. 2003 68

The hypoxia-inducible factor (HIF) is a heterodimeric basic helix-loop-helix transcriptional factor and the activated HIF plays pivotal roles in various pathological conditions, including inflammation and cancer. HIF-1alpha overexpression has been observed in many common human cancers, including brain, breast, colon, lung, ovary, and prostate, and HIF-mediated genes, such as vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and insulin-like growth factor (IGF)-1, are associated with tumor angiogenesis, metastasis, and invasion. Therefore, the pro-oncogenic protein HIF is a novel target of cancer therapy. We examined the effects of VEGFR inhibitors, AAL993, SU5416, and KRN633, on suppression of HIF-1alpha accumulation under the hypoxic condition. We found that VEGFR tyrosine kinase inhibitors, AAL993, SU5416, and KRN633, possess dual functions: inhibition of VEGFR signaling and HIF-1alpha expression under the hypoxic condition. The detailed mechanistic study indicated that SU5416 and KRN633 suppressed HIF-1alpha expression through inhibition of both Akt and ERK phosphorylation signaling pathways, whereas AAL993 suppressed HIF-1alpha expression through ERK inhibition without affecting Akt phosphorylation.
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PMID:Suppression of hypoxia-induced HIF-1alpha accumulation by VEGFR inhibitors: Different profiles of AAL993 versus SU5416 and KRN633. 2037 43

A cell-penetrating peptide consisting of the second intracellular loop (IC2) of the angiotensin II (AngII) type-I receptor (AT1) linked to the HIV-transactivating regulatory protein (TAT) domain was used to identify the role of this motif In intracellular signal transduction. HEK-293 cells stably transfected with AT1R cDNA and primary cultures of human pulmonary artery smooth muscle cells expressing endogenous AT1 receptor were exposed to the cell-penetrating peptide construct, and the effect on angiotensin II signaling was determined. The AT1 IC2 peptide effectively inhibited AngII-stimulated phosphatidylinositol turnover and calcium influx. It also limited the activation of Akt/PKB as determined by an inhibition of phosphorylation of Akt at Ser473, and completely abolished the AngII-dependent activation of the transcriptional factor NFkappaB. In contrast, the AT1 IC2 peptide had no effect on AngII/AT1 receptor activation of ERK. These results illustrate the potential of using cell-penetrating peptides to both delineate receptor-mediated signal transduction and to selectively regulate G protein-coupled receptor signaling.
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PMID:Limiting angiotensin II signaling with a cell-penetrating peptide mimicking the second intracellular loop of the angiotensin II type-I receptor. 2049 49

Ikaros is a member of the Kruppel family of zinc finger DNA-binding proteins. The Ikaros protein contains two separate regions of zinc-finger domains: 4 DNA-binding zinc fingers near the N-terminus and 2 zinc fingers for protein-protein interactions near the C-terminus. Here, we identified the Ikaros gene from 14 vertebrate genomes and found Ikaros existed in all kinds of vertebrate including fish, amphibians, birds and mammals. Moreover, except rat and Xenopus tropicalis Ikaros proteins, which lack the first C2H2-type 1 Zinc finger region, all identified Ikaros proteins contain six C2H2-type 1 Zinc finger regions. We found human Ikaros gene showed a predominant expression in the liver, lymph node, thymus, intestine, lung, mammary gland, bone marrow, brain, heart, placenta and prostate. Moreover, four available SNPs disrupted an existing exonic splicing enhancer were identified in Ikaros. Besides the reported acute lymphoblastic leukemia (ALL), the expression of Ikaros was related to the prognosis of 13 cases of cancers including blood cancers, breast, lung, ovarian and skin cancer. Moreover, the relationship between the expression of Ikaros and prognosis varied in different cancers, even in the same cancer from different database. Two tumor-related transcriptional factor (c-Fos and Elk-1) binding sites were identified within the 1.5-kb regions upstream of the transcriptional start site of human Ikaros, which may be involved in the effect of Ikaros in tumors.
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PMID:Integrative genomic analyses on Ikaros and its expression related to solid cancer prognosis. 2059 48

We previously reported that the disruption of cell spreading by v-Crk was dependent on the activation of the MEK/ERK pathway. Here we demonstrate that the activation of that pathway is sufficient to suppress cell spreading. The MEK/ERK pathway regulates the activity of various proteins including AP-1, which is a transcriptional factor composed of heterodimeric proteins. To examine whether AP-1 activity is required for the suppression of cell spreading by the activation of the MEK/ERK pathway, we expressed BATF, which is a negative regulator of AP-1. The expression of BATF clearly restored cell spreading that was suppressed by the activation of MEK/ERK pathway. In addition, a disrupted formation of stress fibers and focal adhesions by such activation was restored by the suppression of AP-1. Our results define an essential role of the MEK/ERK/AP-1 pathway in the disruption of actin cytoskeleton and cell spreading.
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PMID:Disruption of cell spreading by the activation of MEK/ERK pathway is dependent on AP-1 activity. 2094 68


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