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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor beta 1 (TGF-beta1) is a potent tumor suppressor but, paradoxically, TGF-beta1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-beta type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-beta signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinase-inactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-beta-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-beta-mediated cell migration. Collectively, our results show that TGF-beta-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.
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PMID:ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. 1707 48

Matrix metalloproteinases (MMPs) are responsible for degradation of extracellular matrix and play important roles in cell migration, proliferation, and tissue remodeling related to airway inflammation. Interleukin-1beta (IL-1beta) has been shown to induce MMP-9 production in many cell types and contribute to airway inflammatory responses. However, the mechanisms underlying MMP-9 expression induced by IL-1beta in human tracheal smooth muscle cells (HTSMCs) remain unclear. Here, we investigated the roles of p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB pathways for IL-1beta-induced MMP-9 production in HTSMCs. IL-1beta induced production of MMP-9 protein and mRNA in a time- and concentration-dependent manner determined by zymographic, Western blotting, and RT-PCR analyses, which was attenuated by inhibitors of MEK1/2 (U0126), p38 MAPK (SB202190), JNK (SP600125), and NF-kappaB (helenalin), and transfection with dominant negative mutants of MEK1/2, p38 and JNK, respectively. IL-1beta-stimulated phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK was attenuated by pretreatment with U0126, SB202190, SP600125, or transfection with these dominant negative mutants of MEK, ERK, p38 and JNK, respectively. Furthermore, IL-1beta-stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaB-alpha was blocked by helenalin. Finally, the reporter gene assay revealed that MAPKs and NF-kappaB are required for IL-1beta-induced MMP-9 luciferase activity in HTSMCs. MMP-9 promoter activity was enhanced by IL-1beta in HTSMCs transfected with MMP-9-Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Taken together, the transcription factor NF-kappaB, p42/p44 MAPK, p38 MAPK, and JNK that are involved in MMP-9 expression in HTSMCs exposed to IL-1beta have now been identified.
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PMID:Interleukin-1beta induces MMP-9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells. 1731 Dec 79

The aim of this study was to explore whether cyclosporine A (CsA) can modulate expression of MMP-9 and MMP-2 and invasion of the first-trimester human trophoblast cells. The invasive ability of the trophoblast cells modulated by CsA was observed by Matrigel invasion assay. The effect of CsA on the transcription and translation of MMP-9 and MMP-2 was determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Gelatin Zymography. In-cell Western was used to detect the level of phospho-ERK1/2 of trophoblast cells treated with CsA. We found that CsA(1.0 micromol/L) could remarkably promote the invasive ability of the first-trimester human trophoblast cells; CsA(1.0 micromol/L) could also induce the expression of MMP-9 and MMP-2 at transcriptional and translational level; U0126,a MEK inhibitor,could obviously inhibit the enhanced invasion and expression of MMP-9 and MMP-2 of these cells induced by CsA; CsA (1.0 micromol/L) could activate the ERKl/2 in a time-dependent manner. These results above indicate that CsA can induce the expression of MMP-9 and MMP-2 through activating MAPK/ERK1/2, which contributes to the improved invasion of the first-trimester human trophoblast cells.
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PMID:[Modulation of cyclosporin a on the expression of MMP-9 AND MMP-2 of the first-trimester human trophoblast cells]. 1735 50

Matrix metalloproteinases (MMPs) contribute to the matrix-degrading phenotype of mycobacterial diseases. Considering that MMPs could contribute to the mutual exacerbation of both Mycobacterium avium and HIV in coinfections, it is of importance to understand the mechanisms of M. avium-induced MMP induction. Focusing on MMP-9, our work demonstrates that a cyclooxygenase-2 (COX-2)-dependent signalling loop is critical for activation of MMP-9 transcription in RAW264.7 cells and murine bone marrow-derived macrophages. M. avium-stimulated MMP-9 induction involves the p65 and p50 subunits of NF-kappaB and the c-Fos and c-jun subunits of AP-1. The c-Fos gene is upregulated in a MEK1-dependent manner in M. avium-challenged macrophages. M. avium-induced MMP-9 gene induction requires the histone acetyltransferase p300 and chromatin modifications involving phosphorylation of p65 at serine 276 and its acetylation at lysines 221 and 310. At the same time, histone H3 modified by mitogen and stress-activated protein kinase 1 (MSK1)-dependent phosphorylation on serine 10 and by acetylation on lysine 14, typical signatures linked to transcriptional activation, also associates with the MMP-9 promoter following M. avium challenge. Taken together, our results show that co-ordinated post-translational modifications of p65 and histone H3 involving phosphorylation and acetylation drive COX-2-dependent transcriptional activation of the MMP-9 gene in response to challenge of macrophages with M. avium.
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PMID:Mycobacterium avium-induced matrix metalloproteinase-9 expression occurs in a cyclooxygenase-2-dependent manner and involves phosphorylation- and acetylation-dependent chromatin modification. 1759 Jan 63

The growth factor heregulin-beta1 (HRG-beta1), which is expressed in breast cancer, activates the HER-2 signaling pathway through induction of heterodimeric complexes of HER-2 with HER-3 or HER-4. It has been shown in many studies that HRG-beta1 induces the tumorigenicity and metastasis of breast cancer cells. Matrix metalloproteinase (MMP) 9 is a key enzyme in the degradation of extracellular matrices, and its expression may be dysregulated in breast cancer invasion and metastasis. Resveratrol, a major component in grape, exhibited potential anticarcinogenic activities in both in vitro and in vivo studies. However, the inhibitory effect of resveratrol on HER-2-mediated expression of MMP-9 has not been demonstrated yet. In the present study, we investigated the anti-invasive mechanism of resveratrol in human breast cancer cells. Human breast cancer MCF-7 cells were exposed to resveratrol (2, 5 and 10 microM). The expression activity of MMP-9 was measured by zymogram analysis. Phosphorylated levels of HER-2 and mitogen-activated protein kinase (MAPK)/ERK were measured by Western blot analysis. Total actin was used as internal control for protein expression. HRG-beta1 induced the phosphorylation of HER-2/neu receptor and MMP-9 expression in human breast cancer MCF-7 cells. Resveratrol significantly inhibited HRG-beta1-mediated MMP-9 expression in human breast cancer cells. MEK inhibitor induced a marked reduction in MMP-9 expression, and it suggested that ERK1/2 cascade could play an important role in HRG-beta1-mediated MMP-9 expression. Furthermore, resveratrol significantly suppressed HRG-beta1-mediated phosphorylation of ERK1/2 and invasion of breast cancer cells. However, resveratrol had negligible effects on either HRG-beta1-mediated phosphorylation of HER-2 receptor or expression of the tissue inhibitor of MMP, tissue inhibitor metalloproteinase protein 1. Taken together, our results suggest that resveratrol inhibited MMP-9 expression in human breast cancer cells. The inhibitory effects of resveratrol on MMP-9 expression and invasion of breast cancer cells are, in part, associated with the down-regulation of the MAPK/ERK signaling pathway.
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PMID:Resveratrol inhibits heregulin-beta1-mediated matrix metalloproteinase-9 expression and cell invasion in human breast cancer cells. 1765 59

Lung caner cells have a striking tendency to metastasize to bone. The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively secreted by osteoblasts and bone marrow stromal cells and plays a key role for homing of hematopoietic cells to the bone marrow. Reverse transcriptase-polymerase chain reaction and flow cytometry studies demonstrated SDF-1 receptor (CXCR4) messenger RNA (mRNA) and surface expression of CXCR4 in lung cancer cell lines, especially higher in those with high invasiveness (A549) as compared with lower level in H928 cells and H1299 cells. SDF-1, osteoblast-conditioned medium (OBCM) and stromal cell-conditioned medium all induced the invasiveness of lung cancer cells. Matrix metalloproteinase (MMP)-9 small interfering RNA inhibited the SDF-1alpha- or OBCM-induced MMP-9 expression and thereby significantly inhibited the SDF-1alpha- or OBCM-induced cell invasion. Furthermore, mitogen-activated protein kinase kinase inhibitor PD98059 suppressed SDF-1alpha-induced MMP-9 mRNA expression. Transient transfection with dominant-negative extracellular signal-regulated kinase (ERK) mutant also showed that the ERK-signaling pathway was involved in SDF-1alpha-induced MMP-9 expression. Moreover, nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide suppressed the MMP-9 promoter activity enhanced by SDF-1alpha. Both mitogen-activated protein kinase kinase inhibitor and ERK mutant also antagonized SDF-1alpha-induced NF-kappaB-driven luciferase promoter activity. Taken together, our results indicated that bone marrow-derived-SDF-1alpha enhances the invasiveness of lung cancer cells by increasing MMP-9 expression through the CXCR4/ERK/NF-kappaB signal transduction pathway.
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PMID:Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis. 1791 7

Glycogen synthase kinase (GSK)-3beta and extracellular signal-regulated kinase (ERK) regulate several cellular signaling pathways in common, including embryonic development, cell differentiation and apoptosis. In this study, we investigated whether GSK-3beta inhibition is involved in ERK activation, which affects the activation of NF-kappaB and induction of MMP-9 in cultured rat primary astrocytes. Here, we found that GSK-3beta inhibition using GSK-3beta inhibitor TDZD-8 increased the phosphorylation of GSK-3beta at Ser9 site as well as the phosphorylation of ERK1/2 and Akt at Ser473 site. In this condition, GSK-3beta inhibition increased MMP-9 but not MMP-2 activity in a concentration-dependent manner. In RT-PCR analysis, MMP-9 mRNA level was increased by GSK-3beta inhibition in a concentration-dependent manner. MMP-9 promoter reporter activity was similarly increased by GSK-3beta inhibition. Pretreatment of U-0126 (MEK1/2 inhibitor) completely abolished the GSK-3beta inhibition-induced phosphorylation of ERK1/2. U-0126 prevented GSK-3beta inhibition-mediated induction of MMP-9 reporter activity as well as the MMP-9 gene expression. The transcriptional activity of NF-kappaB was significantly increased by GSK-3beta inhibition, which was determined by nuclear translocation of NF-kappaB. Inhibition of ERK1/2 activity by U-0126 also completely blocked the nuclear translocation of NF-kappaB. Transfection of dominant negative plasmid (S9A) of GSK-3beta significantly decreased phosphorylation of ERK, MMP-9 expression and nuclear translocation of NF-kappaB by GSK-3beta inhibition as compared to wild type GSK-3beta. These data suggest that GSK-3beta inhibition mediates ERK1/2 activation followed by NF-kappaB activation, which directly regulates the induction of MMP-9 in rat primary astrocytes.
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PMID:Inhibition of GSK-3beta mediates expression of MMP-9 through ERK1/2 activation and translocation of NF-kappaB in rat primary astrocyte. 1799 50

Ganoderma lucidum has been reported to be associated with suppressed motility, invasion and metastasis of several types of cancers, but its mechanism of action remains unclear. In our previous study, lucidenic acids A, B, C and N were isolated from a new strain of G.lucidum and all of them were found to have potential anti-invasive activity on phorbol-12-myristate-13-acetate (PMA)-induced HepG(2) cells by suppressing the matrix metalloproteinase (MMP)-9 activity. Here, the lucidenic acid B (LAB) was used to explore its mechanisms underlying MMP-9 expression of HepG(2) cells. The results showed that the LAB suppressed PMA-induced MMP-9 activity in a dose-dependent transcriptional level. The suppression of PMA-induced MMP-9 expression of HepG(2) cells by LAB was through inactivating phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The treatment of mitogen-activated protein kinase kinase (MEK) inhibitors (PD98059 and U0126) and LAB to HepG(2) cells could result in a synergistic reduction on the MMP-9 expression along with an inhibition on cell invasion. Moreover, LAB also strongly inhibited PMA-stimulated nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA-binding activities of HepG(2) cells in dose-dependent manners. A dose-dependent inhibition on protein levels of NF-kappaB, c-Jun and c-Fos in nuclear by LAB treatment was further observed. In conclusion, we demonstrated that the anti-invasive effects of the LAB on the PMA-induced HepG(2) cells might be through inhibiting the phosphorylation of ERK1/2 and reducing AP-1 and NF-kappaB DNA-binding activities, leading to downregulation of MMP-9 expression.
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PMID:Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kappaB and AP-1. 1802 77

Gamma-aminobutyric acid (GABA) was first discovered as an inhibitory neurotransmitter in the central nervous system (CNS) and has been reported to have a variety of functions, including regulation of cell division, cell differentiation and maturation, and to be involved in the development of certain cancers outside the CNS. In the present study, using the human renal cell carcinoma cell line Caki-2, we demonstrated that GABA stimulation significantly increased the expression of MMP-2 and -9 and subsequently increased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with GABA. It was found that GABA stimulation promoted the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. ERK1/2 phosphorylation was sustained for up to 12 h, while phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated GABA-induced MMP-9 expression and that both PD98059 and MMP inhibitors attenuated the GABA-induced invasive activity of Caki-2 cells. Moreover, data obtained by depletion of the MEK/ERK pathway using interfering RNA transfection of Caki-2 cells clearly corroborated the above results, as both MMP-9 expression and GABA-induced invasive ability were decreased significantly. We also demonstrated that the GABA-induced increase in invasive ability via ERK1/2 up-regulation was mediated mainly through the GABA-B receptor. These results indicate that GABA stimulation promotes cancer cell invasion and that the effect is partly due to ERK1/2-dependent up-regulation of MMPs.
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PMID:Invasive ability of human renal cell carcinoma cell line Caki-2 is accelerated by gamma-aminobutyric acid, via sustained activation of ERK1/2 inducible matrix metalloproteinases. 1802 51

Hepatocellular carcinoma (HCC) is a highly malignant cancer with poor prognosis. Inhibitors of EGFR and VEGFR for HCC treatment are currently under investigation. Gefitinib and vandetanib inhibit migration of HCC cells on Laminin-5 and Fibronectin, and invasion through matrigel. Both drugs inhibit p-EGFR after short time, while their efficacy on p-Erk1/2 and p-Akt is progressive and stable over time. PI3K/Akt and MEK/Erk1/2 inhibitors, inhibit migration and invasion as well as inducing de-phosphorylation of downstream effectors. Finally, both inhibitors, vandetanib and gefitinib down-regulated the secretion of matrix metalloproteases MMP-2 and MMP-9. All these biological effects seem to depend on the activity of gefitinib and vandetanib blocking activity towards p-EGFR mediated pathways.
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PMID:EGFR and VEGFR as potential target for biological therapies in HCC cells. 1824 88


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