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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the chitinase 3-like protein HC-gp39 (human cartilage glycoprotein 39) is associated with conditions of increased matrix turnover and tissue remodelling. High levels of this protein have been found in sera and synovial fluids of patients with inflammatory and degenerative arthritis. In order to assess the role of HC-gp39 in matrix degradation induced by inflammatory cytokines, we have examined its effect on the responses of connective tissue cells to TNF-alpha (tumour necrosis factor-alpha) and IL-1 (interleukin-1) with respect to activation of signalling pathways and production of MMPs (matrix metalloproteases) and chemokines. Stimulation of human skin fibroblasts or articular chondrocytes with IL-1 or TNF-alpha in the presence of HC-gp39 resulted in a marked reduction of both p38 mitogen-activated protein kinase and stress-activated protein kinase/Jun N-terminal kinase phosphorylation, whereas nuclear translocation of nuclear factor kappaB proceeded unimpeded. HC-gp39 suppressed the cytokine-induced secretion of MMP1, MMP3 and MMP13, as well as secretion of the chemokine IL-8. The suppressive effects of HC-gp39 were dependent on phosphoinositide 3-kinase activity, and treatment of cells with HC-gp39 resulted in AKT-mediated serine/threonine phosphorylation of apoptosis signal-regulating kinase 1. This process could therefore be responsible for the down-regulation of cytokine signalling by HC-gp39. These results suggest a physiological role for HC-gp39 in limiting the catabolic effects of inflammatory cytokines.
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PMID:The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha. 1501 34

Rheumatoid arthritis (RA) causes a symmetric, inflammatory polyarthritis that results in joint destruction and significant disability. Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in its pathogenesis and represent potential therapeutic targets. The IkappaB kinase (IKK)-related kinase, IKKepsilon/IKKi, which plays a pivotal role in regulating antiviral gene transcription, is constitutively expressed by cultured fibroblast-like synoviocytes (FLS) and could participate in the pathogenesis of RA. In the current studies we demonstrate that IKKepsilon protein is expressed in RA and osteoarthritis synovium and that the protein is found primarily in the synovial intimal lining. Functional studies in cultured FLS showed that IKKepsilon kinase activity is rapidly induced by cytokines, although IkappaB phosphorylation is significantly less compared with IKK2. Because NF-kappaB activation is similar in wild-type and IKKepsilon knockout murine FLS, studies were performed to identify an alternative substrate for IKKepsilon. Interestingly, c-Jun is a more efficient substrate for IKKepsilon immunocomplexes in human FLS and this activity appears to be independent of JNK. The functional relevance of IKKepsilon was examined using murine IKKepsilon(-/-) cultured FLS. IL-1-, TNF-alpha-, and LPS-mediated induction of matrix metalloproteinases, MMP3 and MMP13, is significantly decreased in the IKKepsilon(-/-) cells. These data suggest a novel role for the IKKepsilon complex in synovial inflammation, extracellular matrix destruction, and activation of the viral program and innate immune response in RA.
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PMID:Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes. 1587 44

Asbestos is a known inflammatory, carcinogenic, and fibrotic agent, but the mechanisms leading to asbestos-induced lung diseases are unclear. Using a murine inhalation model of fibrogenesis, we show that asbestos causes significant increases in mRNA levels of lung matrix metalloproteinases (MMPs 12 and 13) and tissue inhibitor of metalloproteinases (TIMP1), as well as increased activities of MMP 2, 9, and 12 in bronchoalveolar lavage fluids (BALF). Asbestos-exposed PKCdelta knockout (PKCdelta-/-) mice exhibited decreased expression of lung MMP12 and MMP13 compared with asbestos-exposed wild-type mice. Studies using small molecule inhibitors in murine alveolar epithelial type II cells (C10) and primary lung fibroblasts confirmed that asbestos transcriptionally up-regulates MMPs via an EGFR (or other growth factor receptors)/PI3K/PKCdelta/ERK1/2 pathway. Moreover, use of a broad-spectrum MMP inhibitor showed that MMPs play an important role in further enhancing asbestos-induced signaling events by activating EGFR. These data reveal a potentially important link between asbestos signaling and integrity of the extracellular matrix (ECM) that likely contributes to asbestos-induced lung remodeling and diseases.
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PMID:Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKCdelta-dependent pathway in murine lung. 1657 79

Papillary thyroid cancers (PTC) are associated with nonoverlapping mutations of genes coding for mitogen-activated protein kinase signaling effectors (i.e., the TK receptors RET or NTRK and the signaling proteins RAS and BRAF). We examined the pattern of gene expression after activation of these oncoproteins in thyroid PCCL3 cells, with the goal of identifying pathways or gene subsets that may account for the phenotypic differences observed in human cancers. We hybridized cDNA from cells treated with or without doxycycline to induce expression of BRAF(V600E), RET/PTC3, or RET/PTC3 with small interfering RNA-mediated knockdown of BRAF, respectively, to slides arrayed with a rat 70-mer oligonucleotide library consisting of 27,342 oligos. Among the RET/PTC3-induced genes, 2,552 did not require BRAF as they were similarly regulated by RET/PTC3 with or without BRAF knockdown and not by expression of BRAF(V600E). Immune response and IFN-related genes were highly represented in this group. About 24% of RET/PTC3-regulated genes were BRAF dependent, as they were similarly modified by RET/PTC3 and BRAF(V600E) but not in cells expressing RET/PTC3 with knockdown of BRAF. A gene cluster coding for components of the mitochondrial electron transport chain pathway was down-regulated in this group, potentially altering regulation of cell viability. Metalloproteinases were also preferentially induced by BRAF, particularly matrix metalloproteinase 3 (MMP3), MMP9, and MMP13. Accordingly, conditional expression of BRAF was associated with markedly increased invasion into Matrigel compared with cells expressing RET/PTC3. The preferential induction of MMPs by BRAF could explain in part the more invasive behavior of thyroid cancers with BRAF mutations.
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PMID:Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. 1681 23

Cerebral ischemia results in a local inflammatory response that contributes to the size of the lesion, however, the involvement of the cerebral vasculature is unknown. We hypothesise that the expression of inflammatory genes (Il6, iNOS, cxcl2, TNF-alpha and Il-1beta) and extracellular-matrix-related genes (MMP9, MMP13) is induced in cerebral arteries following cerebral ischemia via activation of mitogen activated kinases (MAPKs). This hypothesis was tested in vivo by experimental subarachnoid haemorrhage (SAH) and temporal middle cerebral artery occlusion (MCAO), and by organ culture of isolated cerebral arteries with quantitative real time PCR (mRNA expression) and immunohistochemistry (localization of protein expression). The gene promoters were investigated in silica with computer analysis. The mRNA analysis revealed that the ischemic models, SAH and MCAO, as well as organ culture of isolated cerebral arteries resulted in transcriptional upregulation of the abovementioned genes. The protein expression involved phosphorylation of three different MAPKs signalling pathways (p38, ERK 1/2 and SAPK/JNK) and the downstream transcription factors (ATF-2, Elk-1, c-Jun) shown by immunohistochemistry and quantified by image analysis. All three models revealed the same pattern of activation in the cerebrovascular smooth muscle cells. The in silica analysis demonstrated binding sites for said transcription factors. The results suggest that cerebral ischemia and organ culture induce activation of p38, ERK 1/2 and SAPK/JNK in cerebral arteries which in turn activate the transcription factors ATF-2, Elk-1 and c-Jun and the expression of inflammatory and extracellular-matrix-related genes in the wall of cerebral arteries.
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PMID:Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries. 1782 93

A classic model of tubulogenesis utilizes Madin-Darby canine kidney (MDCK) cells. MDCK cells form monoclonal cysts in three-dimensional collagen and tubulate in response to hepatocyte growth factor, which activates multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway. It was shown previously that MAPK activation is necessary and sufficient to induce the first stage of tubulogenesis, the partial epithelial to mesenchymal transition (p-EMT), whereas matrix metalloproteinases (MMPs) are necessary for the second redifferentiation stage. To identify specific MMP genes, their regulators, tissue inhibitors of matrix metalloproteinases (TIMPs), and the molecular pathways by which they are activated, we used two distinct MAPK inhibitors and a technique we have termed subtraction pathway microarray analysis. Of the 19 MMPs and 3 TIMPs present on the Canine Genome 2.0 Array, MMP13 and TIMP1 were up-regulated 198- and 169-fold, respectively, via the MAPK pathway. This was confirmed by two-dimensional and three-dimensional real time PCR, as well as in MDCK cells inducible for the MAPK gene Raf. Knockdown of MMP13 using short hairpin RNA prevented progression past the initial phase of p-EMT. Knockdown of TIMP1 prevented normal cystogenesis, although the initial phase of p-EMT did occasionally occur. The MMP13 knockdown phenotype is likely because of decreased collagenase activity, whereas the TIMP1 knockdown phenotype appears due to increased apoptosis. These data suggest a model, which may also be important for development of other branched organs, whereby the MAPK pathway controls both MDCK p-EMT and redifferentiation, in part by activating MMP13 and TIMP1.
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PMID:Matrix metalloproteinase 13 (MMP13) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1), regulated by the MAPK pathway, are both necessary for Madin-Darby canine kidney tubulogenesis. 1803 71

Chondrocytes regulate the composition of cartilage extracellular matrix in response to mechanical signals, but the intracellular pathways involved in mechanotransduction are still being defined. Mitogen-activated protein kinase (MAPK) pathways are activated by static and dynamic compression of cartilage, which simultaneously induce intratissue fluid flow, pressure gradients, cell, and matrix deformation. First, to determine whether cell and matrix deformation alone could induce MAPK activation, we applied dynamic shear to bovine cartilage explants. Using Western blotting, we measured ERK1/2 and p38 activation at multiple time points over 24 h. Distinct activation time courses were observed for different MAPKs: a sustained 50% increase for ERK1/2 and a delayed increase in p38 of 180%. We then investigated the role of MAPK activation in mechano-induced chondrocyte gene expression. Cartilage explants were preincubated with inhibitors of ERK1/2 and p38 activation before application of 1-24 h of three distinct mechanical stimuli relevant to in vivo loading (50% static compression, 3% dynamic compression at 0.1 Hz, or 3% dynamic shear at 0.1 Hz). mRNA levels of selected genes involved in matrix homeostasis were measured using real-time PCR and analyzed by k-means clustering to characterize the time- and load-dependent effects of the inhibitors. Most genes examined required ERK1/2 and p38 activation to be regulated by these loading regimens, including matrix proteins aggrecan and type II collagen, matrix metalloproteinases MMP13, and ADAMTS5, and transcription factors downstream of the MAPK pathway, c-Fos, and c-Jun. Thus, we demonstrated that the MAPK pathway is a central conduit for transducing mechanical forces into biological responses in cartilage.
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PMID:Shear- and compression-induced chondrocyte transcription requires MAPK activation in cartilage explants. 1808 70

We report a process that results in the acceleration of matrix degradation in human articular cartilage, a phenomenon commonly observed in osteoarthritis (OA). The study was conducted by (1) examining the potential of collagen II in modulating the gene expression profile of primary human chondrocytes (PHCs), and (2) investigating the involvement of pro-inflammatory signaling cascades. We first tested the collagen II-dependent induction of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in PHCs. PHCs were incubated with or without monomeric (i.e., nonfibrillar) collagen II. Cells were then analyzed by RT-PCR for the expression of MMP1, MMP3, MMP13, MMP14, and IL-1beta. ELISA was used to quantify IL-6 and IL-8 release. To examine the influence of collagen II signaling, specifically the role of MAPK p38, a p38-inhibitor was added prior to collagen treatment. Changes in IkappaB concentration were monitored by immunoblot analysis to detect NFkappaB signaling. Results indicated that incubation of PHCs with collagen II did produce a dose-dependent induction of MMP1, MMP3, MMP13, MMP14, as well as cytokines IL-1beta, IL-6, and IL-8. At the same time, inhibition of p38 and IkappaB degradation revealed that collagen II-dependent gene induction also involves MAPK p38 and NFkappaB signaling. Thus, we provide evidence for a collagen II-dependent feed-forward mechanism whereby collagen II induces first MMPs and pro-inflammatory cytokines and then release of collagen II fragments from mature collagen II fibers. This, in turn, induces more pro-inflammatory cytokines and MMPs, and the process is repeated, which results in the acceleration and perpetuation of cartilage matrix degradation.
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PMID:A critical role for collagen II in cartilage matrix degradation: collagen II induces pro-inflammatory cytokines and MMPs in primary human chondrocytes. 1865 32

TIMP-1 (Tissue inhibitor of matrix metalloproteinase-1) is typically associated with inhibition of matrix metalloproteinases (MMP) induced invasion. However, TIMP-1 is overexpressed in many malignancies and is associated with poor prognosis in breast cancer. The mechanisms by which TIMP-1 promotes tumorigenesis are unclear. Reduced levels of TIMP-1 mediated by shRNA in MDA-MB-231 breast cancer cells had no effect on cellular physiology in vitro or tumor growth in SCID mice compared to vector control MDA-MB-231 cells. However, overexpression of TIMP-1 in MDA-MB-231 cells resulted in inhibition of cell invasion and enhanced phosphorylation of p38 MAPK and AKT in vitro. Additionally, treatment of parental MDA-MB-231 cells with purified TIMP-1 protein led to activation of p38 MAPK and MKK 3/6. cDNA array analysis demonstrated that high expression of TIMP-1 in MDA-MB-231 cells resulted in alterations in expression of approximately 200 genes, 1.5 fold or greater compared to vector control cells (P < 0.1). Real-time RT-PCR confirmed changes in expression of several genes associated with cancer progression including DAPK1, FGFR4 and MAPK13. In vivo, high TIMP-1 expression induced tumor growth in SCID mice compared to vector control cells and increased tumor vessel density. Affymetrix array analysis of vector control and TIMP-1 MDA-MB-231 xenograft tumors revealed that TIMP-1 altered expression of approximately 600 genes in vivo, including MMP1, MMP13, S100A14, S100P, Rab25 and ID4. These combined observations suggest that the effects of TIMP-1 differ significantly in a 2-D environment compared to the 3-D environment and that TIMP-1 stimulates tumor growth.
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PMID:TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro. 1878 47

MMP13 is enriched in mature chondrocytes and considered a prime cause of ECM degradation in the osteoarthritic articular cartilage in temporomandibular joints. We asked whether surviving stress to the endoplasmic reticulum (ER) would upregulate transcription of MMP13, and if so, whether a cross-talk would exist between surviving ER stress and p38 MAPK pathways. Using C28/I2 chondrocyte cell line, ER stress was induced by thapsigargin and tunicamycin and upregulation of phosphorylated eIF2alpha and ATF4 protein was observed. Both thapsigargin and tunicamycin elevated the mRNA level of MMP13 and phosphorylation of p38 MAPK. Thapsigargin-induced MMP13 mRNA upregulation was significantly suppressed by SB203580, while its upregulation by tunicamycin was completely attenuated by SB203580. Those results support that homeostasis of chondrocytes is affected by the surviving ER stress through p38 MAPK pathways, suggesting a potential role of ER stress in joint diseases such as osteoarthritis.
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PMID:Involvement of p38 MAPK in regulation of MMP13 mRNA in chondrocytes in response to surviving stress to endoplasmic reticulum. 1910 Sep 62


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