Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 beta (IL-1beta) is a central mediator of inflammation and connective tissue destruction in rheumatoid arthritis. IL-1beta activates articular chondrocytes to produce matrix metalloproteinase-1 (MMP-1), an enzyme capable of dismantling the collagen scaffold of articular cartilage. To define the transcription factors and signaling intermediates that activate MMP-1 transcription in chondrocytes, we performed transient transfection of MMP-1 promoter constructs followed by reporter assays. These studies identified an IL-1beta-responsive region of the human MMP-1 promoter that contains a consensus CCAAT enhancer-binding protein (C/EBP) binding site. Deletion of this site reduced overall transcriptional activity of the MMP-1 promoter, as well as decreased fold induction by IL-1beta. IL-1beta stimulation of chondrocytes increased binding of C/EBP-beta to the MMP-1 C/EBP site. Extracellular signal regulated kinase (ERK) pathway-dependent phosphorylation of C/EBP-beta on threonine 235 activates this transcription factor. Here we show that IL-1beta stimulation of chondrocytes induced phosphorylation of C/EBP-beta on threonine 235, and that the ERK pathway inhibitor PD98059 reduced this phosphorylation. We further show that PD98059 reduces IL-1beta-induced MMP-1 mRNA expression in chondrocytes. Moreover, inhibition of the ERK pathway by expression of dominant-negative forms of ERK1 and ERK2 impaired the ability of IL-1beta to transactivate the MMP-1 promoter. Our findings demonstrate a novel role for C/EBP-beta in IL-1beta-induced connective tissue disease and define a new nuclear target for the ERK pathway in MMP-1 gene activation.
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PMID:Interleukin-1 beta induction of matrix metalloproteinase-1 transcription in chondrocytes requires ERK-dependent activation of CCAAT enhancer-binding protein-beta. 1645 2

The transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) regulates the expression of key genes in inflammation but little is known about the involvement of C/EBPbeta in glial activation. In this report, we have studied the patterns of astroglial and microglial C/EBPbeta expression in primary mouse cortical cultures. We show that both astrocytes and microglia express C/EBPbeta in untreated mixed glial cultures. C/EBPbeta is upregulated when glial activation is induced by lipopolysaccharide (LPS). The LPS-induced upregulation of glial C/EBPbeta is rapid (2 h at mRNA level, 4 h at protein level). It is elicited by low concentrations of LPS (almost maximal effect at 1 ng/mL) and it is reversed by the protein synthesis inhibitor cycloheximide. C/EBPbeta nuclear levels increase both in astrocytes and microglia after LPS treatment, and the response is more marked in microglia. The LPS-induced increase in microglial C/EBPbeta is prevented by coadministration of the MAP kinase inhibitors SB203580 (p38 inhibitor) + SP600125 (JNK inhibitor) or SB203580 + U0126 (ERK inhibitor). Systemic injection of LPS also increases brain nuclear levels of C/EBPbeta as shown by Western blot, and this increase is localized in microglial cells as shown by double immunofluorescence, in the first report to our knowledge of C/EBPbeta expression in activated glial cells in vivo. These findings support a role for C/EBPbeta in the activation of astrocytes and, particularly, microglia. Given the nature of the C/EBPbeta-regulated genes, we hypothesize that this factor participates in neurotoxic effects associated with glial activation. (c) 2006 Wiley-Liss, Inc.
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PMID:Upregulation of CCAAT/enhancer binding protein beta in activated astrocytes and microglia. 1707 24

Nobiletin is a polymethoxylated flavone found in certain citrus fruits. Here we demonstrate that nobiletin enhance differentiation of 3T3-L1 preadipocytes. Nobiletin dose-dependently increased accumulation of lipid droplets in adipocytes. Quantitative RT-PCR analyses indicated that nobiletin increased the expression of genes critical for acquisition of the adipocyte phenotype. Some of them were known peroxisome proliferator activated receptor gamma (PPARgamma) targets and PPARgamma itself, however, nobiletin did not exhibit PPARgamma ligand activity. We observed the expression of CCAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor for PPARgamma, was increased by nobiletin. The activation of cAMP-responsive element binding protein (CREB) and extracellular signal-regulated kinase (ERK), which play important roles in C/EBPbeta expression were also potentiated by nobiletin. Furthermore, nobiletin stimulated lipolysis in differentiated adipocytes, which is known to be stimulated by cAMP pathway. These results suggested that nobiletin enhanced both differentiation and lipolysis of adipocyte through activation of signaling cascades mediated by cAMP/CREB.
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PMID:Nobiletin enhances differentiation and lipolysis of 3T3-L1 adipocytes. 1743 53

Keratinocyte growth factor (KGF) and alpha(5)beta(1)-integrin are not expressed in normal skin but they are both highly upregulated in the migrating epidermis during wound healing. Here we report that KGF increased alpha(5) mRNA and protein levels in epidermoid carcinoma cells and stratified bioengineered epidermis. Interestingly, KGF increased integrin alpha(5) in the basal as well as suprabasal cell epidermal layers. Promoter studies indicated that KGF-induced integrin alpha(5) promoter activation was dependent on the C/EBP transcription factor binding site. Accordingly, KGF induced sustained phosphorylation of C/EBP-beta that was dependent on activation of ERK1/2. In addition, a dominant negative form of C/EBP-beta inhibited alpha(5) promoter activity and blocking C/EBP-beta with siRNA diminished integrin alpha(5) expression. Taken together, our data indicate that KGF increased integrin alpha(5) expression by phosphorylating C/EBP-beta. Interestingly, KGF-induced upregulation of integrin alpha(5) was more pronounced in three-dimensional tissue analogues than in conventional two-dimensional culture suggesting that stratified epidermis may be useful in understanding the effects of growth factors in the local tissue microenvironment.
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PMID:KGF promotes integrin alpha5 expression through CCAAT/enhancer-binding protein-beta. 1759 95

Matrix metalloproteinases (MMPs) degrade collagen and mediate tissue remodeling. The novel cytokine IL-17 is expressed during various inflammatory conditions and modulates MMP expression. We investigated the effect of IL-17 on MMP-1 expression in primary human cardiac fibroblasts (HCF) and delineated the signaling pathways involved. HCF were treated with recombinant human IL-17. MMP-1 expression was analyzed by Northern blotting, RT-quantitative PCR, Western blotting, and ELISA; transcriptional induction and transcription factor binding by EMSA, ELISA, and reporter assay; and p38 MAPK and ERK1/2 activation by protein kinase assays and Western blotting. Signal transduction pathways were investigated using pharmacological inhibitors, small interfering RNA (siRNA), and adenoviral dominant-negative expression vectors. IL-17 stimulated MMP-1 gene transcription, net mRNA levels, protein, and promoter-reporter activity in HCF. This response was blocked by IL-17 receptor-Fc chimera and IL-17 receptor antibodies, but not by IL-6, TNF-alpha, or IL-1beta antibodies. IL-17-stimulated type I collagenase activity was inhibited by the MMP inhibitor GM-6001 and by siRNA-mediated MMP-1 knockdown. IL-17 stimulated activator protein-1 [AP-1 (c-Fos, c-Jun, and Fra-1)], NF-kappaB (p50 and p65), and CCAAT enhancer-binding protein (C/EBP)-beta DNA binding and reporter gene activities, effects attenuated by antisense oligonucleotides, siRNA-mediated knockdown, or expression of dominant-negative signaling proteins. Inhibition of AP-1, NF-kappaB, or C/EBP activation attenuated IL-17-stimulated MMP-1 expression. IL-17 induced p38 MAPK and ERK1/2 activation, and inhibition by SB-203580 and PD-98059 blunted IL-17-mediated transcription factor activation and MMP-1 expression. Our data indicate that IL-17 induces MMP-1 in human cardiac fibroblasts directly via p38 MAPK- and ERK-dependent AP-1, NF-kappaB, and C/EBP-beta activation and suggest that IL-17 may play a critical role in myocardial remodeling.
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PMID:IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1/2-dependent C/EBP-beta , NF-kappaB, and AP-1 activation. 1792 24

Staphylococcus aureus, a major sepsis-causing Gram-positive bacterium, invades pulmonary epithelial cells and causes lung diseases. In the lung, alveolar type II epithelial cells play an important role in innate immunity by secreting chemokines and antimicrobial peptides upon bacterial infection whereas type I cells mainly function in gas-exchange. In this study, we investigated the ability of S. aureus peptidoglycan (PGN) to induce expression of a chemokine, IL-8, in a human alveolar type II epithelial cell line, A549. PGN induces IL-8 mRNA and protein expression in a dose- and time-dependent manner. Supplementation of soluble CD14 further enhanced the PGN-induced IL-8 expression. Interestingly, PGN-induced IL-8 expression was inhibited by nystatin, a specific inhibitor for lipid rafts, but not by chlorpromazine, a specific inhibitor for clathrin-coated pits. Furthermore, PGN-induced IL-8 expression was attenuated by inhibitors for MAP kinases such as ERK, p38 kinase, and JNK/SAPK, whereas no inhibitory effect was observed by inhibitors for reactive oxygen species or protein kinase C. Electrophoretic mobility shift assay demonstrates that PGN increased the DNA binding of the transcription factors, AP-1 and NF-kappaB while minimally, NF-IL6, all of which are involved in the transcription of IL-8. Taken together, these results suggest that PGN induces IL-8 expression in a CD14-enhanced manner in human alveolar type II epithelial cells, through the formation of lipid rafts and the activation of MAP kinases, which ultimately leads to activation of AP-1, NF-kappaB, and NF-IL6.
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PMID:Peptidoglycan-mediated IL-8 expression in human alveolar type II epithelial cells requires lipid raft formation and MAPK activation. 1799 61

Hepatic oxidative stress plays a critical role in metabolic forms of steatohepatitis. Phyllanthus urinaria, an herbal medicine, has been reported to have potential antioxidant properties. We tested the effects of P. urinaria on nutritional steatohepatitis both in vitro and in vivo. Immortalized normal hepatocytes (AML-12) or primary hepatocytes were exposed to control, the methionine-and-choline-deficient (MCD) culture medium, in the presence or absence of P. urinaria for 24 hours. Hepatocyte triglyceride, release of alanine aminotransferase, lipoperoxides, and reactive oxygen species production were determined. Age-matched C57BL/6 and db/db mice were fed control or MCD diet for 10 days with or without P. urinaria. Hepatic steatosis, necroinflammation, triglycerides, and lipid peroxide levels were determined. Hepatic expression of inflammatory factors and lipid regulatory mediators were assayed. P. urinaria reduced steatosis and alanine aminotransferase (ALT) levels in culture of hepatocytes in a dose-dependent manner. Phyllanthus prevented MCD-induced hepatic fat accumulation and steatohepatitis in mice. This effect was associated with repressed levels of hepatic lipid peroxides, reduced expression of cytochrome P450-2E1, pro-inflammatory tumor necrosis factor alpha, interleukin-6, dampened activation of inflammatory c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-kappaB), increased expression of lipolytic cytochrome P450 (Cyp4a10), and suppressed transcriptional activity of lipogenic CCAAT/enhancer binding protein beta (C/EBPbeta). Hepatic acyl co-enzyme A oxidase that regulated hepatic beta-oxidation of fatty acid and other lipid regulators were not affected by P. urinaria. In conclusion, P. urinaria effectively alleviated the steatohepatitis induced by the MCD, probably through dampening oxidative stress, ameliorating inflammation, and decreasing lipid accumulation.
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PMID:Phyllanthus urinaria ameliorates the severity of nutritional steatohepatitis both in vitro and in vivo. 1815 36

Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activities are modulated in a manner that reflects the secretory demand on beta cells to integrate long- and short-term nutrient sensing information. Our studies have focused on the mechanisms of ERK1/2 activation in beta cells and on the actions of ERK1/2 that regulate beta cell function. Insulin and growth factors regulate ERK1/2 in beta cells in a largely calcium-independent manner. Nutrients and anticipatory hormones, in contrast, activate ERK1/2 in a calcium-dependent manner in these cells. We are exploring the key intermediates in these distinct activation pathways and find that calcineurin is essential for the nutrient pathway but is not essential for the growth factor pathway. Using reporter assays, heterologous reconstitution, electrophoretic mobility shift assays, Northern analysis, Q-PCR and chromatin immunoprecipitation, we have examined several genes that are regulated by ERK1/2, primarily the insulin gene and the apoptotic factor C/EBP-homologous protein (CHOP)-10 (GADD153/DDIT-3), a bZIP protein. ERK1/2-sensitive transcriptional regulators common to these two genes are C/EBP-beta and MafA. The insulin promoter is both positively and negatively regulated by glucose and other nutrients. Exposure to glucose for minutes to hours causes an increase in the rate of insulin gene transcription. In contrast, exposure to elevated glucose for 48 h or more results in inhibition of the insulin gene promoter. Both of these processes depend on ERK1/2 activity. Expression of CHOP is induced by stresses including nutrient deprivation and endoplasmic reticulum stress. CHOP gene expression, especially that regulated by nutrients, is also ERK1/2-dependent in beta cells, These studies support the hypothesis that the genes regulated by ERK1/2 and the mechanisms employed are key to maintaining normal beta cell function.
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PMID:The protein kinases ERK1/2 and their roles in pancreatic beta cells. 1817 25

Substances of abuse, such as opiates, and astroglial-derived proinflammatory cytokines, such as interleukin (IL)-1beta, likely contribute to the neuroinflammatory and neurodegenerative processes observed in NeuroAIDS in injection drug users. Furthermore, uncontrolled synthesis and activation of complement component C3 in the brain can also lead to inflammation and neurodegeneration. We hypothesized that morphine may alter regulation of the C3 gene by IL-1beta in astrocytes. Our studies demonstrate that IL-1beta induces C3 promoter activity in a CAAT/enhancer-binding protein (C/EBP)-dependent manner. Inhibition of IL-1beta mediated C3 promoter activation by the dominant negative mutant of p38-alpha mitogen-activated protein kinase suggests that IL-1beta induces C3 expression through the activation of C/EBP. Morphine (0.01 microM) in combination with IL-1beta further induced C3 promoter activity. Similarly, the C/EBP-beta isoform liver activating protein and C/EBP-delta-induced C3 promoter activity were upregulated by morphine and IL-1beta. Taken together, this study illustrates that morphine modulates IL-1beta-mediated C3 expression in astrocytic cells.
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PMID:Regulation of complement component C3 in astrocytes by IL-1beta and morphine. 1824 23

Transcription factor C/EBP-beta regulates a number of physiological responses. During an investigation of the growth-suppressive effects of interferons (IFNs), we noticed that cebpb(-/-) cells fail to undergo apoptosis upon gamma IFN (IFN-gamma) treatment, compared to wild-type controls. To examine the basis for this response, we have performed gene expression profiling of isogenic wild-type and cebpb(-/-) bone marrow macrophages and identified a number of IFN-gamma-regulated genes that are dependent on C/EBP-beta for their expression. These genes are distinct from those regulated by the JAK-STAT pathways. Genes identified in this screen appear to participate in various cellular pathways. Thus, we identify a new pathway through which the IFNs exert their effects on cellular genes through C/EBP-beta. One of these genes is death-associated protein kinase 1 (dapk1). DAPK1 is critical for regulating the cell cycle, apoptosis, and metastasis. Using site-directed mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we show that C/EBP-beta binds to the promoter of dapk1 and is required for the regulation of dapk1. Both mouse dapk1 and human dapk1 exhibited similar dependences on C/EBP-beta for their expression. The expression of the other members of the DAPK family occurred independently of C/EBP-beta. Members of the C/EBP family of transcription factors other than C/EBP-beta did not significantly affect dapk1 expression. We identified two elements in this promoter that respond to C/EBP-beta. One of these is a consensus C/EBP-beta-binding site that constitutively binds to C/EBP-beta. The other element exhibits homology to the cyclic AMP response element/activating transcription factor binding sites. C/EBP-beta binds to this site in an IFN-gamma-dependent manner. Inhibition of ERK1/2 or mutation of an ERK1/2 site in the C/EBP-beta protein suppressed the IFN-gamma-induced response of this promoter. Together, our data show a critical role for C/EBP-beta in a novel IFN-induced cell growth-suppressive pathway via DAPK1.
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PMID:Critical role for transcription factor C/EBP-beta in regulating the expression of death-associated protein kinase 1. 1825 Jan 55


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