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)

The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-beta (TGF-beta) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF-beta-induced effects on primary human cardiac fibroblasts. BNP inhibited TGF-beta-induced cell proliferation as well as the production of collagen 1 and fibronectin proteins as measured by Western blot analysis. cDNA microarray analysis was performed on RNA from cardiac fibroblasts incubated in the presence or absence of TGF-beta and BNP for 24 and 48 hours. TGF-beta, but not BNP, treatment resulted in a significant change in the RNA profile. BNP treatment resulted in a remarkable reduction in TGF-beta effects; 88% and 85% of all TGF-beta-regulated mRNAs were affected at 24 and 48 hours, respectively. BNP opposed TGF-beta-regulated genes related to fibrosis (collagen 1, fibronectin, CTGF, PAI-1, and TIMP3), myofibroblast conversion (alpha-smooth muscle actin 2 and nonmuscle myosin heavy chain), proliferation (PDGFA, IGF1, FGF18, and IGFBP10), and inflammation (COX2, IL6, TNFalpha-induced protein 6, and TNF superfamily, member 4). Lastly, BNP stimulated the extracellular signal-related kinase pathway via cyclic guanosine monophosphate-dependent protein kinase signaling, and two mitogen-activated protein kinase kinase inhibitors, U0126 and PD98059, reversed BNP inhibition of TGF-beta-induced collagen-1 expression. These findings demonstrate that BNP has a direct effect on cardiac fibroblasts to inhibit fibrotic responses via extracellular signal-related kinase signaling, suggesting that BNP functions as an antifibrotic factor in the heart to prevent cardiac remodeling in pathological conditions.
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PMID:B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. 1472 74

There is a group of cells, called hyalocytes, in the cortical vitreous. Although hyalocytes were discovered more than a hundred years ago, the molecular and cellular biological characteristics of hyalocytes have yet to be elucidated. In this study, we investigated various aspects of hyalocytes and, also performed triamcinolone acetonide (TA)-assisted vitrectomy to remove the hyalocytes for diabetic macular edema. Immunohistochemical analysis of rat eyes showed that 90% of hyalocytes were negative for ED1 but positive for ED2, indicating that hyalocyte is a tissue macrophage. Chimeric mice were created by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated wild-type mice, showing the origin of hyalocyte to be bone marrow cells. Bovine hyalocytes were cultured successfully. The proliferation of hyalocytes was significantly enhanced by hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF-2) and inhibited by transforming growth factor(TGF)-beta. Among these, PDGF-BB stimulated the proliferation most potently through the MEK 1 pathway. Hyalocyte migration assessed by double chamber assay was also stimulated by PDGF-BB and it was mediated by the PI3K and p38 MAPK pathways. Cellular contraction of hyalocyte was significantly enhanced by PDGF-BB and TGF-beta through Rho kinase, p44/42 MAPK, and protein kinase C pathways, as measured by collagen gel contraction assay. Next, the relationship between the vitreous cavity(VC) and the immune system was studied after intravitreous inoculation with ovalbumin (OVA). Injection of OVA into the VC of C 57 BL/6 mice resulted in suppressed systemic cell-mediated immunity to OVA as determined by the ear swelling assay. This aberrant immune responsiveness following VC injection of OVA was termed VC-associated immune deviation or VCAID. The phenomenon of VCAID was mediated by intravitreous antigen-presenting cells. The histological study of chimeric mice showed these cells to be intravitreous residential cells, namely hyalocytes. VCAID was abolished by intravitreous inflammation such as experimental autoimmune uveitis. Finally, TA-assisted vitrectomy for diabetic macular edema was performed to remove cortical vitreous, because it contained many hyalocytes which could secrete inflammatory cytokines including VEGF. Although the number of treated eyes was limited, the surgical results have been favorable so far. The investigation of hyalocytes would open a new avenue for better understanding and development of treatment for various vitreo-retinal diseases.
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PMID:[Cell biology of hyalocytes]. 1473 34

Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the pathogenesis of progressive glomerulonephritis (GN). Previous studies have reported that PDGF-BB stimulates mesangial cells (MCs)-induced collagen matrix remodeling through enhancement of alpha1beta1 integrin-dependent migratory activity. To determine the cell signaling pathway responsible for abnormal MC-related mesangial matrix remodeling in progressive GN, we studied the involvement of the extracellular signal-regulated kinase (ERK)/activator protein-1 (AP-1) pathway in PDGF-BB-enhanced collagen gel contraction. Western blotting and gel shift assay revealed that MC-induced gel contraction resulted in ERK activation in parallel with that of AP-1 binding, peaking at 4 h and lasting at least for 24 h. Application of the MEK inhibitor, U0126, and the c-jun/AP-1 inhibitor, curcumin, inhibited gel contraction and AP-1 activity, respectively, dose dependently. PDGF-BB enhanced not only gel contraction but ERK phosphorylation and AP-1 activity by MCs. Marked inhibitory effects on PDGF-BB-induced gel contraction and ERK/AP-1 activity were observed in the presence of either function blocking anti-alpha1- or anti-beta1-integrin antibody or U0126. Consistently, AP-1-inactive MCs expressing a dominant-negative mutant of c-jun showed a significant decrease of PDGF-BB-induced gel contraction as compared with mock-transfected MCs. Finally, migration assay showed that ERK/AP-1 activity is required for PDGF-BB-stimulated alpha1beta1 integrin-dependent MC migration to collagen I. These results indicated that PDGF-BB enhances alpha1beta1 integrin-mediated collagen matrix reorganization through the activation of the ERK/AP-1 pathway that is crucial for MC migration. We conclude that the ERK/AP-1 pathway plays an important role in PDGF-BB-induced alpha1beta1 integrin-dependent collagen matrix remodeling; therefore, the inhibition of its pathway may provide a novel approach to regulate abnormal collagen matrix remodeling in progressive GN.
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PMID:PDGF-BB enhances alpha1beta1 integrin-mediated activation of the ERK/AP-1 pathway involved in collagen matrix remodeling by rat mesangial cells. 1475 52

Mitogen-activated protein kinase-extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signaling has been implicated in the regulation of tumor cell invasion and metastasis. Migration of HT1080 cells on type I collagen was suppressed by the matrix metalloproteinase (MMP) inhibitors BB94 and tissue inhibitor of metalloproteinase (TIMP)-2 but not by TIMP-1. TIMP-2-specific inhibition suggests that membrane type 1 MMP (MT1-MMP) is likely involved in this process. Activation of ERK was induced in HT1080 cells adhered on dishes coated with type I collagen, and this was inhibited by BB94. MMP-2 processing in HT1080 cells, which also was stimulated by cultivation on type I collagen, was inhibited by MEK inhibitor PD98059. Expression of a constitutively active form of MEK1 promoted MMP-2 processing concomitant with the increase of MT1-MMP levels, suggesting that MT1-MMP is regulated by MEK/ERK signaling. In addition, expression of the hemopexin-like domain of MT1-MMP in HT1080 cells interfered with MMP-2 processing, ERK activation, and cell migration, implying that the enzymatic activity of MT1-MMP is involved in collagen-induced ERK activation, which results in enhanced cell migration. Thus, adhesion of HT1080 cells to type I collagen induces MT1-MMP-dependent ERK activation, which in turn causes an increase in MT1-MMP levels and subsequent cell migration.
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PMID:Membrane type 1 matrix metalloproteinase regulates collagen-dependent mitogen-activated protein/extracellular signal-related kinase activation and cell migration. 1487 36

We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3. These mice displayed incomplete hypertrophy of chondrocytes in the growth plates and a general delay in endochondral ossification, whereas chondrocyte proliferation was unaffected. Immunohistochemical analysis of the cranial base in transgenic embryos showed reduced staining for collagen type X and persistent expression of Sox9 in chondrocytes. These observations indicate that the MAPK pathway inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation. Expression of a constitutively active mutant of MEK1 in chondrocytes of Fgfr3-deficient mice inhibited skeletal overgrowth, strongly suggesting that regulation of bone growth by FGFR3 is mediated at least in part by the MAPK pathway. Although loss of Stat1 restored the reduced chondrocyte proliferation in mice expressing an achondroplasia mutant of Fgfr3, it did not rescue the reduced hypertrophic zone, the delay in formation of secondary ossification centers, and the achondroplasia-like phenotype. These observations suggest a model in which Fgfr3 signaling inhibits bone growth by inhibiting chondrocyte differentiation through the MAPK pathway and by inhibiting chondrocyte proliferation through Stat1.
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PMID:Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. 1487 28

Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesterol-depleting agent beta-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.
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PMID:Hyaluronan cell surface binding is induced by type I collagen and regulated by caveolae in glioma cells. 1501 31

Mechanical strain plays a crucial role in bone remodeling during growth and development and healing of bone besides systemic and local factors. One of the major factors involves in remodeling process is matrix metalloproteinases (MMPs) such as MMP-13 that has been shown to degrade the native interstitial collagens in several tissues. To study how mechanical strain affects extracellular matrix degradation by MMP-13, a biaxial strain was applied to MC3T3-E1 osteoblastic cells plated onto a collagen-coated flexible elastic membrane. The MMP-13 protein and mRNA expression were determined by Western blotting and reverse transcriptase-PCR, respectively. The zymographic activities of MMP-13 increased dramatically at 30 min, reached a peak by 2-fold at 1 h, and maintained up to 4 h. Moreover, the MMP-13 and c-fos mRNA expressed at 5 min, increased to 2.8- and 3-fold at 1 h, respectively, and gradually declined thereafter. Cycloheximide and actinomycin D did not inhibit the MMP-13 and c-fos mRNA expression, suggesting that such expression does not require de novo protein synthesis and not change their stabilities. To investigate which of the mitogen-activated protein kinase (MAPK) pathways involves in the expression of MMP-13, inhibitors such as PD98059, SB203580, and SP600125 were used. However, only PD98059 (an inhibitor of MEK1/2 activation) inhibited MMP-13 and c-fos gene expression; the result was further substantiated by transfecting with the dominant negative mutants of MEK1/2 (MEK K97R) and ERK2. Taken together, our results showed that mechanical strain induces the MMP-13 expression through MEK-ERK signaling pathway to regulate mechanical adaptation.
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PMID:Mechanical strain induces collagenase-3 (MMP-13) expression in MC3T3-E1 osteoblastic cells. 1504 66

The ability of cancer cells to proliferate abnormally and invade surrounding tissue is among the most important features of the malignant phenotype. The mechanisms by which the mitogen activated protein kinase (MAPK) cascade regulates these phenotypes have been investigated for many years. Activated GTP bound Ras binds the upstream protein kinases Raf-1 and B-Raf. The MAPK kinases 1 and 2, known as MKK or MEK, are phosphorylated and activated by Raf. MEKs phosphorylate the extracellular signal regulated kinases ERK1 and ERK2. A unique member of the MAPK family is p97MAPK, the human homolog of rat ERK3. p97MAPK is ubiquitously expressed but whether its cellular functions are different from ERK1 and ERK2 is unknown. p97MAPK is highly expressed in human cancer cell lines. In the present study, expression of p97MAPK was unique among the ERK family in that its expression was induced when human carcinoma cell lines are plated on type IV collagen. This increased expression correlated with slower cancer cell proliferation on collagen compared to plastic tissue culture dishes. Overexpression of p97MAPK was sufficient to inhibit cellular proliferation with concomitant changes in cell cycle regulatory protein expression. p97MAPK also inhibited cancer cell migration and invasion by decreasing Rac1 expression but not that of matrix metalloproteinase 9 which is regulated by other ERKs. These data represent the first reported function of p97MAPK in human cancer cells.
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PMID:Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines. 1506 37

Hepatic fibrogenesis is a consequence of hepatic stellate cells that become activated and transdifferentiate into a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. In this process, platelet-derived growth factor (PDGF) is the most potent stimulus for hepatic stellate cell proliferation and migration, and is overexpressed during active hepatic fibrogenesis. This cytokine binds to the PDGF receptor type beta, activates Ras and sequentially propagates the stimulatory signal sequentially via phosphorylation of Raf-1, MEK and the extracellular-signal regulated kinases ERK1/ERK2. Hepatic injury is associated with both increased autocrine PDGF signaling and upregulation of PDGF receptor. In this study, we report that a dominant-negative soluble PDGF-beta receptor consisting of a chimeric IgG containing the extracellular portion of the PDGF receptor type beta blocks HSC activation and attenuates fibrogenesis induced by ligation of the common bile duct in rats. In culture-activated hepatic stellate cells, the soluble receptor blocks phosphorylation of endogenous PDGF receptor, phosphorylation of the ERK1/EKR2 signal and reduces proliferative activities of HSC. In vivo, both the delivery of the purified soluble PDGF antagonist and the administration of adenoviruses expressing the artificial transgene were able to reduce significantly the expression of collagen and alpha-smooth muscle actin. Our results demonstrate that PDGF plays a critical role in the progression and initiation of experimental liver fibrogenesis, and suggest that early anti-PDGF intervention should have a therapeutical impact on the treatment of liver fibrogenesis.
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PMID:Dominant-negative soluble PDGF-beta receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis. 1507 22

Increased expression of hyaluronan (HA) has been associated with both acute renal injury and progressive renal disease, although the functional significance of this remains unclear. There is overwhelming evidence that transforming growth factor (TGF)-beta1 is critical to the development of progressive renal disease. Recent studies suggest an interaction between HA and TGF-beta signaling in cancer cell biology. The aim of this study was to examine the potential role of HA as a modulator of TGF-beta1 function in renal proximal tubular epithelial cells (PTC). Under resting conditions, co-localization of the principal receptor for HA, CD44, and both the TGF-beta type I and type II receptors was demonstrated by immunoprecipitation and western analysis and further confirmed by immunocytochemistry and confocal microscopy. Stimulation of PTC with TGF-beta1 led to increased synthesis of both type III and type IV collagen assessed by Western analysis. Addition of HA did not alter collagen synthesis, but abrogated TGF-beta1-mediated increase in type III and type IV collagen. This effect was blocked by the addition of a blocking antibody to CD44 and also by inhibition of MAP kinase kinase (MEK) activity. Furthermore HA decreased TGF-beta1 activation of a luciferase-SMAD responsive construct, and decreased translocation of SMAD4 into the cell nucleus. We have previously demonstrated an anti-migratory effect of TGF-beta1 in a scratch wounding model. As with HA antagonism of TGF-beta1 extracellular matrix generation, HA reduced the anti-migratory effect of TGF-beta1 in a CD44-dependent manner. In contrast to the effect of TGF-beta1 on collagen synthesis, which is SMAD-dependent, the anti-migratory effect of TGF-beta1 in this model is known to be dependent of activation of RhoA. In the presence of HA, TGF-beta1-mediated activation of RhoA was also abrogated in a CD44-dependent manner. The results suggest that co-localization of CD44 and TGF-beta receptors facilitate modulation of both SMAD and non-SMAD-dependent TGF-beta1-mediated events by HA. Our results therefore suggest that alteration of HA synthesis may represent an endogenous mechanism to limit renal injury.
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PMID:Hyaluronan attenuates transforming growth factor-beta1-mediated signaling in renal proximal tubular epithelial cells. 1516 34


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