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)

Activated protein C (APC) and protein C inhibitor (PCI) are the major components of the anticoagulant protein C pathway. Recently, APC and PCI have been demonstrated to play many roles not only in the regulation of hemostasis but also in cell inflammation, proliferation, apoptosis, tumor cell migration, invasion, and metastasis. Here we summarize the role of APC and PCI in malignancy. APC increases migration of ovarian cancer cells and choriocarcinoma cells in a Transwell invasion assay in the presence of plasminogen activator inhibitor (PAI)-1; this finding suggests that APC stimulates urokinase-type plasminogen activator (uPA) by forming a complex with PAI-1 leading to activation of extracellular matrix proteases and increased invasion. It was recently reported that APC, independent of PAI-1, may increase invasion and chemotaxis of breast cancer cells by activating specific signaling pathways through endothelial protein C receptor (EPCR) and protease-activated receptor (PAR)-1. APC also increased proliferation of vascular endothelial cells and angiogenesis by EPCR-mediated activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and endothelial nitric oxide synthase (eNOS) pathways. On the other hand, we have previously reported that both uPA and PCI are synthesized in renal proximal tubular epithelial cells (RPTECs) and that PCI expression in RPTEC-derived tumor cells is significantly decreased compared with normal RPTECs. The RPTEC-derived renal carcinoma cell line Caki-1 also showed decreased expression of PCI. PCI inhibited in vitro invasive activity of Caki-1 and breast cancer cells by its protease inhibitory activity. However, PCI was found to inhibit the growth and metastatic potential of breast cancer cells independent of its protease inhibitory activity in severe combined immunodeficient mice. PCI can also inhibit angiogenesis in vivo and in vitro assays independent of its protease inhibitory activity. Overall, these data show that APC promotes tumor cell invasion by EPCR-mediated and PAR-1-mediated protease activity and that PCI inhibits tumor cell invasion in vitro by its protease inhibitory activity and suppresses tumor cell growth, metastasis, and angiogenesis independent of its protease inhibitory activity.
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PMID:Protein C and its inhibitor in malignancy. 1800 Jul 93

Tea polyphenols like epigallocatechin gallate and theaflavins are established chemopreventive agents for colorectal carcinogenesis. However, studies on evaluating similar chemopreventive properties of thearubigins or polymeric black tea polyphenols (PBPs), the most abundant polyphenols in black tea, are limited. Hence, in the present study we aim to investigate chemopreventive effects along with probable mechanisms of action of PBP extract employing 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in Sprague-Dawley rats as experimental model. The present study suggests that PBPs, like other tea polyphenols, also inhibit DMH-induced colorectal tumorigenesis by decreasing tumor volume and multiplicity. This study also shows that although the pretreatment with PBP extract could induce detoxifying enzymes in hepatic and colorectal tissue, it did not show any additional chemopreventive effects when compared to treatments with PBP extract after initiation with DMH. Mechanistically, PBP extract may inhibit colorectal carcinogenesis by decreasing DMH-induced cell proliferation via Wnt/beta-catenin pathway. Treatments with PBP extract showed decreased levels of COX-2, c-MYC and cyclin D1 proteins which aid cell proliferation probably by regulating beta-catenin by maintaining expression of APC and decreasing inactivation of GSK3beta. DMH-induced activation of MAP kinases such as ERK and JNK was also found to be inhibited by treatments with PBP extract. In conclusion, the protective effects of PBP extract could be attributed to inhibition of DMH-induced cellular proliferation probably through beta-catenin regulation.
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PMID:Polymeric black tea polyphenols inhibit 1,2-dimethylhydrazine induced colorectal carcinogenesis by inhibiting cell proliferation via Wnt/beta-catenin pathway. 1803 52

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by left ventricular hypertrophy (LVH) predominantly affecting the interventricular septum. Cardiac myosin-binding protein C (cMyBP-C) mutations are common causes of FHC. Gene expression profiling was performed in left ventricles of 9-week-old wild-type mice, heterozygous cMyBP-C KO mice displaying asymmetric septal hypertrophy, and homozygous mice developing eccentric LVH. Knocking out one or two cMyBP-C genes leads primarily to gene expression changes indicating an increased energy demand, activation of the JNK and p38 parts of the MAPK pathway and deactivation of the ERK part, and induction of apoptosis. Altered gene expression for processes related to cardiac structure, contractile proteins, and protein turnover was also identified. Many of the changes were more pronounced in the homozygous KO mice. These alterations point to physiological and pathological adaptations in the prehypertrophic heterozygous KO mice and the hypertrophic homozygous mice.
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PMID:Altered myocardial gene expression reveals possible maladaptive processes in heterozygous and homozygous cardiac myosin-binding protein C knockout mice. 1806 Jul 37

Several models have been suggested above, describing possible modes of spindle checkpoint action: 1. Cdc20 sequestration (by Mad2-Cdc20 and/or MCC). 2. Stable MCC-APC/C association. 3. Cdc20 turnover (in budding yeast). 4. Cdc20-APC/C modification (by Mps1, Bub1, MAPK, Aurora B or BubR1 kinases). Several of these mechanisms could affect APC/C activity by modifying, competing for, and/or blocking the binding site(s) for its substrates. Alternatively, they could reduce the processivity of ubiquitination of substrates, or prevent the release of substrates and thereby reduce substrate turnover. Indeed, the processivity of ubiquitination can determine the order of destruction of APC/C substrates (Rape et al., 2006). Most substrates require multiple APC/C binding events in order to build polyubiquitin chains, and only polyubiquitinated substrates are recognised by the 26S proteasome for destruction. Thus, if the processivity of ubiquitination or the turnover of APC/C substrates were impaired in mitosis, the degradation of securin and cyclin would no longer take place, which would result in mitotic arrest. Our results have highlighted the importance of Mad3 as an anaphase inhibitor, and suggest that it usually acts in concert with Mad2 to efficiently inhibit Cdc20-APC/C. Further experiments are necessary to fully understand their mechanism of action, and this will require a wide range of approaches including dynamic studies of the 'flux' of Mad2 and BubR1 through signalling scaffolds, further structural insights, the identification of important phosphorylation sites on both the checkpoint proteins and Cdc20-APC/C, and an in vitro reconstitution of MCC inhibition of the APC/C. We look forward to seeing the complex regulation of mitotic progression being described over the coming years.
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PMID:The spindle checkpoint: how do cells delay anaphase onset? 1836 27

Colorectal cancer arises from the progressive accumulation of mutations and epigenetic alterations in colon epithelial cells. Such alterations often deregulate signaling pathways that affect the formation of colon cancer, such as the Wnt, RAS-MAPK and TGF-beta pathways. The tumor promoting effects of mutations in genes, such as APC, have been demonstrated in cancer cell lines and in mouse models of intestinal cancer; however, the biological effects of most epigenetic events identified in colorectal cancer remain unknown. Consequently, we assessed whether the aberrant methylation of TSP1, the gene for thrombospondin 1, a regulator of TGF-beta ligand activation, is an epigenetic mechanism for inhibiting the TGF-beta signaling pathway. We found methylated TSP1 occurs in colon cancer cell lines (33%), colon adenomas (14%) and colon adenocarcinomas (21%). In primary colorectal cancers, loss of TSP1 expression correlated with impaired TGF-beta signaling as indicated by decreased Smad2 phosphorylation and nuclear localization. Furthermore, methylation-induced silencing of TSP1 expression reduced the concentration of secreted active TGF-beta1 and attenuated TGF-beta signaling. Reversal of TSP1 methylation resulted in increased TSP1 mediated activation of the latent LAP:TGF-beta complex and subsequent TGF-beta receptor activation. Our results demonstrate that the aberrant methylation of TSP1 has biological consequences and provide evidence that the aberrant methylation of TSP1 is a novel epigenetic mechanism for suppressing TGF-beta signaling in colorectal cancer.
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PMID:The aberrant methylation of TSP1 suppresses TGF-beta1 activation in colorectal cancer. 1842 17

Heat shock proteins (HSPs) are potent inducers of an antigen-specific immunological response. A role of chaperon of immunogenic peptides and a direct effect on APC activation and function have been described. However, the signal transduction events involved in the activation of human APCs are poorly characterized. We investigated, using human monocyte-derived dendritic cells (DCs), the signal transduction pathways activated by a human recombinant HSP70 (r)HSP70 purified from eukaryotic cells. rHSP70 effectively induced a partial maturation of DCs in vitro and a significant increase in the titers of antigen-specific IgG when used as a vaccine adjuvant in vivo. rHSP70 did not desensitize human DCs to LPS stimulation and retained its adjuvant properties in C3H/HeJ mice, which are LPS-resistant as a result of a mutation in TLR-4, ruling out the potential interference of LPS contamination. Effects on DC maturation and in vivo functions correlate to the ability of rHSP70 to activate IkappaB-alpha/NF-kappaB and ERK1/2 pathways in human DCs. No activation of p38 was induced in the same experimental conditions. Our data suggest that the IkappaB-alpha/NF-kappaB pathway has a critical role in the partial maturation of DCs induced by rHSP70.
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PMID:Human recombinant heat shock protein 70 affects the maturation pathways of dendritic cells in vitro and has an in vivo adjuvant activity. 1845 18

Tendon injuries cause considerable morbidity in the general adult population. The tenocytes within the tendon have the full capacity to heal the tendon intrinsically. Activated protein C (APC) plays an important role in coagulation and inflammation and more recently has been shown to promote cutaneous wound healing. In this study we examined whether APC can induce a wound healing phenotype in tenocytes. Sheep tenocytes were treated with APC, endothelial protein C receptor (EPCR) blocking antibody (RCR252) and/or EPCR small interfering (si)RNA. Cell proliferation and migration were measured by crystal violet assay and a scratch wounding assay, respectively. The expression of EPCR, matrix metalloproteinase (MMP)-2, type I collagen and MAP kinase activity were detected by real time PCR, zymography, immunofluorescence, immunohistochemistry and Western blotting. APC stimulated proliferation, MMP-2 activity and type I collagen deposition in a dose-dependent manner and promoted migration of cultured tenocytes. APC dose-dependently stimulated phosphorylated (P)-ERK2 and inhibited P-p38. Interestingly, tenocytes expressed EPCR protein, which was up-regulated by APC. When tenocytes were pre-treated with RCR252 or EPCR siRNA the effect of APC on proliferation, MMP-2 and type 1 collagen synthesis and MAP kinases was blocked. APC promotes the growth, MMP-2 activity, type I collagen deposition and migration of tenocytes. Furthermore, EPCR is expressed by tenocytes and mediates the actions of APC, at least partly by signalling through selective MAP kinases. These data implicate APC as a potential healing agent for injured tendons.
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PMID:Activated protein C mediates a healing phenotype in cultured tenocytes. 1846 56

We studied the activities of several kinds of beta-glucans, including sonifilan, grifolan, Sclerotinia sclerotiorum glucan, laminarin and zymosan, on macrophages. Preculture of macrophages with inactive beta-glucans rendered the cells unresponsive to subsequent stimulation with grifolan, suggesting a specific pathway in the beta-glucan structure. The importance of protein C and phosphorylation of mitogen-activated protein kinase was demonstrated in the activation with grifolan or zymosan. Immunoprecipitation of complement receptor (CR3), coprecipitated other proteins carrying phosphotyrosine residues in stimulation with grifolan. These data suggest that protein kinase C and tyrosine kinases are essential for signal transduction, and that CR3 might participate in the activation through interaction with other intracellular proteins.
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PMID:Leukocyte activation by (1-->3)-beta-D glucans. 1847 53

The protective effect of recombinant activated protein C therapy in patients with severe sepsis likely reflects the ability of recombinant activated protein C to modulate multiple pathways implicated in sepsis pathophysiology. In this study, we examined the effects of recombinant activated protein C on the anti-inflammatory cytokine IL-10 and on the procoagulant molecule tissue factor (TF) in LPS-challenged blood monocytes. Treatment of LPS-stimulated monocytes with recombinant activated protein C resulted in an up-regulation of IL-10 protein production and mRNA synthesis. The up-regulation of IL-10 required the serine protease activity of recombinant activated protein C and was dependent on protease-activated receptor-1, but was independent of the endothelial protein C receptor. At the intracellular level, p38 MAPK activation was required for recombinant activated protein C-mediated up-regulation of IL-10. We further observed that incubation of LPS-stimulated monocytes with recombinant activated protein C down-regulated TF Ag and activity levels. This anticoagulant effect of recombinant activated protein C was dependent on IL-10 since neutralization of endogenously produced IL-10 abrogated the effect. In patients with severe sepsis, plasma IL-10 levels were markedly higher in those treated with recombinant activated protein C than in those who did not receive recombinant activated protein C. This study reveals novel regulatory functions of recombinant activated protein C, specifically the up-regulation of IL-10 and the inhibition of TF activity in monocytes. Our data further suggest that these activities of recombinant activated protein C are directly linked: the recombinant activated protein C-mediated up-regulation of IL-10 reduces TF in circulating monocytes.
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PMID:Activated protein C up-regulates IL-10 and inhibits tissue factor in blood monocytes. 1864 55

Thrombomodulin (TM), a widely expressing glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system. TM appears to exhibit anti-inflammatory ability through both protein C-dependent and -independent pathways. We presently have demonstrated that recombinant N-terminal lectinlike domain of TM (rTMD1) functions as a protective agent against sepsis caused by Gram-negative bacterial infections. rTMD1 caused agglutination of Escherichia coli and Klebsiella pneumoniae and enhanced the macrophage phagocytosis of these Gram-negative bacteria. Moreover, rTMD1 bound to the Klebsiella pneumoniae and lipopolysaccharide (LPS) by specifically interacting with Lewis Y antigen. rTMD1 inhibited LPS-induced inflammatory mediator production via interference with CD14 and LPS binding. Furthermore, rTMD1 modulated LPS-induced mitogen-activated protein kinase and nuclear factor-kappaB signaling pathway activations and inducible nitric oxide synthase expression in macrophages. Administration of rTMD1 protected the host by suppressing inflammatory responses induced by LPS and Gram-negative bacteria, and enhanced LPS and bacterial clearance in sepsis. Thus, rTMD1 can be used to defend against bacterial infection and inhibit LPS-induced inflammatory responses, suggesting that rTMD1 may be valuable in the treatment of severe inflammation in sepsis, especially in Gram-negative bacterial infections.
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PMID:Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. 1871 Oct 2


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