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)

We found that striptease-positive mast cells were abundant in the invasive front of human colon adenocarcinoma by examining 30 cases. Because tryptase has been suggested to be the agonist proteinase for protease-activated receptor-2 (PAR-2), we investigated the effects of stimulation of PAR-2 by tryptase on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line. PAR-2 stimulation by tryptase induced the increase in [Ca(2+)](i), which was desensitized by the prior application of PAR-2 activating peptide (AP). The proliferative responses of DLD-1 to tryptase and PAR-2 AP were associated with the phosphorylation of MEK and MAP kinase. Inhibition of MEK by PD98059 completely inhibited the proliferation-enhancing effects of tryptase and PAR-2 AP as well as phosphorylation of MAP kinase. Moreover, tryptase and PAR-2 AP stimulated the production of prostaglandin E2 and the inhibition of prostaglandin synthesis by indomethacin or NS398 resulted in the complete inhibition of the proliferative responses to tryptase and PAR-2 AP. Furthermore, the tryptase-stimulated proliferation of DLD-1 was concentration-dependently inhibited by nafamostat mesilate, a specific inhibitor of tryptase. These results as a whole indicated that tryptase has proliferative effects on DLD-1 through cyclooxygenase- and MAP kinase-dependent manners acting on PAR-2 by its proteolytic activity.
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PMID:Mast cell tryptase stimulates DLD-1 carcinoma through prostaglandin- and MAP kinase-dependent manners. 1609 13

A Down's syndrome associated gene, Single Minded 2 gene short form (SIM2-s), is specifically expressed in colon tumors but not in the normal colon. Antisense inhibition of SIM2-s in a RKO-derived colon carcinoma cell line causes growth inhibition, apoptosis, and inhibition of tumor growth in a nude mouse tumoriginicity model. The mechanism of cell death in tumor cells is unclear. In the present study, we investigated the pathways underlying apoptosis. Apoptosis was seen in a tumor cell-specific manner in RKO cells but not in normal renal epithelial cells, despite inhibition of SIM2-s expression in both of these cells by the antisense. Apoptosis was depended on WT p53 status and was caspase-dependent; it was inhibited by a pharmacological inhibitor of mitogen-activated protein kinase activity. Expression of a key stress response gene, growth arrest and DNA damage gene (GADD)45alpha, was up-regulated in antisense-treated tumor cells but not in normal cells. In an isogenic RKO cell line expressing stable antisense RNA to GADD45alpha, a significant protection of the antisense-induced apoptosis was seen. Whereas antisense-treated RKO cells did not undergo cell cycle arrest, several markers of differentiation were deregulated, including alkaline phosphatase activity, a marker of terminal differentiation. Protection of apoptosis and block of differentiation showed a correlation in the RKO model. Our results support the tumor cell-selective nature of SIM2-s gene function, provide a direct link between SIM2-s and differentiation, and may provide a model to identify SIM2-s targets.
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PMID:Inhibition of Single Minded 2 gene expression mediates tumor-selective apoptosis and differentiation in human colon cancer cells. 1612 20

Isothiocyanate sulforaphane (SFN) is a potent cancer chemopreventive agent. We investigated the mechanisms underlying the anti-proliferative effects of SFN in the human colon carcinoma cell line, HT-29. We demonstrate that SFN inhibits the growth of HT-29 cells in a dose- and time-dependent manner. Treatment of serum-stimulated HT-29 cells with SFN suppressed the re-initiation of cell cycle by inducing a G(1) phase cell cycle arrest. At high doses (>25 microM), SFN dramatically induces the expression of p21(CIP1) while significantly inhibits the expression of the G(1) phase cell cycle regulatory genes such as cyclin D1, cyclin A, and c-myc. This regulation can be detected at both the mRNA and protein levels as early as 4 h post-treatment of SFN at 50 microM. Additionally, SFN activates MAPKs pathways, including ERK, JNK and p38. Exposure of HT-29 cells with both SFN and an antioxidant, either NAC or GSH, completely blocked the SFN-mediated activation of these MAPK signaling cascades, regulation of cyclin D1and p21(CIP1) gene expression, and G(1)phase cell cycle arrest. This finding suggests that SFN-induced oxidative stress plays a role in these observed effects. Furthermore, the activation of the ERK and p38 pathways by SFN is involved in the upregulation of p21(CIP1) and cyclin D1, whereas the activation of the JNK pathway plays a contradictory role and may be partially involved in the downregulation of cyclin D1. Because cyclin D1 and p21(CIP1) play opposing roles in G(1) phase cell cycle progression regulation, blocking the activation of each MAPK pathway with specific MAPK inhibitors, is unable to rescue the SFN-induced G(1) phase cell cycle arrest in HT-29 cells.
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PMID:p53-independent G1 cell cycle arrest of human colon carcinoma cells HT-29 by sulforaphane is associated with induction of p21CIP1 and inhibition of expression of cyclin D1. 1617 May 70

In the present study, we demonstrate that Ca2+-induced growth inhibition and induction of differentiation in a line of human colon carcinoma cells (CBS) is dependent on mitogen-activated protein (MAP) kinase signaling and is associated with upregulation of extracellular calcium-sensing receptor (CaSR) expression. When CBS cells were grown in Ca2+-free medium and then switched to medium supplemented with 1.4 mM Ca2+, proliferation was reduced and morphologic features of differentiation were expressed. E-cadherin, which was minimally expressed in nonsupplemented medium, was rapidly induced in response to Ca2+ stimulation. Sustained activation of the extracellular signal-regulated kinase (ERK) occurred in Ca2+-supplemented medium. When an inhibitor of ERK activation (10 microM U0126) was included in the Ca2+-supplemented culture medium, ERK-activation did not occur. Concomitantly, E-cadherin was not induced, cell proliferation remained high and differentiation was not observed. The same level of Ca2+ supplementation that induced MAP kinase activation also stimulated CaSR upregulation in CBS cells. A clonal isolate of the CBS line that did not upregulate CaSR expression in response to extracellular Ca2+ was isolated from the parent cells. This isolate failed to produce E-cadherin or undergo growth inhibition/induction of differentiation when exposed to Ca2+ in the culture medium. However, ERK-activation occurred as efficiently in this isolate as in parent CBS cells or in a cloned isolate that underwent growth reduction and differentiation in response to Ca2+ stimulation. Together, these data indicate that CaSR upregulation and MAP kinase signalling are both intermediates in the control of colon carcinoma cell growth and differentiation. They appear to function, at least in part, independently of one another.
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PMID:Upregulation of calcium-sensing receptor and mitogen-activated protein kinase signalling in the regulation of growth and differentiation in colon carcinoma. 1627 66

Growing evidence shows that Interleukin (IL)-1beta and Cyclooxygenase 2 (COX-2) play a crucial role in the pathogenesis of inflammatory diseases and tumor growth, particularly in the gastrointestinal tract. Here, we have analyzed the regulation of COX-2 by IL-1beta in the human colon carcinoma cell line Caco-2, showing that COX-2 induction by this cytokine is due to both nuclear factor (NF)-kappaB-dependent transcriptional and p38 mitogen-activated protein kinase (MAPK)-mediated post-transcriptional mechanisms. Treatment of these cells with IL-1beta increased the levels of COX-2 mRNA and protein and hence the production of PGE2. IL-1beta induced NF-kappaB activation in Caco-2 cells, promoting the binding of this transcription factor to DNA and increasing NF-kappaB-dependent transcription. Inhibition of NF-kappaB activation diminished IL-1beta-mediated transcriptional activation of COX-2. Furthermore, mutation or deletion of a putative NF-kappaB binding site in the human COX-2 promoter greatly diminished its induction by IL-1beta. In addition, this cytokine induced a rapid increase in p38 MAPK activation. Interestingly, inhibition of p38 MAPK by SB203580 severely decreased induction of COX-2 expression by IL-1beta. p38 MAPK signalling was required for IL-1beta-dependent stabilization of COX-2 transcript. Given the importance of COX-2 expression in intestinal inflammation and colon carcinogenesis, these findings contribute to determine the key signalling pathways involved in the regulation of COX-2 expression in colorectal cells by inflammatory stimuli, such as IL-1beta.
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PMID:Up-regulation of cyclooxygenase-2 by interleukin-1beta in colon carcinoma cells. 1632 73

Nr-CAM, a cell-cell adhesion molecule of the immunoglobulin-like cell adhesion molecule family, known for its function in neuronal outgrowth and guidance, was recently identified as a target gene of beta-catenin signaling in human melanoma and colon carcinoma cells and tissue. Retrovirally mediated transduction of Nr-CAM into fibroblasts induces cell motility and tumorigenesis. We investigated the mechanisms by which Nr-CAM can confer properties related to tumor cell behavior and found that Nr-CAM expression in NIH3T3 cells protects cells from apoptosis in the absence of serum by constitutively activating the extracellular signal-regulated kinase and AKT signaling pathways. We detected a metalloprotease-mediated shedding of Nr-CAM into the culture medium of cells transfected with Nr-CAM, and of endogenous Nr-CAM in B16 melanoma cells. Conditioned medium and purified Nr-CAM-Fc fusion protein both enhanced cell motility, proliferation, and extracellular signal-regulated kinase and AKT activation. Moreover, Nr-CAM was found in complex with alpha4beta1 integrins in melanoma cells, indicating that it can mediate, in addition to homophilic cell-cell adhesion, heterophilic adhesion with extracellular matrix receptors. Suppression of Nr-CAM levels by small interfering RNA in B16 melanoma inhibited the adhesive and tumorigenic capacities of these cells. Stable expression of the Nr-CAM ectodomain in NIH3T3 cells conferred cell transformation and tumorigenesis in mice, suggesting that the metalloprotease-mediated shedding of Nr-CAM is a principal route for promoting oncogenesis by Nr-CAM.
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PMID:The shed ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell transformation. 1635 71

4-Hydroxynonenal (HNE) has been demonstrated to exert its antiproliferative effect by up-regulating the c-Jun-N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family (MAPKs). Transforming growth factor-beta1 (TGF-beta1) is the major negative regulatory factor in controlling cell proliferation, and Smads are its intracellular transducers. Recent data on human colon adenocarcinoma has shown a low HNE content paralleled by a marked alteration of TGF-beta1 levels within the tumor mass. The two events appear related because of the demonstrated marked ability of HNE to up-regulate expression and synthesis of TGF-beta1; the combined decreases of HNE and TGF-beta1 found in cancer cells provide a favorable condition for neoplastic progression. Furthermore, HNE is likely able to interact with the cytokine to enhance apoptosis and increase intracellular reactive oxygen species (ROS) formation in the CaCo-2 colon carcinoma cell line. The probable mechanism whereby HNE and TGF-beta1 interact to induce apoptosis is through cross-talk between the main signaling pathways of the two molecules (JNK and Smads), and the observed ROS production might only contribute to amplifying the apoptotic pathways. The network between the two signaling pathways here involved is now under investigation.
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PMID:4-hydroxynonenal and TGF-beta1 concur in inducing antiproliferative effects on the CaCo-2 human colon adenocarcinoma cell line. 1640 84

Previous results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay. PPARgamma ligand-dependent transcriptional activity was measured by a luciferase assay. A dominant-negative PPARgamma mutant was transfected in Caco-2 cells to suppress PPARgamma-mediated functions. Resveratrol inhibits cell growth of both Caco-2 and HCT-116 cells in a dose- and time-dependent manner (P < 0.001). In contrast to Caco-2-wild type cells (P < 0.05), resveratrol failed to increase SSAT activity in dominant-negative PPARgamma cells. PPARgamma involvement was further confirmed via ligand-dependent activation (P < 0.01) as well as by induction of cytokeratin 20 (P < 0.001) after resveratrol treatment. Coincubation with SB203580 abolished SSAT activation significantly in Caco-2 (P < 0.05) and HCT-116 (P < 0.01) cells. The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines. Resveratrol further increased the expression of PPARgamma coactivator PGC-1alpha (P < 0.05) as well as SIRT1 (P < 0.01) in a dose-dependent manner after 24 hours of incubation. Based on our findings, p38 MAPK and transcription factor PPARgamma can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer.
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PMID:Peroxisome proliferator-activated receptor gamma as a molecular target of resveratrol-induced modulation of polyamine metabolism. 1684 86

E-selectin-mediated adhesion of colon cancer cells to endothelial cells is a key event in metastasis. However, the signaling mechanisms that confer metastatic advantages to cancer cells adhering to E-selectin are ill defined. By using affinity column chromatography and pull-down assays on purified membrane extracts of HT29 and LoVo cells coupled to mass spectrometry analysis, we obtained the first evidence indicating that E-selectin binds to death receptor-3 (DR3) expressed by the cancer cells. Thereafter, we accumulated several results, suggesting that DR3 is an E-selectin receptor on colon cancer cells and that its activation by E-selectin triggers the activation of p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) and confers migration and survival advantages. First, by Western blotting, we found that the E-selectin-binding protein, identified as DR3, is recognized by two anti-DR3 antibodies. Second, the neutralization of DR3 with an antibody and its knockdown by small interfering RNA decrease the adhesion of colon cancer cells to E-selectin and E-selectin-expressing human umbilical vein endothelial cells. Third, inhibiting DR3 and knocking down its expression impair transendothelial migration of HT29 cells and block the activation of p38 and ERK by E-selectin. Fourth, high molecular weight isoforms of DR3 are expressed in samples of primary human colon carcinoma but not in samples from normal colon tissue. Intriguingly, DR3 is a death receptor but its activation by E-selectin does not induce apoptosis in colon cancer cells, except when ERK is inhibited. Our findings identify novel signaling and functional roles of DR3 activated in response to E-selectin and highlight the potential link between DR3 and metastasis.
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PMID:Death receptor-3, a new E-Selectin counter-receptor that confers migration and survival advantages to colon carcinoma cells by triggering p38 and ERK MAPK activation. 1698 54

Resveratrol (3,4',5-tri-hydroxystilbene), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. Resveratrol-induced dose-dependent apoptotic cell death in colon carcinoma cells, as measured by FACS analysis and internucleosomal DNA fragmentation assays. We demonstrate for the first time that resveratrol induce CCAAT/enhancer-binding protein-homologous protein (CHOP). Resveratrol-induced CHOP mRNA (and also protein) expression was inhibited by JNK specific inhibitor, but not ERK, p38 MAPK, PI3K and NF-kappaB inhibitors. Resveratrol-induced expression of CHOP involves the putative Sp1 site within the CHOP promoter region. Using a combination of the Sp1 cDNA transfection, the luciferase reporter assay and Sp1 inhibitor assay, we found that Sp1 site is required for resveratrol-mediated activation of the CHOP promoter. Suppression of CHOP expression by CHOP siRNA and treatment with mithramycin A attenuated resveratrol-induced apoptosis. Taken together, the present studies suggest that induction of CHOP protein may be involved, at least in part, in resveratrol-induced apoptosis.
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PMID:Elevated gadd153/chop expression during resveratrol-induced apoptosis in human colon cancer cells. 1704 95


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