Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological and experimental data suggest that dietary fiber and fat are major determinants of colorectal cancer. However, the mechanisms by which these dietary constituents alter the incidence of colon cancer have not been elucidated. Evidence indicates that dominant gain-of-function mutations short-circuit protooncogenes and contribute to the pathogenesis of cancer. Therefore, we began to dissect the mechanisms whereby dietary fat and fiber, fed during the initiation, promotion and progression stages of colon tumorigenesis, regulate ras p21 localization, expression and mutation frequency. Male Sprague-Dawley rats (140) were provided with corn oil or fish oil and pectin or cellulose plus or minus the carcinogen azoxymethane (AOM) in a 2 x 2 x 2 factorial design and killed after 34 weeks. We have previously shown adenocarcinoma incidence in these animals to be 70.3% (52/74) for corn oil + AOM and 56.1% (37/66) for fish oil + AOM (P < 0.05). Total ras expression as well as ras membrane:cytosol ratio was 4- to 6-fold higher in colon tumors than in mucosa from AOM- or saline-injected rats. Expression of ras in the mucosal membrane fraction was 13% higher for animals fed corn oil compared with fish oil feeding (P < 0.05), which is noteworthy since ras must be localized at the plasma membrane to function. The elevated ras membrane:cytosol ratio in tumors was not due to increased farnesyl protein transferase activity or prenylation state, as nearly all detectable ras was in the prenylated form. Phosphorylated p42 and p44 mitogen activated protein kinase (ERK) expression was two-fold higher in tumor extracts compared with uninvolved mucosa from AOM- and saline-injected rats (P < 0.05). The frequency of K-ras mutations was not significantly different between the various groups, but there was a trend toward a greater incidence of mutations in tumors from corn oil fed rats (85%) compared with fish oil fed rats (58%). Our results indicate that the carcinogen-induced changes in ras expression and membrane localization are associated with the in vivo activation of the ERK pathway. In addition, suppression of tumor development by dietary n-3 polyunsaturated fatty acids may be partly due to a combined effect on colonic ras expression, membrane localization, and mutation frequency.
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PMID:Carcinogen and dietary lipid regulate ras expression and localization in rat colon without affecting farnesylation kinetics. 1033 94

The present study shows how an original mouse metastatic lung model was established from the MXT mammary adenocarcinoma. This metastatic model was obtained by injecting the C/MET clone into the tail veins of B6D2F1 mice. The C/MET clone corresponds to one of eleven cell clones that were isolated in vitro from the MXT model. Of these 11 clones, only the C/MET leads to lung metastatic tumor development when injected i.v. into mice. Furthermore, the C/MET clone colonizes the lung only. The present data show that the C/MET metastatic model and the MXT parental line are weakly (if reference is made to the P388 leukemia model) sensitive to adriamycin, clyclophosphamide and etoposide. However, under specific experimental conditions, the chemosensitivity of the C/MET model can be significantly increased. The C/MET model therefore appears to be an interesting pharmacological tool to test new investigational agents with anti-tumor potentialities to lung metastases.
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PMID:Characterization of biological features and chemosensitivity of a new experimental lung metastasis model originating from the MXT mouse mammary adenocarcinoma. 1036 71

Patients with Barrett's columnar-lined esophagus are at increased risk of developing esophageal adenocarcinoma, the incidence of which has increased rapidly especially in the USA. Although the number of patients with Barrett's adenocarcinoma is fewer in Japan than in the USA, all gastroenterologist should know its multistep carcinogenic process. Tumor suppressor genes (p53, p16), oncogenes (c-erbB-2, H-ras, K-ras, cyclin D1, src), and growth factor/receptor (TGF-alpha, EGFR) seem to cause the malignant transformation of Barrett's esophagus. Because detection of these molecular alterations is feasible, more accurate diagnosis of Barrett's esophageal biopsy specimens should be made by adding the molecular examination to the conventional pathologic examination.
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PMID:[Molecular alterations in Barrett's esophagus and adenocarcinoma]. 1037 32

One of the characteristic responses of HT29 human colon adenocarcinoma cells to hypoxic stress is the induction of c-jun expression and binding to the activator-protein 1 (AP-1) element. To study the mechanism of c-jun activation during hypoxia, inhibitors of signaling pathways leading to the activation of AP-1 transcription factor were used. One of them, the benzoquinone ansamycin geldanamycin (GA) Mr-90,000 heat-shock protein (hsp90)-binding antibiotic, is known to disrupt signaling pathways by inducing destabilization of the enzyme complexes and degradation of signaling intermediates involving the proteasome. In our experiments, GA inhibited both basal and hypoxia-induced c-jun expression (IC50 = 75 nM). GA also abolished the hypoxia-induced increase in c-Jun NH2-terminal kinase (JNK1) catalytic activity and demonstrated an inhibitory effect on stress-activated protein kinase/ERK kinase-1 (SEK1); other participants in the mitogen-activated protein kinase and p38 signal transduction pathways were not affected to the same degree. GA treatment led to a decrease in the nuclear content of c-Jun but not that of c-Fos or of activating transcription factor 2. Functional consequences of these effects were suggested by the inhibition of AP-1 binding in hypoxic HT29 cells in the presence of GA. Pretreatment with the proteasome inhibitor lactacystin before the addition of GA resulted in the elevation of overall c-jun level, but it was unable to restore the hypoxia-induced c-jun expression. Our results demonstrate that GA acts as a highly potent inhibitor of hypoxia-induced c-jun expression, affecting the activation of JNK and of the AP-1 transcription factor. However, the effect of GA cannot be attributed solely to the inhibition of signaling through JNK, and additional mechanisms remain to be identified.
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PMID:Effects of geldanamycin on signaling through activator-protein 1 in hypoxic HT29 human colon adenocarcinoma cells. 1046 87

Because the efficacy of 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3] in treatment of colon cancer might critically depend on its ability to specifically counteract epidermal growth factor (EGF)-stimulated tumor cell growth, we utilized human colon adenocarcinoma-derived cells in primary culture as well as the Caco-2 cell line to elucidate possible sites of interaction of 1alpha,25-(OH)2D3 with signaling from EGF receptor activation. In both types of colon cancer cells investigated, 10(-8) M 1alpha,25-(OH)2D3 reduced basal cell proliferation by about 50%, and prevented any rise in proliferation when colon cancer cells were treated with 25 ng/ml EGF: this can be explained by a marked inhibitory effect of 1alpha,25-(OH)2D3 on EGFR mRNA and protein expression. The steroid hormone also seemingly promotes EGF-induced internalization of apical and basolateral membrane EGFR. In addition, 1alpha,25-(OH)2D3 significantly reduced basal and EGF-stimulated expression of cyclin D1 at the mRNA and protein level in primary cultures as well as in the Caco-2 cell line. The ability of 1alpha,25-(OH)2D3 to interfere with a key event in cell cycle control and thereby to block mitogenic signaling from EGF could be seen as advantageous for the potential use of vitamin D compounds in colon cancer therapy.
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PMID:Mechanism of antimitogenic action of vitamin D in human colon carcinoma cells: relevance for suppression of epidermal growth factor-stimulated cell growth. 1048 63

We have identified a novel fibroblast growth factor, FGF-19, the most distant member of the FGF family described to date. FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. Human FGF-19 maps to chromosome 11 q13.1, a region associated with an osteoporosis-pseudoglioma syndrome of skeletal and retinal defects. FGF-19 message is expressed in several tissues including fetal cartilage, skin, and retina, as well as adult gall bladder and is overexpressed in a colon adenocarcinoma cell line.
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PMID:FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. 1052 10

The neu (c-erbB-2) proto-oncogene encodes a tyrosine kinase receptor that is overexpressed in 20 to 30% of human breast tumors. Herein, cyclin D1 protein levels were increased in mammary tumors induced by overexpression of wild-type Neu or activating mutants of Neu in transgenic mice and in MCF7 cells overexpressing transforming Neu. Analyses of 12 Neu mutants in MCF7 cells indicated important roles for specific C-terminal autophosphorylation sites and the extracellular domain in cyclin D1 promoter activation. Induction of cyclin D1 by NeuT involved Ras, Rac, Rho, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38, but not phosphatidylinositol 3-kinase. NeuT induction of the cyclin D1 promoter required the E2F and Sp1 DNA binding sites and was inhibited by dominant negative E2F-1 or DP-1. Neu-induced transformation was inhibited by a cyclin D1 antisense or dominant negative E2F-1 construct in Rat-1 cells. Growth of NeuT-transformed mammary adenocarcinoma cells in nude mice was blocked by the cyclin D1 antisense construct. These results demonstrate that E2F-1 mediates a Neu-signaling cascade to cyclin D1 and identify cyclin D1 as a critical downstream target of neu-induced transformation.
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PMID:Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. 1061 Dec 46

Epidemiologic studies suggest that alcohol may be an inducing factor in human colon tumorigenesis. As colon cells are frequently under autocrine control by growth factors, involvement of the EGFR pathway in alcohol-related colon tumor progression was investigated in the human colon adenocarcinoma-derived cell line Caco-2 which shows EGFR distribution mainly in basolateral cell membranes. EGF treatment results in almost complete downregulation of the basolateral receptor. Low concentrations of ethanol (0.22 mM, 0.1%) however, lead to significantly increased EGFR mRNA and protein expression and a raised mitotic rate mainly in basolaterally treated cells. Alcohol-induced overexpression of EGFR is paralleled by increased cyclin D1 expression. This suggests a possible mechanism for low blood levels of alcohol to stimulate in vivo proliferation of colonocytes by elevating transcription of a growth factor receptor as well as by modifying expression of a cell cycle regulator.
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PMID:Induction of epidermal growth factor receptor expression and mitogenesis by alcohol in human colon adenocarcinoma-derived Caco-2 cells. 1065 28

Neurotensin (NT), a gastrointestinal (GI) hormone, binds its receptor (NTR) to stimulate proliferation of normal and neoplastic GI tissues; the molecular mechanisms remain largely undefined. Mitogen-activated protein kinases (MAPKs) are a family of intracellular kinases that transmit mitogenic signals by translocating to the nucleus and activating transcription factors. The purposes of this study were: (1) to identify whether the MAPKs (ERK1/2 and JNK) are activated by NT and (2) to determine the effect of NT on downstream transcription factors using the human pancreatic adenocarcinoma cell line, MIA PaCa-2, which possesses high-affinity NTR. Both ERK and JNK activity were stimulated within 3-6 min by treatment with NT (10 nM); steady-state levels of ERK and JNK protein were unchanged. Moreover, NT treatment resulted in increased AP-1 binding activity as determined by gel shift analysis. Delineating the signal transduction mechanisms regulating the cellular effects of NT will provide important insights into the molecular pathways responsible for NT-mediated effects on both normal and neoplastic cells.
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PMID:Neurotensin-mediated activation of MAPK pathways and AP-1 binding in the human pancreatic cancer cell line, MIA PaCa-2. 1072 Apr 80

Malignant pleural effusion (PE) is associated with advanced human lung cancer. We found recently, using a nude mouse model, that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is responsible for PE induced by non-small cell human lung carcinoma cells. The purpose of this study was to determine the therapeutic potential of a VEGF/VPF receptor tyrosine kinase phosphorylation inhibitor, PTK 787, against PE formed by human lung adenocarcinoma (PC14PE6) cells. PTK 787 did not affect the in vitro proliferation of PC14PE6 cells, whereas it specifically inhibited proliferation of human dermal microvascular endothelial cells stimulated by VEGF/VPF. A specific platelet-derived growth factor receptor tyrosine kinase inhibitor, CGP57148 (used as a control because PTK 787 also inhibits platelet-derived growth factor receptor tyrosine kinases), had no effect on proliferation of PC14PE6 or human dermal microvascular endothelial cells. i.v. injection of PC14PE6 cells into nude mice produced lung lesions and a large volume of PE containing a high level of VEGF/VPF. Oral treatment with CGP57148 had no effect on PE or lung metastasis. In contrast, oral treatment with PTK 787 significantly reduced the formation of PE but not the number of lung lesions. Furthermore, treatment with PTK 787 significantly suppressed vascular hyperpermeability of PE-bearing mice but did not affect the VEGF/VPF level in PE or expression of VEGF/VPF protein and mRNA in the lung tumors of PC14PE6 cells in vivo. These findings indicate that PTK 787 reduced PE formation mainly by inhibiting vascular permeability, suggesting that this VEGF/VPF receptor tyrosine kinase inhibitor could be useful for the control of malignant PE.
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PMID:Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation. 1074 21


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