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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ERK gene has been isolated as a genomic DNA encoding a part of the receptor protein-tyrosine kinase which belongs to the EPH subfamily. We previously identified a partial complementary DNA (cDNA) encompassing the catalytic domain of ERK from the expression library of human gastric cancer with an antiphosphotyrosine antibody. Using this cDNA as a probe, the cDNAs encoding mature ERK protein were isolated. The putative mature ERK protein, a total of 967 deduced amino acid residues, showed high homology with chicken Cek5 (92.5%) and mouse Nuk (99.1%). Chromosomal in situ hybridization revealed that human ERK cDNA is localized to chromosome 1p34-35. In Northern blot analysis of normal human tissues, the ERK gene was ubiquitously expressed mainly in cells of epithelial origin but not in the brain. Studies on RNAs from 76 human tumor tissues and cell lines showed that ERK is expressed at higher levels in various tumors of epithelial origin than in corresponding normal tissues, most frequently in gastric cancers (12 of 16, 75.0%). Overexpression of ERK was also detected in one osteosarcoma cell line. These findings suggest that ERK plays some significant role in carcinogenesis in the stomach and other tissues.
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PMID:Overexpression of ERK, an EPH family receptor protein tyrosine kinase, in various human tumors. 803 77

Recently, constitutively active mutants of MEK (MAP/ERK kinase) were shown to be capable of transforming cells to tumorigenicity suggesting that MEK can function as a dominant oncogene and potentially play a role in human carcinogenesis. Human lung cancer cells exhibit mutations in other components of the MAP kinase signaling pathway such as the Her-2/neu and ras oncogenes. Thus, the coding sequences of both MEK-1 and MEK-2 cDNAs from human lung cancer cell lines were screened by single strand conformation polymorphism analysis and DNA sequencing for alterations in these two genes. In 37 lung cancer cell lines we found: an allelic variant in MEK-1 cDNA, nt 783 G-->A, (no amino acid change); a MEK-2 cDNA change (nt 977 C-->T mutation leading to 298 Pro-->Leu change); a MEK-2 cDNA change nt 537 C-->T (no amino acid change); and a frequent MEK-2 cDNA germline polymorphism nt 744, A-->C (no amino acid change) with an allele frequency of 0.5 for each form. These results suggest that mutations in the MEK-1 and MEK-2 gene occur at a very low frequency in human lung cancer.
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PMID:Mutation analysis of the coding sequences of MEK-1 and MEK-2 genes in human lung cancer cell lines. 912 73

Phorbol ester-sensitive EL4 murine thymoma cells respond to phorbol 12-myristate 13-acetate with activation of ERK mitogen-activated protein kinases, synthesis of interleukin-2, and death, whereas phorbol ester-resistant variants of this cell line do not exhibit these responses. Additional aspects of the resistant phenotype were examined, using a newly-established resistant cell line. Phorbol ester induced morphological changes, ERK activation, calcium-dependent activation of the c-Jun N-terminal kinase (JNK), interleukin-2 synthesis, and growth inhibition in sensitive but not resistant cells. A series of protein kinase C activators caused membrane translocation of protein kinase C's (PKCs) alpha, eta, and theta in both cell lines. While PKC eta was expressed at higher levels in sensitive than in resistant cells, overexpression of PKC eta did not restore phorbol ester-induced ERK activation to resistant cells. In sensitive cells, PKC activators had similar effects on cell viability and ERK activation, but differed in their abilities to induce JNK activation and interleukin-2 synthesis. PD 098059, an inhibitor of the mitogen activated protein (MAP)/ERK kinase kinase MEK, partially inhibited ERK activation and completely blocked phorbol ester-induced cell death in sensitive cells. Thus MEK and/or ERK activation, but not JNK activation or interleukin-2 synthesis, appears to be required for phorbol ester-induced toxicity. Alterations in phorbol ester response pathways, rather than altered expression of PKC isoforms, appear to confer phorbol ester resistance to EL4 cells.
Carcinogenesis 1997 Sep
PMID:Effects of protein kinase C activators on phorbol ester-sensitive and -resistant EL4 thymoma cells. 932 80

Mitogen-activated protein kinase (MAPK) is a serine-threonine kinase that is activated by various extracellular stimuli. Extracellular signal-regulated kinases (ERK1 and ERK2), an MAPK subfamily, are activated by many oncogenes, such as ras and raf, and they induce cell proliferation. myc is also an oncogene and one of the targets of ERKs. Mutations of ras and overexpression of myc were found in various human cancers, and ERKs were also reported to play a role in carcinogenesis. In this study, we examined 39 biopsy specimens of oral squamous cell carcinoma (OSCC) and 5 of normal gingival mucosa for the expression of ERK protein and the proliferation marker, MIB-1 (Ki-67 antibody). Thirteen OSCC specimens and five normal gingival biopsies were also examined for the expression of ERKs mRNA by in situ hybridization. Double staining for ERKs and MIB-1 was also performed. Histologically, 18 patients (46%) were diagnosed with well-differentiated SCC, 17 (44%) with moderately differentiated SCC, and 4 (10%) with poorly differentiated SCC. The histologic grade correlated with the MIB-1 index. The localization of ERK1 was similar to that of ERK2. Positive signals for ERK proteins were localized in superficial keratinocytes in normal gingival mucosa, whereas these mRNAs were weakly positive in the basal and spinous layer. Basal and suprabasal cells were positive for MIB-1. In well-differentiated and moderately differentiated OSCC, positive signals for ERK mRNA and proteins were found at higher levels than in normal gingival mucosa in keratotic cells around cancer pearls. Some cells showed positive signals for ERKs and MIB-1. Furthermore, most cancer cells in poorly differentiated SCC were positive for both ERK and MIB-1. The histologic grade was statistically related to the percentage of cells positive for both ERK and MIB-1. This suggested that ERKs might be related to proliferation in OSCC.
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PMID:Overexpression of the ERK/MAP kinases in oral squamous cell carcinoma. 975 69

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.
Carcinogenesis 1999 May
PMID:Carcinogen and dietary lipid regulate ras expression and localization in rat colon without affecting farnesylation kinetics. 1033 94

An elevation in total MAP kinase activity and expression has been observed in breast cancer tissue. However, the mechanisms underlying these changes in kinase activity and regulation by growth factors are not well characterized. In these studies, the effect of the potent mammary mitogen, epidermal growth factor (EGF), on the activation of the mitogen-activated protein kinases, ERK1 and ERK2 (extracellular regulated protein kinases 1 and 2, respectively), was compared in primary cultures of normal mouse mammary epithelial cells and in a hormone-responsive mouse mammary tumor. In normal epithelium, EGF stimulated an early rise in ERK activity at 4 min followed by a rapid decline, whereas a sustained (1 h) elevation of ERK activity was observed in the tumor cells. The time course of ERK activity in both cell types coincided with the phosphorylation state of the EGF receptor, suggesting that altered regulation of EGF receptor phosphorylation or EGF receptor turnover produces an enhanced ERK response to EGF in tumor cells. The MEK inhibitor, PD 098059 inhibited EGF-stimulated proliferation and ERK activity in a parallel, dose-dependent manner showing that ERK activation is at least permissive for the proliferative response to EGF. In addition, tumor cells showed a 4-fold elevation in basal (or ligand-independent) activity over normal cells without an increase in total enzyme level, and a preferential activation of ERK1 by EGF. These EGF-dependent and -independent changes in ERK regulation in the hormone-responsive mammary tumor underscore how multiple alterations in the regulation of this pathway may play a role in mammary tumorigenesis.
Carcinogenesis 1999 Jul
PMID:Altered MAP kinase (ERK1,2) regulation in primary cultures of mammary tumor cells: elevated basal activity and sustained response to EGF. 1038 90

In this study we have explored the involvement of oxidative stress in Cr(VI)-induced JNK, p38 and ERK signaling pathways and their effects on Cr(VI) cytotoxicity in human non-small cell lung carcinoma CL3 cells. Exposure to K(2)Cr(2)O(7) markedly activated JNK and p38 and moderately activated ERK in a dose- (10-80 microM) and time-dependent (1-12 h) manner. The activated p38 decreased markedly and rapidly and the activated JNK decreased gradually when Cr(VI) was removed from the medium. Post-incubation of Cr(VI)-treated cells with H(2)O(2) increased the activities of JNK and p38, but not ERK. Co-administering Cr(VI) with 3-amino-1,2, 4-triazole (3AT), a catalase inhibitor, enhanced p38 activation, but did not influence JNK and ERK activation by Cr(VI). Conversely, co-administering Cr(VI) with mannitol, a hydroxyl radical scavenger and a Cr(V) chelator, reduced p38 activation and increased JNK and ERK activation by Cr(VI). These results indicate that p38 activation by Cr(VI) is positively correlated with oxidative stress, while JNK activity can be enhanced by either a quencher (mannitol) or activator (H(2)O(2)) of redox reactions in Cr(VI)-exposed CL3 cells. However, both 3AT and mannitol reduced the cytotoxicity of Cr(VI), but H(2)O(2) did not. The JNK activated by Cr(VI) was decreased (approximately 50%) by expression of a kinase-defective form of MKK7 (MKK7A) but not that of MKK4 (MKK4KR), suggesting that activation of JNK by Cr(VI) is mediated through MKK7. SB202190, a specific inhibitor of p38, markedly decreased JNK but did not change ERK activation by Cr(VI). PD98059, a specific inhibitor of ERK kinases MKK1/2, blocked ERK and p38 but did not alter JNK activation by Cr(VI). Neither the specific kinase inhibitors nor expression of MKK7A altered Cr(VI)-induced cytotoxicity. Together, these results suggest that activation of the JNK, p38 and ERK pathways by Cr(VI) is mediated through diverse redox mechanisms, yet their activation does not correlate with Cr(VI) cytotoxicity.
Carcinogenesis 2000 Aug
PMID:Activation of JNK, p38 and ERK mitogen-activated protein kinases by chromium(VI) is mediated through oxidative stress but does not affect cytotoxicity. 1091 Sep 49

Increased expression of cyclooxygenase-2 (COX-2) expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, and the stimulation of angiogenesis. In the present studies, we found that transforming growth factor beta1 (TGF-beta1) and epidermal growth factor (EGF) synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2) production in mink lung epithelial (Mv1Lu) cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-beta1-induced apoptosis in Mv1Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptotic effect of EGF receptor ligands. The combination of TGF-beta1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1) cells and completely prevented sodium butyrate (NaBu)-induced apoptosis. The synergistic induction of COX-2 by TGF-beta1 and EGF was not observed in R1B-L17 cells, a line derived from Mv1Lu cells that lacks the TGF-beta type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-beta1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, and SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-beta1. These results suggest an important collaborative interaction of TGF-beta1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.
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PMID:Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells. 1093 98

Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in human. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the biological actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicity in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase II gene assay, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 microM with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MAPK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 microM to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTP
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PMID:Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. 1115 83

Tea (Camellia sinensis) preparations have been shown to inhibit tumorigenesis at the initiation, promotion, and progression stages in different animal models. The anti-proliferative effects of tea polyphenols may be a key mechanism, especially in the NNK-induced lung tumorigenesis model with mice. Studies with cell lines have demonstrated that tea polyphenols inhibit cell proliferation and induce apoptosis. The effective concentrations used in these studies (20-100 microM) are usually higher than those observed in blood and tissues of humans and animals, which are in the low micromolar range. Glucuronide and sulfate conjugated and methylated catechins as well as ring fission products (due to intestinal microflora) have been observed in human plasma and urine. Purified green and black tea polyphenols inhibited the H-ras induced milogen-activated protein kinases, AP-1 activities, and the growth of 30.7b Ras 12 and BES21 cells. Among the catechins, both the galloyl structure on the B ring and the gallate moiety are important for the inhibition. Both (-)-epigallocatechin-3-gallate and theaflavin-3,3'-digallate inhibited the phosphorylation of c-jun and p44/42 (ERK 1/2). More mechanistic and human studies in these areas will help us to understand the possible inhibitory action of tea against carcinogenesis in humans.
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PMID:Mechanisms of inhibition of carcinogenesis by tea. 1123 3


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