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)

Differential hybridization was used to isolate genes potentially involved in the process of metastasis. Ten complementary DNAs (cDNAs) that were differentially expressed between a highly metastatic (MTLn3) and a nonmetastatic (MTC.4) line of the rat 13762NF mammary adenocarcinoma were isolated and sequenced. Examination of the EMBL/GenBank database revealed that one of the genes had a high degree of homology (98.8%) to annexin I (also known as calpactin II). Quantitative analysis of Northern blot hybridizations showed that the annexin I-like sequence was expressed 4- to 7-fold higher in MTLn3 than in MTC.4 cells. Steady state mRNA levels were also low in MTLn2, a cell line of low metastatic potential closely related to MTLn3, but were not related to metastatic potential in colon adenocarcinoma or melanoma cells. Two of the cDNAs (designated 8.11 and 10.14) were found to be novel. The expression of 10.14 mRNA (3.2 kb) was 4-fold higher in MTLn3 than in MTC.4 cells. Sequencing of the 10.14 cDNA (2.2 kb) revealed a putative open reading frame of 583 amino acids that was also novel. Expression of 8.11 mRNA (> 7 kb) inversely correlated with metastatic potential. Another differentially transcribed gene was highly homologous to ERK2 (extracellular signal related kinase 2), a mitogen-activated protein kinase (MAPK). Northern analysis of ERK2 expression revealed 3-fold higher amounts of a 1.3 kb mRNA in MTLn3 than in MTC.4 cells. Higher levels of ERK2 mRNA were generally seen in the more metastatic human colon but not in melanoma cell lines. We also corroborated the work of Taniguchi (Nucl Acids Res 19:6949, 1991) by independently identifying EF-1 alpha as a putative metastasis-associated gene.
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PMID:Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. 834 48

An adenocarcinoma cell line which has the ability to arrest in G0 phase under exhausted culture conditions was established. Using the cell line, we investigated the expression of cell cycle-associated proteins including cdc2, cdk2, cyclin A, cyclin Dl, and Rb during entry into or withdrawal from the cell cycle. MAP kinase expression was also investigated as one of the most downstream proteins of the signal transduction of growth factors. The cells in the quiescent state did not express cdc2. In contrast, cdk2 was expressed weakly, and cyclin A and cyclin D1 were strongly expressed in the quiescent cells. The expression of cdk2 and cyclin D1 in the quiescent cells was reduced after stimulation by renewal of the medium and then increased, accompanied by Rb phosphorylation and cdc2 expression around the G1/S transition. Cdc2 and the hyperphosphorylated form of Rb disappeared as the cells became quiescent. MAP kinase expression was unchanged throughout all the phases analyzed. The results indicate that down-regulation of neither cdk2, cyclin A, cyclin D1, nor MAP kinase is necessary to arrest cells in G0, but that only Rb dephosphorylation and down-regulation of cdc2 are accompanied by an arrest of cell proliferation in G0 in the cell line.
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PMID:Behavior of the cell cycle-associated proteins in an unusual G0-arrestable cancer cell line. 863 20

Neurotensin (NT) is a neuropeptide that is important in a variety of biological processes such as signal transduction and cell growth. NT effects are mediated by a single class of cell-surface receptors, known as neurotensin receptors (NTRs), which exhibit structural features of the G-protein-coupled receptors superfamily. We investigated NTR signalling properties with Chinese hamster ovary (CHO) cells stably transformed with human NTR (hNTR). First, we showed that NTR stimulation by NT induced the activation of the mitogen-activated protein kinases (MAPKs) in time- and dose-dependent manners. Both p42 and p44 MAPK isoforms were retarded in gel-shift assays, which was consistent with their activation by phosphorylation. In addition we showed that NT caused a prolonged activation of MAPK as measured by in-gel kinase assay. Secondly, we demonstrated that NT induced the expression of the growth-related gene Krox-24 at the protein level, as assessed by Western-blot analysis, and at the transcriptional level, as demonstrated in CHO cells transfected with hNTR and a reporter gene for Krox-24. Activation of MAPK and induction of Krox-24 were both prevented by the NTR antagonist SR 48692, confirming the specific action on NTR. Furthermore we observed coupling of NTR to a mitogenic pathway and Krox-24 induction in the human adenocarcinoma cell line HT29, which naturally expresses NTRs. Considering coupling pathways between NTR stimulation and MAPK activation, we observed a partial inhibition by pertussis toxin (PTX) and a complete blockade by the protein kinase C (PKC) inhibitor GF 109203X. Taken together, these results suggest that (1) stimulation of NTR activates the MAPK pathway by mechanisms involving dual coupling to both PTX-sensitive and PTX-insensitive G-proteins as well as PKC activation, and (2) these effects are associated with the induction of Krox-24, which might be a target of MAPK effector.
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PMID:Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24. 894 79

Point mutations in the Ras oncogene cause Ras to remain in its active GTP-bound state sending signals downstream continuously. Since 75 to 90% of all human pancreatic ductal adenocarcinomas harbor activating mutations at codon 12 of the K-ras oncogene it was our belief that Raf-1-MEK-MAPK will be activated in the majority of human pancreatic cancers. The aim of this study was to confirm activation of Raf-1 in K-ras mutant human pancreatic cancer. Additionally, we sought to determine if Raf-1 activation differed in K-ras mutant and nonmutant pancreatic cancer. Furthermore, we were interested in determining if Raf-1 activation in pancreatic cancer led to subsequent activation of downstream effectors such as MAP kinase. The presence of mutations in codon 12 of the K-ras oncogene in 14 human pancreatic adenocarcinoma cell lines was determined by use of mutant allele-specific PCR restriction fragment length polymorphism analysis. Raf-1 expression of quiescent cells was determined by immunoblotting using a rabbit anti-human polyclonal antibody and enhanced chemiluminescence. MAP kinase activity was determined by measuring the incorporation of phosphate into Myelin Basic Protein. Seven cell lines were noted to have mutations in codon 12 of K-ras while seven cell lines did not. There was no difference in expression of the 74 kDa-activated form of Raf-1 in K-ras mutant vs K-ras nonmutant cell lines. However, there was a significant increase in MAP kinase activity in the nonmutant cell lines compared to the cell lines with Ras mutations (P = 0.026). We conclude that Raf-1 is expressed in its active form in human pancreatic cancer regardless of K-ras status. However, signalling downstream of Raf-1 differs in cell lines with K-ras mutations compared to those cell lines without K-ras mutations.
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PMID:Activation of Raf-1 in human pancreatic adenocarcinoma. 920 70

In this study we demonstrate that prothrombin activates the cell proliferation of the lung adenocarcinoma A549 cells. The A549 cell expresses factor Xa-like prothrombinase activity on its surface and prothrombin was converted to thrombin on the cell surface. Furthermore, thrombin induced the activation of PKC, increased [Ca2+]i and potentiated MAP kinase activity through thrombin receptor. The mitogenic activity of prothrombin and the conversion to thrombin were completely abolished by the synthetic coagulation factor Xa inhibitor, DX9065a. These findings suggest that DX9065a is an effective agent for a therapeutic strategy against cancer itself and prothrombotic complications associated with malignancy.
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PMID:DX9065a, an Xa inhibitor, inhibits prothrombin-induced A549 lung adenocarcinoma cell proliferation. 946 1

The ovarian adenocarcinoma cell line HEY was used as an in vitro model to study the influence of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on epithelial tumours such as ovarian cancer. Serum-starved cells were treated with rhG-CSF in a time- and dose-dependent manner. Cell proliferation, measured as cell division and DNA synthesis, was stimulated about 40% by rhG-CSF. After harvesting, cells were examined for the presence of G-CSF receptor (FACS analysis and RT-PCR), as well as for expression of genes involved in mitogen signalling (ERKs, JNKs) and early gene expression (c-jun). rhG-CSF affected mitogen-activated pathways and was receptor-mediated if the G-CSF receptor was present. After rhG-CSF induction, Janus N-terminal kinases (JNK 1 and 2) were simultaneously increased in the cytosol, up to 30-fold as measured by Western blotting), whereas ERK 1 and 2 accumulated maximally by 2.5-fold 1 hr after rhG-CSF induction. c-Jun was up-regulated strongly by this cytokine at the translational level. Our data suggest that rhG-CSF affects genes involved in mitogen signalling and early gene expression in solid tumours. We also noted the presence of G-CSF receptor on ovarian cancer cell lines.
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PMID:rhG-CSF affects genes involved in mitogen signalling and early gene expression in the ovarian cancer cell line HEY. 950 29

MAPK (Mitogen-Activated Protein Kinase) is one of the elements of kinase cascades (MAPK, MEK-MAP kinase, kinase, Raf-1, Ras) regulating cellular proliferation and differentiation processes. It seems that the changes in its number and activity may be the factor having influence on carcinogenesis. In some human carcinomas a significant increase of its activity is observed, in others a decrease of its activity is described. Our research aimed at the evaluation of the dynamics of precancerous and cancerous changes in the stomach stump in rats after the experimental, partial stomach resection. Apart from histological and ultrastructural examination we also determined the activity of the sub-unit p42 MAP kinase. The material comprised segments of gastric mucosa of the stomach stump of 15 rats after subtotal gastrectomy. Part of the rats after the procedure were administered carcinogen orally (MNNG). On the histological and ultrastructural examination we used routine methods, the activity of MAP kinase was determined by western-blotting method with the use of IgG against MAPK p42, Santa Cruz #154). In 8 examined rats we observed the increase of MAP kinase activity. We established probable correlation (without statistical analysis, regarding miserly material) between the increase of MAPK activity and histological and ultrastructural changes. Among three cases diagnosed as adenoma tubulare in two we observed the increase of MAPK activity. A clear increase of this kinase was also present in the stomach stump of a rat, which was diagnosed as adenocarcinoma. On the basis of our research carried so far we think that the increase of the MAPK activity may be one of the causes of the neoplasm development. It seems important to obtain the confirmation of our results and to establish a possible usefulness of MAPK activity determination as a prognostic indicator in case of the neoplasm of stomach stump.
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PMID:The level of MAP kinase activity in the stomach stump in rats after subtotal gastrectomy. 957 May 7

To clarify the relationship between ruffling and lamellipod extension in growth factor-stimulated chemotactic responses, we utilized cell lines derived from the rat 13762 NF mammary adenocarcinoma. Nonmetastatic MTC cells expressing the human EGF receptor (termed MTC HER cells) demonstrated chemotactic responses to TGF-alpha, an EGF receptor ligand typically present in mammary tissue. In microchemotaxis chambers, peak chemotactic responses occurred in response to 5 nM TGF-alpha. MTC HER cells showed dramatic ruffling edges in the absence of external stimuli, and addition of 5 nM TGF-alpha led to a transient reduction in ruffling concomitant with lamellipod extension. Lamellipod extension correlated with an overall increase in actin polymerization. These responses were blocked by the PI 3 kinase inhibitor wortmannin but not by the MAP kinase inhibitors PD98059 and SB203580. We conclude that the initial chemotactic response to TGF-alpha involves lamellipod extension and that ruffling reflects a dynamic turnover of lamellipodia that is arrested during lamellipod extension. By regulating the dissolution of ruffles and extension of lamellipods, a chemotactic response can be achieved, which may contribute to the metastatic process.
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PMID:Suppression of ruffling by the EGF receptor in chemotactic cells. 966 7

Hepatocyte growth factor (HGF) markedly induced the spreading, dissociation and scattering of Madin-Darby canine kidney epithelial cells (MDCK) and human stomach adenocarcinoma cells (TMK1). Scattering of MDCK and TMK1 cells was induced by 12-O-tetradecanoyl-phorbol-13-acetate (PMA) and epidermal growth factor (EGF), respectively. In all these agent-stimulated cells, rapid activation of Raf-1, MAP kinase/ERK kinase (MEK), 41/43 kDa MAP kinases and p90rsk was commonly observed. In contrast, PMA neither induced the scattering nor activation of all these kinases in TMK1 cells. Pretreatment of MDCK and TMK1 cells with 2-(2-amino-3-methoxyphenyl) choromone (AMPC), a specific inhibitor of MEK, selectively inhibited the HGF-, PMA- and EGF-stimulated activities of MEK, 41/43 kDa MAP kinases and p90rsk in a dose dependent manner. AMPC-pretreatment, however, did not affect HGF-, PMA- or EGF-induced activation of Raf-1, nor HGF-induced activation of phosphatidylinositol 3-kinase in these cells. Importantly, HGF-, PMA- and EGF-induced scattering of MDCK and TMK1 cells was inhibited at doses of AMPC similar to those that gave comparable levels of inhibition of the activities of MEK, 41/43 kDa MAP kinases and p90rsk. These results suggest that activation of the 41/43 kDa MAP kinase signaling pathway is required for the motility response of MDCK and TMK1 cells induced by agents such as HGF, PMA and EGF.
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PMID:Activation of the 41/43 kDa mitogen-activated protein kinase signaling pathway is required for hepatocyte growth factor-induced cell scattering. 967 14

Mitogen-activated protein kinase (MAPK) has been known to play a critical role in the regulation of the carcinogenesis in human cancers. In an effort to understand the functional role of the MAPK in the carcinogenesis of human gastric tissues, we examined the changes of MAPK levels in human gastric adenocarcinoma. We found that increased MAPK activity was accompanied by overexpression of mitogen-activated protein kinase phosphatase-1 (MKP-1), suggesting that signaling pathways leading to the activation of MAPK and the induction of MKP-1 expression are associated with carcinogenesis of human gastric adenocarcinoma.
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PMID:Increased MAPK activity and MKP-1 overexpression in human gastric adenocarcinoma. 973 28


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