Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The role of hepatitis B virus HBx protein in the carcinogenesis associated with chronic viral infection remains ill-defined. Indeed, pleiotropic effects have been ascribed to HBx: in addition to its well-documented ability to indirectly stimulate transcription, the protein has been reported to affect cell growth, signal transduction, DNA repair and apoptosis. In this work, we generated Chang (CCL-13)-derived cell lines constitutively expressing wild type or mutant HBx, as a model of HBx-host cell interaction closer to the chronic infection setting, than the classically used transient expression systems. We document the potentiation by HBx of the apoptotic cell death pathway in the recipient cells. This effect is unlikely to rely on p53 activity since the protein is functionally inactivated in CCL-13. In addition, antioxidants and cyclosporin A failed to reduce the apoptotic response back to the normal level, suggesting that production of reactive oxygen species and calcineurin activation are not directly involved in the proapoptotic effect of HBx. In contrast, our data show that transactivation and stimulation of apoptosis are tightly linked HBx activities. Finally, expression of transactivation-active protein did not result in detectable change in the pattern of MAP kinases phosphorylation nor did it affect the ability of the host cell to repair in vitro irradiated plasmid DNA.
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PMID:The proapoptotic effect of hepatitis B virus HBx protein correlates with its transactivation activity in stably transfected cell lines. 1036 57

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

Ongoing studies in our laboratory have demonstrated that dietary energy restriction (DER) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced AP-1 transcription factor binding to DNA in the epidermis of SENCAR mice. To dissect the specific signal transduction pathways through which DER inhibits the AP-1:DNA binding, we analyzed the activities of three major MAP kinases that lead to the induction of AP-1. The changes in ERK1 and ERK2 protein expression and phosphorylation were further characterized by western blot analysis. Female SENCAR mice were pre-fed ad libitum (AL) or 40% DER diet for 8-10 weeks. The kinase activities in mouse epidermis were determined by immune complex kinase assays at 0.5, 1, 4, or 6 h following treatment with 3.2 nmol TPA to the shaved dorsal backs. ERK activity at 1 h post-TPA treatment was nearly 5-fold (P< 0.005) above basal levels in AL mice while the increase was abolished in DER mice. The TPA-induced ERK activity in AL mice was accompanied by increased phosphorylation of ERK1 and ERK2 (P< 0.05), which was abrogated in DER mice. In addition, DER mice exhibited reduced expression of total ERK1 and ERK2 and higher proportions of ERK1 and ERK2 phosphorylation in comparison with AL mice (P<0.05). JNK activity was decreased at 1 and 6 h but increased at 4 h (P<0.05) post-TPA treatment. TPA did not change p38 kinase activity at the time points tested. Neither JNK nor p38 activity was altered by DER. Taken together, our results indicated for the first time that DER blocked the TPA stimulation of ERK activity and suggested that the inhibition of TPA-induced AP-1 activity by DER is likely through inhibition of ERK but not JNK or p38 kinase pathway.
Carcinogenesis 2001 Apr
PMID:Dietary energy restriction inhibits ERK but not JNK or p38 activity in the epidermis of SENCAR mice. 1128 96

The roles of p38 MAP kinases and ERK in UVB induced cox-2 gene expression were studied in a human keratinocyte cell line, HaCaT. UVB significantly increased cox-2 gene expression at both protein and mRNA levels. As we reported previously, p38 and ERK were significantly activated after UVB irradiation in HaCaT cells. In addition, treating the cells with p38 inhibitor SB202190 or MEK inhibitor PD98059 specifically inhibited UVB induced p38 or ERK activation, respectively. In this study, we further examined the roles of p38 and ERK in UVB induced cox-2 gene expression in HaCaT cells. We found that SB202190 strongly inhibited UVB induced COX-2 protein expression at different time points and various UVB doses. Furthermore, SB202190 markedly inhibited UVB induced cox-2 mRNA. Our data indicated that ERK did not play a role in UVB induced cox-2 gene expression in human keratinocytes since suppression of ERK did not significantly alter UVB induced increase of COX-2 protein and mRNA. These results suggested, for the first time, that activation of p38 is required for UVB induced cox-2 gene expression in human keratinocytes. Since cox-2 expression plays an important role in UV carcinogenesis, p38 could be a potential molecular target for chemoprevention of skin cancer.
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PMID:Role of p38 MAP kinases and ERK in mediating ultraviolet-B induced cyclooxygenase-2 gene expression in human keratinocytes. 1143 56

Transforming growth factor (TGF)-beta represents a prototype of multifunctional cytokine. Its broad activities include, among others, context-specific inhibition or stimulation of cell proliferation, control of extracellular matrix (ECM) synthesis and degradation, control of mesenchymal-epithelial interactions during embryogenesis, mediation of cell and tissue responses to injury, control of carcinogenesis, and modulation of immune functions. Regulation of production and turnover of ECM components is essential for tissue homeostasis and function. TGF-beta exerts its effects on cell proliferation, differentiation, and migration in part through its capacity to modulate the deposition of ECM components. Specifically, TGF-beta isoforms have the ability to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. Deregulation of these functions is associated with abnormal connective tissue deposition, as observed, for example, during scarring or fibrotic processes. In this review we discuss the current understanding of the signaling mechanisms used by TGF-beta to elicit its effects on target genes, focusing primarily on Smad proteins and their role in the transcriptional regulation of ECM gene expression. Other signaling mechanisms, such as the MAP/SAP kinase or Ras pathways, although potentially important for transmission of some of the TGF-beta signals, will not be described. Transforming growth factor-beta (TGF-beta) plays a critical role in the regulation of extracellular matrix gene expression. Its overexpression is believed to contribute to the development of tissue fibrosis. The recent identification of Smad proteins, TGF-beta receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, has increased our understanding of the molecular mechanisms underlying TGF-beta action. This review focuses primarily on the mechanisms underlying Smad modulation of gene expression and how they relate to wound healing. Potential implications for the development of therapeutic approaches against tissue fibrosis are discussed.
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PMID:Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. 1184 35

High concentrations of non steroidal antiinflammatory drugs (NSAIDs) exert preventive effects against carcinogenesis. Their molecular mechanism of action remains to be elucidated. Based on previous reports with salicylate, we have made the hypothesis that various NSAIDs can activate the mitogen-activated protein kinases (MAPK). Moreover, we tested the idea that NSAIDs act by increasing the effects of oxidative stress. We report that in human colorectal carcinoma cells NSAIDs stimulated the three families of MAPK, extracellular regulated kinases, c-Jun N-terminal kinases, p38 MAPK and that this stimulation is prevented by N-acetyl cysteine. In cultured astrocytes, a biological system less sensitive to oxidative stress, we show that a short treatment by NSAIDs strongly activated the three MAP kinases in the presence of H(2)O(2). A 25 microM H(2)O(2), unable to stimulate by itself the MAP kinases, promote an almost complete activation of MAP kinases in the presence of NSAIDs. The activation of MAP kinases by H(2)O(2) and NSAIDs was suppressed by quinone reductase inhibitors, suggesting that "redox cycling" was involved in the activation mechanisms of MAP kinases by H(2)O(2) and NSAIDs. The mobility on SDS-PAGE of the apoptosis signal-regulating kinase, which activates C-Jun N-terminal kinases and p38 MAPK cascades, was reduced by H(2)O(2) and NSAIDs, suggesting, that H(2)O(2) and NSAIDs activated apoptosis signal-regulating kinase by increasing its state of phosphorylation. In conclusion, we demonstrate that various NSAIDs can activate the three families of MAP kinases and that this activation depends on the presence of reactive oxygenated species. These results give a new insight into the mechanism of the action of NSAIDs.
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PMID:Role of redox status on the activation of mitogen-activated protein kinase cascades by NSAIDs. 1184 90

Modulation of gap junctional intercellular communication (GJIC) is a known cellular event associated with tumor promotion. The present study was undertaken to test the potential preventive effect of mushroom Phellinus linteus extract (PL) on the inhibition of GJIC, induced by hydrogen peroxide (H(2)O(2)), in WB-F344 rat liver epithelial cells (WB cells). Cells were pre-incubated with PL (5 and 25 microg/ml) for 24 h and this was followed by co-treatment with PL and H(2)O(2) (500 microM) for 1 h. PL (at 5 and 25 microg/ml) prevented the inhibition of GJIC and blocked the hyper-phosphorylation of connexin 43 by H(2)O(2). Moreover, H(2)O(2) activated p38 kinase, extracellular signal-regulated protein kinases (ERK)1/2 and c-Jun N-terminal kinase (JNK) in WB cells. The present study indicates that PL is able to inactivate both ERK1/2 and p38 MAP kinases. However, PL did not affect the JNK pathway. For this reason, to elucidate the relation between MAP kinases and GJIC, we treated cells with PD98059 (an MEK inhibitor) and SB202190 (a p38 kinase inhibitor). These inhibitors were also found to prevent the inhibition of GJIC induced by H(2)O(2), which suggests that PL may act as a natural anticancer product by preventing the inhibition of GJIC through the inactivation of ERK1/2 and p38 MAP kinases. In addition, our results indicate that the p38 kinase signaling pathway may be closely related functionally to the gap junction in rat liver epithelial cells.
Carcinogenesis 2002 Jul
PMID:The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide. 1211 74

Genetic aberrations are the primary events leading to carcinogenesis in various tissues and are characteristic for certain tumor types. Amplification of N-myc and deletion of 1p significantly correlate with poor prognosis of neuroblastoma patients. Very little informations is available on the regulation of N-myc expression by external factors. Insulin-like growth factor-II (IGF-II) has been identified as an autocrine growth factor in neuroblastoma. Four neuroblastoma cell lines were examined for their expression of IGF-II and IGF-receptor. Stimulation of neuroblastoma cells with IGF-II leads to an increased activity of the MAP-kinase Erk1, an induction of N-myc expression and an enhanced proliferation rate. In order to disrupt the signal transduction of the IGF-receptor, we inactivated the Ras-proteins in neuroblastoma cells by inhibition of the farnesyl-protein transferase by FTI-277. This inactivation prevented activation of MAP-kinase Erk1 and induction of N-myc expression by IGF-II. Inactivation of Ras by farnesyltransferase inhibitors might become a promising new approach in future treatments of neuroblastoma tumors.
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PMID:Induction of N-myc in neuroblastoma by autocrine IGF-II depends on farnesylated Ras. Application of farnesyltransferase inhibitors. 1255 57

Resveratrol is a plant polyphenol found in grapes and red wine. It has been found to have beneficial effects on the cardiovascular system. Resveratrol also inhibits the growth of various tumor cell lines in vitro and inhibits carcinogenesis in vivo. In this study we examined the effect of resveratrol on growth of two human melanoma cell lines. We found that this plant polyphenol inhibited growth and induced apoptosis in both cell lines, with the amelanotic cell line A375 being more sensitive. The potential involvement of different MAP kinases in the action of resveratrol was also examined. Although resveratrol did not alter the phosphorylation of p38 or JNK MAP kinases in either cell line, it induced phosphorylation of ERK1/2 in A375, but not in SK-mel28 cells. These results suggest that in vivo studies of the effect of resveratrol on melanoma are warranted and that this plant polyphenol might have effectiveness as either a therapeutic or chemopreventive agent against melanoma.
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PMID:Resveratrol is a potent inducer of apoptosis in human melanoma cells. 1256 70


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