Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-alpha) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-alpha and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.
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PMID:Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. 1367 57

BRAF is a serine/threonine kinase that receives a mitogenic signal from RAS and transmits it to the MAP kinase pathway. Recent studies have reported that mutations of the BRAF gene were detected with varying frequencies in several cancers, notably more than 60% in melanoma. We analysed mutations of BRAF and RAS genes in 100 cases of thyroid carcinoma to investigate genetic aberrations in the RAS/RAF/MEK/MAP kinase pathway. BRAF mutations were detected exclusively in papillary carcinomas (40 in 76 cases: 53%), and were exclusively V599E, a mutation frequently observed in other carcinomas. NRAS mutation was observed in six cases (6%), all in histological types other than papillary carcinoma, and was exclusively Q61R. No mutations were found in KRAS or HRAS. Our results suggest that BRAF mutations may play a critical role in the carcinogenesis of papillary carcinoma of the thyroid.
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PMID:BRAF mutations in papillary carcinomas of the thyroid. 1450 25

Arsenic is a well-known carcinogen that possibly promotes tumors and the development of various types of cancer in individuals chronically exposed to arsenic in their work or living environment. Many studies have demonstrated the activation of mitogen-activated protein kinase (MAPK) in several cell types by using lethal concentrations of arsenic in the range of 50-500 micro M. Since the exposure of humans to arsenic is normally at a much lower level in the workplace or in daily life, it is more relevant to study the effects of arsenic at this lower exposure level. In the present study we aimed at redefining the role of signal transduction pathways in arsenic-induced malignant transformation as well as apoptosis using our established in vitro rat lung epithelial cell model system. Our results indicate a molecular mechanism by which MAPK pathways might differentially contribute to cell growth regulation and cell death in response to different dosages of arsenite. A low level (2 micro M) of arsenite stimulated extracellular signal-regulated kinase (ERK) signaling pathway and enhanced cell proliferation, and this arsenite-induced ERK activity was blocked by MEK inhibitor, PD98059. In contrast, a high level (40 micro M) of arsenite stimulated the c-Jun N-terminal kinase (JNK) signaling pathway and induced cell apoptosis, and this arsenite-induced JNK activity was blocked by JNK inhibitor II, SP600125. The implications of these findings are that a high concentration of arsenic exposure causes apoptosis, whereas a low concentration of arsenic exposure is carcinogenic and may result in aberrant cell accumulation.
Carcinogenesis 2004 Jan
PMID:Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. 1451 59

Dietary phytochemicals have been shown to be protective against various types of cancers. However, the precise underlying protective mechanisms are poorly understood. In the present study, we report that treatment of A549 cells with quercetin resulted in a dose-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 1.2 +/- 0.8, 6.3 +/- 0.9, 16.5 +/- 1.5, 36.4 +/- 2.6 and 42.5 +/- 5.8% on treatment with 0.1% dimethylsulfoxide, 14.5, 29.0, 43.5 and 58.0 micro M quercetin, respectively. Concomitantly, quercetin treatments led to a 1.1-, 1.1-, 2.5- and 3.5-fold increase in Bax. Similar elevations were also observed in Bad, which increased 1.1-, 2.1-, 2.2- and 2.3-fold, respectively, as compared with control. While Bcl-2 was decreased by 30%, Bcl-x(L) was elevated in a dose-dependent fashion. Quercetin also induced the cleavage of caspase-3, caspase-7 and PARP (poly ADP-ribose polymerase). While Akt-1 and phosphorylated Akt-1 were inhibited, the extracellular signal-regulated kinase (ERK) was phosphorylated following quercetin treatment in a dose-dependent fashion. Phosphorylation of ERK and c-Jun occurred at 3 h and was sustained over 14 h. Phosphorylation of MEK1/2 was increased in concordance with ERK activation. Quercetin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and cleavage of caspase-3 occurred 6 h after quercetin exposure and before cleavage of caspase-7 and PARP was detected. Inhibition of MEK1/2 but not PI-3 kinase, p38 kinase or JNK abolished quercetin-induced phosphorylation of c-Jun, cleavage of caspase-3 and -7, cleavage of PARP and apoptosis. Inhibition of caspase activation completely blocked quercetin-induced apoptosis. Expression of constitutively activated MEK1 in A549 cells led to activation of caspase-3 and apoptosis. The results suggest that in addition to inactivation of Akt-1 and alteration in the expression of the Bcl-2 family of proteins, activation of MEK-ERK is required for quercetin-induced apoptosis in A549 lung carcinoma cells.
Carcinogenesis 2004 May
PMID:The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. 1468 22

Point mutations of the K-ras gene, which are found in 10 to 30% of lung adenocarcinomas, are regarded as being an early event during the carcinogenesis. Autonomous vigorous motility of neoplastic cells, as well as growth and survival advantages, are considered to be necessary for cancer development and progression. The present study describes the contributions of the K-ras gene mutation and its downstream pathway via phosphatidylinositol 3-OH kinase (PI3K)-Akt to the cell motility in an immortalized human peripheral airway epithelial cell (HPL1D) and lung adenocarcinoma cells (A549, H820, TKB6, and TKB14). We have also evaluated the relationship between pathological events and the K-ras-Akt pathway using surgically resected lung tumors. The HPL1D cells transfected with the mutated K-ras gene (HPL-V12) showed a significant increase in cell motility compared to those transfected with empty vector (HPL-E) or wild-type K-ras gene (HPL-K). The enhanced motility in the HPL-V12 cells was markedly reduced by either treatment with inhibitors of ras, PI3K, and/or MEK, or by transfection with the dominant-negative mutant Akt (dnAkt). The lung adenocarcinoma cells bearing the K-ras gene mutation (A549 and H820) showed consistently higher levels of cell motilities than those without the mutation (TKB6 and TKB14), and the motility of A549 and H820 cells were significantly inhibited by dnAkt transfection. These results suggest that the K-ras gene mutation could enhance the motility of neoplastic cells through a pathway involving PI3K-Akt. Actually, among the surgically resected lung tumors, the adenocarcinomas with the K-ras gene mutation tended to show a higher frequency and intensity of immunoreactivity for phosphorylated Akt (p-ser473Akt) than those without the mutation, supporting the in vitro observation that the mutated K-ras can activate the PI3K-Akt pathway. Immunoreactivity for p-ser473Akt was also seen in the pre-malignant and early lesions at a frequency similar to that in the advanced lung adenocarcinomas,. No correlation was seen between p-ser473Akt immunoreactivity and lymphatic/organ metastasis or prognosis. These results taken together suggest that the K-ras-Akt pathway might facilitate the motility of neoplastic cells during the early period of carcinogenesis in lung adenocarcinomas, and may contribute to their non-invasive expansion along the alveolar septa, rather than invasion or metastasis.
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PMID:K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation: possible contribution to non-invasive expansion of lung adenocarcinoma. 1469 23

Celecoxib, the first US FDA-approved selective cyclooxygenase-2 (COX-2) inhibitor initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, was reported to reduce the polyp burden in patients with familial adenomatous polyposis. This specific COX-2 inhibitor also protects against experimentally induced carcinogenesis, but molecular mechanisms underlying its chemopreventive activities remain largely unresolved. In the present work, we found that celecoxib inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of COX-2 in female ICR mouse skin when applied topically 30 min prior to TPA as determined by both immunoblot and immunohistochemical analyses. In another study, celecoxib attenuated the DNA binding activity of activator protein 1 (AP-1) through suppression of c-Jun and c-Fos expression in TPA-treated mouse skin. In addition, celecoxib inhibited both the catalytic activity and phosphorylation of p38 mitogen-activated protein (MAP) kinase. In the same animal model, TPA treatment resulted in rapid activation via phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and p38 MAP kinase, which are upstream of AP-1 in mouse skin. In order to clarify the roles of p38 and ERK in TPA-induced AP-1 activation, we utilized the pharmacologic inhibitors of these enzymes. The p38 inhibitor SB203580 blocked TPA-mediated AP-1 activation, while the MEK1/2 inhibitor U0126 was not inhibitory despite suppression of c-Fos expression in mouse skin. Furthermore, SB203580 markedly inhibited COX-2 expression induced by TPA. Taken together, these findings suggest that celecoxib down-regulates COX-2 by blocking activation of p38 MAP kinase and AP-1, which may represent molecular mechanisms underlying antitumor promoting effects of this drug on mouse skin tumorigenesis.
Carcinogenesis 2004 May
PMID:Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. 1472 83

Prostate cancer (PCA) is the second most frequently diagnosed and leading cause of cancer-related deaths in men in the USA. The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis of PCA has led to the development of MMP inhibitors as cancer therapeutic agents. As part of our efforts to develop newer and effective chemopreventive agents for PCA, we evaluated the effect of proanthocyanidins from grape seeds (GSP) on metastasis-specific MMP-2 and -9 in human prostate carcinoma DU145 cells by employing western blot and gelatinolytic zymography. Treatment of GSP dose-dependently inhibited cell proliferation (15-100% by 5-80 microg/ml of GSP), viability (30-80% by 20-80 microg/ml of GSP) and fibroblast conditioned medium (FCM)-induced expression of MMP-2 and -9 in DU145 cells. Since the signaling cascade of mitogen-activated protein kinases (MAPK) have been shown to regulate the expression of MMPs in tumor cells, we found that the treatment of DU145 cells with GSP (20-80 microg/ml) resulted in marked inhibition of FCM-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 and p38 but had little effect on c-Jun N-terminal kinase under similar experimental conditions. GSP treatment (20-80 microg/ml) to DU145 cells also dose-dependently inhibited FCM-induced activation of NF kappa B concomitantly with inhibition of MMP-2 and -9 expression in the same system. Additionally, the treatment of inhibitors of MEK (PD98059) and p38 (SB203580) to DU145 cells resulted in the reduction of FCM-induced phosphorylation of ERK1/2 and p38 concomitantly marked reduction in MMP-2 and -9 expressions. In further studies, treatment of androgen-sensitive LNCaP cells with a synthetic androgen R1881, resulted in an increase of MMP-2 and -9, which were completely abrogated in the presence of GSP (20-60 microg/ml). These data suggest that inhibition of metastasis-specific MMPs in tumor cells by GSP is associated with the inhibition of activation of MAPK and NF kappa B pathways, and thus provides the molecular basis for the development of GSP as a novel chemopreventive agent for both androgen-sensitive and -insensitive prostate cancer therapies.
Carcinogenesis 2004 Jun
PMID:Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. 2253 77

Increasingly, evidence supports the function of the helix-loop-helix protein Id-1 (inhibitor of differentiation/DNA binding-1) as an oncogene. Over-expression of Id-1 is not only observed in many types of human cancer but its expression levels have been correlated with cancer progression. However, little is known about the molecular mechanisms responsible for the function of Id-1. Recently, we and others reported that Id-1-induced cell proliferation was mediated through a Raf/MEK signalling pathway. In this study, we investigated if ectopic Id-1 expression in nasopharyngeal carcinoma cells had any protective effect on taxol-induced death, which is also regulated through Raf/MEK pathway. Using four stable Id-1 transfectant clones, we found that exogenous Id-1 expression led to phosphorylation of Raf-1 and MEK1/2 kinases, which was associated with resistance to taxol. Treatment of the Id-1 expressing cells with a MEK inhibitor, PD098059, resulted in an increased taxol-induced apoptosis rate in Id-1 transfectants compared with the vector control. In addition, the fact that the taxol-induced apoptosis rate, down-regulation of Bcl-2 and up-regulation of Bax were suppressed by PD098059 treatment in Id-1 expressing cells indicates that the Id-1 induced cellular protection against apoptosis is mediated through Raf/MEK signalling pathways. Our results suggest that Id-1 may be an upstream regulator of the Raf/MEK signalling pathway, which plays an essential role in protection against taxol-induced apoptosis. Our evidence also indicates a novel treatment strategy to increase anticancer drug-induced apoptosis through inactivation of the Id-1 protein.
Carcinogenesis 2004 Jun
PMID:Id-1-induced Raf/MEK pathway activation is essential for its protective role against taxol-induced apoptosis in nasopharyngeal carcinoma cells. 1474 19

Phosphorylation at Ser727 in signal transducer and activator of transcription 1 (STAT1) is essential for its activation and signal transduction. However, the upstream kinases responsible for phosphorylating Ser727 are still elusive. Here, we provide evidence showing that UVA-induced mitogen-activated protein kinase (MAPK) signaling pathways lead to STAT1 Ser727 phosphorylation. Our experimental results show that UVA-induced Ser727 phosphorylation of STAT1 was, to different degrees, diminished by PD98059 and U0126, two specific inhibitors of MEKs, and SB202190 and PD169316, inhibitors of p38 kinase and c-Jun N-terminal kinases (JNKs), respectively. STAT1 phosphorylation was also blocked by a dominant negative mutant of p38beta kinase or JNK1, JNK1- or JNK2-deficiency, or an N-terminal or C-terminal kinase-dead mutant of mitogen- and stress-activated protein kinase 1 (MSK1), a downstream kinase closer to p38 kinase and extracellular signal-regulated kinases (ERKs). In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S-transferase pull down show that active ERK1, JNK1, p38 kinase, MEK1 and MSK1 stimulated phosphorylation of STAT1 (Ser727) indirectly through an unidentified factor or a downstream kinase. Overall, our data indicate that phosphorylation of STAT1 at Ser727 occurs through diverse MAPK cascades including MEK1, ERKs, p38 kinase, JNKs and MSK1 in the cellular response to UVA.
Carcinogenesis 2004 Jul
PMID:Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1. 1496 18

FADD has been shown to be phosphorylated at Ser194 at the G2/M transition of the cell cycle. Here we have investigated the contribution of this phosphorylation to apoptosis induced by anticancer drugs in two human prostate cancer cell lines, LNCaP and DU145. Both were arrested at G2/M and FADD was found to be phosphorylated at Ser194 on treatment with paclitaxel. Inhibition of paclitaxel-induced c-jun NH2-terminal kinase (JNK) activation by treatment with a specific inhibitor, SP600125, or overexpression of a dominant-negative mutant form of upstream kinases, MEK kinase 1 (MEKK1) and mitogen-activated protein kinase kinase (MKK) 7, significantly reduced the increase in phosphorylated FADD. It is noteworthy that pretreatment with paclitaxel significantly up-regulated MEKK1 expression, resulting in enhancement of etoposide- or cisplatin-induced MEKK1/MKK7-dependent JNK activation and apoptosis in LNCaP and DU145 cells. Interestingly, MEKK1 up-regulation and the synergistic effects of paclitaxel on anticancer drug-induced apoptosis were abolished by overexpression of mutant FADD (Ser194-->Ala). The results clearly show that FADD phosphorylation at Ser194 affects functions both upstream and downstream of the MEKK1/MKK7/JNK1 pathway and is closely associated with chemosensitivity in prostate cancer cells. This is the first report indicating that phosphorylated FADD plays an essential role in the mechanisms of amplifications of chemotherapy-induced apoptosis.
Carcinogenesis 2004 Jul
PMID:Phosphorylation of FADD is critical for sensitivity to anticancer drug-induced apoptosis. 1500 34


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