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)

The diterpene ester PEP005 is a novel anticancer agent that activates protein kinase C (PKC) and induces cell death in melanoma at high doses. We now describe the in vitro cytostatic effects of PEP005 and the diterpene ester phorbol 12-myristate 13-acetate, observed in 20% of human melanoma cell lines. Primary cultures of normal human neonatal fibroblasts were resistant to growth arrest, indicating a potential for tumor selectivity. Sensitive cell lines were induced to senesce and exhibited a G(1) and G(2)-M arrest. There was sustained expression of p21(WAF1/CIP1), irreversible dephosphorylation of the retinoblastoma protein, and transcriptional silencing of E2F-responsive genes in sensitive cell lines. Activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 by PKC was required for diterpene ester-induced senescence. Expression profiling revealed that the MAP kinase inhibitor HREV107 was expressed at a higher transcript level in resistant compared with sensitive cell lines. We propose that activation of PKC overstimulates the RAS/RAF/MEK/ERK pathway, resulting in molecular changes leading to the senescent phenotype.
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PMID:Induction of senescence in diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of the mitogen-activated protein kinase pathway. 1704 72

Small GTPase RAS plays a critical role in cellular signaling and oncogenic transformation. Proteomics analysis of genetically defined human ovarian cancer models identified the tumor susceptibility gene 101 (TSG101) as a downstream target of RAS oncogene. Mechanistic studies revealed a novel post-translational regulation of TSG101 through the RAS/RAF/MEK/MAPK signaling pathway and downstream molecules p14(ARF)/HDM2. Immunoanalysis using ovarian cancer samples and microtissue array revealed elevated TSG101 levels in human ovarian carcinomas. Silencing of TSG101 by short interfering RNA in ovarian cancer cells led to growth inhibition and cell death. Concurrent with the apparent growth-inhibitory effect, the levels of the CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) and hypoxia-inducible factor 1alpha (HIF-1alpha), as well as its cellular activity, were markedly reduced after TSG101 knockdown. These results demonstrate that TSG101 is important for CITED2- and HIF-1alpha-mediated cellular regulation in ovarian carcinomas.
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PMID:Up-regulation of tumor susceptibility gene 101 protein in ovarian carcinomas revealed by proteomics analyses. 1711 Apr 34

The mitogen-activated protein kinases (MAPKs), also called extracellular signal-regulated kinases (ERKs), are a group of serine/threonine terminal protein kinases activated downstream of a pleiotrophy of transmembrane receptors. Main intracellular components of the MAPK signalling pathway are the RAF, MEK, and ERK proteins, which work in a cascade of activator and effector proteins. They regulate many fundamental cellular functions, including cell proliferation, cell survival, and cell differentiation by transducing extracellular signals to cytoplasmic and nuclear effectors. To reveal more details about possible activation cascades in this pathway, the present study gives a complete description of the differential expression of Braf, Mek1, Mek2, Mek5, Erk1, Erk2, Erk3, and Erk5 in the adult murine brain by way of in situ hybridization analysis. In this study, we found that each gene is widely expressed in the whole brain, except for Mek2, but each displays a very distinct expression pattern, leading to distinct interactions of the MAPK components within different regions. Most notably we found that 1) Braf and Erk3 are coexpressed in the hippocampus proper, confirming a possible functional interaction; 2) in most forebrain areas, Mek5 and Erk5 are coexpressed; and 3) in the neurogenic regions of the brain, namely, the olfactory bulb and the dentate gyrus, Braf is absent, indicating that other activator proteins have to take over its function. Despite these differences, our results show widespread coexpression of the pathway components, thereby confirming the hypothesis of redundant functions among several MEK and ERK proteins in some regions of the brain.
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PMID:Differential mRNA distribution of components of the ERK/MAPK signalling cascade in the adult mouse brain. 1712 Feb 91

Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms).
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PMID:Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. 1717 82

Papillary thyroid carcinoma (PTC) is the most frequent malignant neoplasm of the thyroid originating from the thyroid follicular cell (TFC). Although the formation of PTC is believed to result from rearrangements of RET or TRK oncogenes or MET point mutations, these structural aberrations or point mutations do not correlate with the clinicopathological features of PTC and do not seem to be a useful prognostic marker of the disease. Therefore, further experiments should be carried out in order to find new practical clinical markers. Recently, oncogene BRAF has become a subject of great interest. The mutation of BRAF gene is characteristic for PTC and poorly differentiated and/or undifferentiated cancers derived from PTC. The occurrence of BRAF mutation has often been observed in various human tumours. The presence of mutation was confirmed in melanoma, colon cancer, gliomas and lung cancer. In the majority of cases, there is only one type of point mutation - V600E. The RAS/RAF/MEK/MAPK kinase pathway mediates the cellular response to mitogenic signals. BRAF gene mutation results in increased kinase activity, leading to excessive activation of the above mitogenic pathway and to uncontrolled proliferation of cancer cells. Some correlation was noticed between BRAF gene mutation and the clinical stage of the neoplastic disease in question. Preliminary investigations indicate that the presence of BRAF mutation might be a valuable diagnostic and prognostic marker of the disease. Further investigations could also bring further improvements into the therapeutic management of thyroid cancer. There are reports emphasizing the possibility of using the inhibitors of BRAF proteins in the treatment of PTC. Certainly, in order to confirm the diagnostic usefulness of this marker, further studies should be carried out.
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PMID:BRAF mutations in papillary thyroid carcinoma. 1720 87

There has been much recent progress in our understanding of the role played by the RAS-RAF-MEK-ERK cascade in human cancer. RAS is an oncogene and this pathway is known to promote proliferation and malignant transformation. More recently, however, RAF has become the focus of attention, particularly in melanoma, where approximately 70% of cases carry mutations in the BRAF gene. The majority of the mutations in BRAF in cancer are activating, but rare mutants that cannot activate MEK have provided new insight into RAF signalling networks that exist in cancer and normal cells. Surprisingly, germline mutations in BRAF that occur in rare genetic syndromes have also recently been described. The induction of BRAF mutations in melanoma depends on the type of UV exposure that the skin receives, and some studies have suggested the existence of susceptibility loci that make it more likely that some individuals will acquire these mutations. Importantly, genetic profiling and microarray studies have provided insight into the spectrum of melanomas in which BRAF plays a role and also revealed intriguing new data that could be important for the diagnosis and treatment of human cancers.
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PMID:New insight into BRAF mutations in cancer. 1720 30

The protein kinase BRAF, a component of the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, regulates cell fate in response to extracellular signals. Activating mutations in BRAF occur in approximately 70% of human melanomas. The active proteins stimulate constitutive pathway signaling, proliferation, and survival. Thus, inhibition of BRAF signaling in melanoma cells causes cell cycle arrest and induces cell death through apoptosis, validating BRAF as an important therapeutic target. Here, we show that the apoptosis induced by inhibition of BRAF signaling in melanoma cells can be prevented if the cells are treated with tumor necrosis factor (TNF)-alpha. This allows the cells to recover from the inhibition of BRAF signaling and reenter the cell cycle. This effect occurs due to a specific TNF-alpha and BRAF interaction because TNF-alpha does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin. Furthermore, the cytokines Fas ligand, TNF-related apoptosis-inducing ligand, interleukin (IL)-1, and IL-6 do not prevent cell death when BRAF signaling is inhibited. The survival mechanism requires nuclear factor-kappaB (NF-kappaB) transcription factor activity, which is strongly induced by TNF-alpha in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-alpha and/or NF-kappaB signaling to provide exciting new therapeutic opportunities for the treatment of melanoma.
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PMID:Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. 1721 Jun 91

Molecularly targeting signaling pathways that are involved in the pathogenesis of hematopoietic malignancies may lead to more specific and efficacious therapies. Activation of the RAS signal transduction cascade is a common feature in the molecular pathogenesis of hematologic malignancies. A number of novel agents targeting RAS signaling have been developed over the past decade. This review will focus on these agents, which include inhibitors of RAS post-translational modification (farnesyl transferase (FTase)-, geranylgeranyl transferase-I (GGTase-I)-, isoprenylcysteine carboxylmethyltransferase (ICMTase)-inhibitors, statins, bisphosphonates), and inhibitors of RAF and MEK activity. Although some of these inhibitors (e.g. FTase, RAF and MEK inhibitors) were developed to specifically inhibit RAS signaling, it has become clear that RAS may not be the only critical target of these compounds. This review provides a background on RAS signaling in hematologic malignancies and discusses opportunities to exploit aberrant cancer cell signaling in order to develop better treatment options for patients suffering from these diseases.
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PMID:Targeting the RAS signaling pathway in malignant hematologic diseases. 1730

In melanoma, the RAS/RAF/MEK/ERK signalling pathway is an area of great interest, because it regulates tumor cell proliferation and survival. A varying mutation rate has been reported for B-RAF and N-RAS, which has been largely attributed to the differential source of tumor DNA analyzed, e.g., fixed tumor tissues or in vitro propagated melanoma cells. Notably, this variation also interfered with interpreting the impact of these mutations on the clinical course of the disease. Consequently, we investigated the mutational profile of B-RAF and N-RAS in biopsies and corresponding cell lines from metastatic tumor lesions of 109 melanoma patients (AJCC stage III/IV), and its respective impact on survival. 97 tissue biopsies and 105 biopsy-derived cell lines were screened for B-RAF and N-RAS mutations by PCR single strand conformation polymorphism and DNA sequencing. Mutations were correlated with patient survival data obtained within a median follow-up time of 31 months. B-RAF mutations were detected in 55% tissues and 51% cell lines, N-RAS mutations in 23% tissues and 25% cell lines, respectively. There was strong concordance between the mutational status of tissues and corresponding cell lines, showing a differing status for B-RAF in only 5% and N-RAS in only 6%, respectively. Patients with tumors carrying mutated B-RAF showed an impaired median survival (8.0 versus 11.8 months, p = 0.055, tissues; 7.1 versus 9.3 months, p = 0.068, cell lines), whereas patients with N-RAS-mutated tumors presented with a favorable prognosis (median survival 12.5 versus 7.9 months, p = 0.084, tissues; 15.4 versus 6.8 months, p = 0.0008, cell lines), each in comparison with wildtype gene status. Multivariate analysis qualified N-RAS (p = 0.006) but not B-RAF mutation status as an independent prognostic factor of overall survival. Our findings demonstrate that B-RAF and N-RAS mutations are well preserved during short term in vitro propagation and, most importantly, differentially impact the outcome of melanoma patients.
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PMID:B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. 1731 Nov 3

Aberrant signaling caused by mutations in the RAS-RAF-MEK-ERK pathway and its upstream activators critically contributes to human tumor development. Strategies, which aim at inhibiting hyperactive signaling molecules, appear conceptually straight forward, but their translation into clinical practice has been hampered by many setbacks. Understanding structure, function and regulation of this intracellular pathway as well as its crosstalk with other signaling activities in the cell will be essential to ensure reasonable usage of new therapeutic possibilities. This review provides an understanding of this signaling cascade as revealed by genetic and biochemical approaches and discusses the existing or arising possibilities to interfere with unphysiological activation in cancer. Signaling aberrations and signal transduction therapies will be discussed exemplary for two types of hematological neoplasia, acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS). In the future understanding the role of tumor stem cells, both as a source of tumor recurrence and tumor heterogeneity, the signals controlling their fate as well as epigenetic changes in cancer will be the next critical steps to further advance the applicability of these novel therapeutic strategies.
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PMID:Signaling through RAS-RAF-MEK-ERK: from basics to bedside. 1734 50


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