Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of specific proteins involved in regulation of cell proliferation and apoptosis was studied at the initial (7-8 days after tumor inoculation), median (13-14 days), and terminal (20-21 days) stages of murine NK/Ly lymphoma development. Western-blot analysis using antibodies to MEK-ERK signaling pathway, E2F-1/2 and c-Myc, pSTAT1, pSTAT3, pSTAT5, anti-apoptotic Bcl-XL and pro-apoptotic p53 and Rb proteins, as well as active cleaved forms of caspases-3, -6, -7, was carried out to investigate the growth and survival status of NK/Ly cells. There was a marked increase in the expression of E2F-1/2 transcription factors, MAPK signaling cascade and c-Myc, which suggests intensive proliferation of lymphoma cells at terminal stage of tumor development. However, cytomorphological investigation and electrophoretic study of DNA fragmentation have shown degeneration of NK/Ly lymphoma cells and increase in their death. No expression of p53 protein or cleaved forms of caspases-3, -6, -7 was found, which suggests a caspase-independent type of apoptosis in these cells. Ascitic fluid collected at a terminal stage of NK/Ly lymphoma development was significantly weaker in supporting tumor cell growth than ascitic fluid collected at the initial stage of tumor development. It is suggested that uncontrolled cell proliferation at terminal stage of the NK/Ly lymphoma development causes nutrient deprivation and deficiency of specific growth factors in the ascitic fluid, due to overexpression of MEK-ERK, E2F and c-Myc, thereby leading to the induction of apoptosis.
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PMID:Changes in signaling pathways of cell proliferation and apoptosis during NK/Ly lymphoma aging. 1859 74

Delta(9)-Tetrahydrocannabinol (THC) is the active metabolite of cannabis, which has demonstrable cytotoxic activity in vitro. In support of our previously published data, we have investigated the interactions between THC and anti-leukemia therapies and studied the role of the signalling pathways in mediating these effects. Results showed clear synergistic interactions between THC and the cytotoxic agents in leukemic cells. Additionally, exposure of cells to sub lethal levels of THC (1 microM) sensitised cells to these cytotoxic agents, by reducing IC(50) values by approximately 50%. Sensitisation appeared to be dependent upon the ability of THC to down regulate phosphorylated ERK, as cells dominantly expressive of MEK were not sensitised to the cytotoxic drugs by equi-molar amounts of THC. Overall, these results demonstrate for the first time that a combination approach with THC and established cytotoxic agents may enhance cell death in vitro. Additionally the MAPK/ERK pathway appears responsible in part for these effects.
Leuk Lymphoma 2008 Sep
PMID:Enhancing the in vitro cytotoxic activity of Delta9-tetrahydrocannabinol in leukemic cells through a combinatorial approach. 1860 61

Rapid apoptotic cell engulfment is crucial for prevention of inflammation and autoimmune diseases and is conducted by special immunocompetent cells like macrophages or immature dendritic cells. We recently demonstrated that endothelial cells (ECs) also participate in apoptotic cell clearance. However, in contrast to conventional phagocytes they respond with an inflammatory phenotype. To further confirm these pro-inflammatory responses human ECs were exposed to apoptotic murine ECs and changes in thrombospondin-1 (TSP-1) expression and in activation of intracellular signalling cascades were determined by real-time qPCR, immunoblotting and immunocytochemistry. Human primary macrophages or monocytic lymphoma cells (U937) were incubated with conditioned supernatant of human ECs exposed to apoptotic cells and changes in activation, migration and phagocytosis were monitored. Finally, plasma levels of TSP-1 in patients with anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis (AAV) were determined by ELISA. We provided evidence that apoptotic cells induce enhanced expression of TSP-1 in human ECs and that this increase in TSP-1 is mediated by the mitogen-activated protein kinases (MAPK) ERK1 and 2 and their upstream regulators MEK and B-Raf. We also showed that plasma TSP-1 levels are increased in patients with AAV. Finally, we showed that conditioned supernatant of ECs exposed to apoptotic cells induces pro-inflammatory responses in monocytes or U937 cells and demonstrated that increased TSP-1 expression enhances migration and facilitates engulfment of apoptotic cells by monocyte-derived macrophages or U937 cells. These findings suggest that under pathological conditions with high numbers of uncleared dying cells in the circulation endothelial-derived elevated TSP-1 level may serve as an attraction signal for phagocytes promoting enhanced recognition and clearance of apoptotic cells.
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PMID:Endothelial-derived thrombospondin-1 promotes macrophage recruitment and apoptotic cell clearance. 1950 84

Using immunohistochemistry with antibodies against the phosphoserine residues in both S6rp and 4E binding protein 1, we identified the activation of the mammalian target of rapamycin (mTORC)1 pathway in 29 cases of AIDS-related lymphoma. These cases represented a diverse spectrum of histological types of non-Hodgkin lymphoma (24 cases) and classic Hodgkin lymphoma (five cases). mTORC1 was also activated in the hyperplastic but not involuted follicles of HIV-associated lymphadenopathy in eight cases, supporting the notion that mTORC1 activation is a common feature of transformed lymphocytes irrespective of either their reactive or malignant phenotype. We also found that in B-cell lines that represent diffuse large B-cell lymphoma, Burkitt lymphoma, Epstein-Barr virus-infected lymphocytes, and human herpesvirus 8-positive primary effusion lymphoma, inhibitors of Syk, MEK, and, seemingly, phosphoinositide 3 kinases suppressed mTORC1 activation, in particular when these inhibitors were used in combination. These findings indicate that AIDS-related lymphoma and other histologically similar types of lymphomas that are derived from transformed B lymphocytes may display clinical responses to inhibitors that directly target mTORC1 or, possibly, upstream activators of the mTORC1 pathway.
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PMID:Activation of mTORC1 signaling pathway in AIDS-related lymphomas. 1960 73

The MCT-1 oncogene was originally identified from lymphoma cell lines. Herein we establish that MCT-1 is highly expressed in 85% of human diffuse large B-cell lymphomas (DLBCL) and that knocking down MCT-1 by a specific short hairpin RNA in DLBCL cells induces apoptosis, supporting a critical role for MCT-1 in DLBCL cell survival. However, the mechanism underlying MCT-1 regulation is largely unknown. We find that MCT-1 is phosphorylated and up-regulated by extracellular signal-regulated kinase (ERK). Furthermore, by using a small inhibitory molecule targeting ERK, we interrupted MCT-1 phosphorylation and stability. Significantly, cells with distinct levels of MCT-1 protein displayed differential sensitivity to ERK inhibitor-induced apoptosis. Treatment with the ERK inhibitor showed marked in vivo antitumor activity in a human DLBCL xenograft model. Our findings establish a functional molecular interaction between MCT-1 and the MEK/ERK signaling pathway and suggest that the activation of MCT-1 function by its upstream kinase ERK plays an important role in lymphomagenesis.
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PMID:Extracellular signal-regulated kinase positively regulates the oncogenic activity of MCT-1 in diffuse large B-cell lymphoma. 1978 40

The expression of nicotinic acetylcholine receptors (nAChRs) in the chicken pre-B-lymphoma DT40 cell line was investigated. DT40 cells were shown to express at least alpha7-containing nAChRs; their amount increased upon incubation with 10 microM nicotine. Addition of 10 microM choline favoured the inclusion of 3-[4.5dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT); the effect of choline was inhibited by 2.5-25 nM methyllicaconitine (MLA) or 10-100 nM alpha-cobra-toxin indicating the alpha7 nAChR role in maintaining the proliferative potential of DT40 cells. Nicotine and choline potentiated the effect of 0.5 microM ionomycin, which suppresses cell viability via Ca2+ ions influx. Contrariwise, the suppressive effect of 1 microM hydrogen peroxide, mainly affecting cell mitochondria, was weakened by choline, but was increased by 2.5 nM MLA. MEK1/2 and PKC kinases activity was necessary for maintaining the proliferative potential of DT40 cells. MLA increased the effect of the MEK1/2 kinase inhibitor (U0126), while suppressive effect of MLA itself was decreased. The presence of CaMKII kinase inhibitor (KN-62) also decreased MLA effect. MLA favoured cell survival in the presence of PKC inhibitor (chelerythrine). These data indicate that MEK1/2 and CaMKII kinases are involved in alpha7-containing nAChR signaling in DT40 cells and that PKC plays a key role in this process.
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PMID:[Analysis of signaling pathways activated by nicotinic acetylcholine receptors in B-lymphocyte-derived cells]. 1987 17

The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL.
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PMID:A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. 1996 90

Interactions between the multi-kinase inhibitor sorafenib and MEK1/2 inhibitors were investigated in DLBCL cells. Sorafenib (3-10 microM) triggered apoptosis in multiple GC and ABC lymphoma cells. Unexpectedly, sorafenib did not cause sustained ERK1/2 inactivation, and in SUDHL-6 and -16 cells, triggered ERK1/2 activation. Marginally toxic MEK1/2 inhibitor concentrations (5 microM PD184352) abrogated ERK1/2 activation in sorafenib-treated cells and synergistically potentiated apoptosis. MEK1 shRNA transfection also significantly increased sorafenib-mediated lethality. Sorafenib/PD184352 co-administration accelerated Mcl-1 down-regulation without up-regulating Bim(EL). Finally, ectopic Mcl-1 expression attenuated sorafenib/PD184352-mediated apoptosis. Together, these findings provide a theoretical basis for potentiating sorafenib anti-lymphoma activity by MEK1/2 inhibitors.
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PMID:Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apoptosis. 2011 35

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. Mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. BRAF mutations are involved in more than 80% of CFC syndrome patients, and we have reported earlier that 2 CFC patients with BRAF mutations developed acute lymphoblastic leukemia. Here we report a boy with CFC syndrome who developed non-Hodgkin lymphoma. At 2 months of age, he developed pneumonia with pleurisy and was diagnosed as having non-Hodgkin lymphoma (precursor T-cell lymphoblastic lymphoma) by cytopathologic examination of the pleural fluid. He was suspected of having Noonan syndrome because of his facial appearance, webbed neck, and cubitus valgus. Precursor T-cell lymphoblastic lymphoma was treated by the TCCSG NHL 94-04 protocol. At 9 years of age, he was clinically reevaluated and diagnosed as having CFC syndrome because of his distinctive facial appearance, multiple nevi, and moderate mental retardation. Sequencing analysis showed a germline p.A246P (c.736G>C) mutation in BRAF reported earlier in CFC syndrome. Molecular diagnosis and careful observation should be considered in children with CFC syndrome.
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PMID:Non-hodgkin lymphoma in a patient with cardiofaciocutaneous syndrome. 2052 44

Myc is deregulated by Kaposi's sarcoma-associated herpesvirus (KSHV) latent proteins, but its role in KSHV latency is not clear. We found that Myc knockdown with RNA interference (RNAi) induced KSHV reactivation and increased the protein and mRNA levels of RTA, a key viral regulator of KSHV reactivation. Myc knockdown increased, whereas Myc overexpression inhibited, RTA promoter activity. KSHV reactivation and the activation of the RTA promoter induced by Myc depletion were inhibited by c-Jun N-terminal kinase (JNK) and p38 inhibitors but not by a MEK1 inhibitor. Myc knockdown inhibited primary effusion lymphoma (PEL) cell proliferation through inducing apoptosis and G(1) cell cycle arrest. Thus, Myc may be a key cellular node coupling cellular transformation and KSHV latency.
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PMID:Myc is required for the maintenance of Kaposi's sarcoma-associated herpesvirus latency. 2057 31


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