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)

Sequential activation of protein kinases within the mitogen-activated protein kinase (MAPK) cascades is a common mechanism of signal transduction in many cellular processes. Four such cascades have been elucidated thus far, and named according to their MAPK tier component as the ERK1/2, JNK, p38MAPK, and ERK5 cascades. These cascades cooperate in transmitting various extracellular signals, and thus control cellular processes such as proliferation, differentiation, development, stress response, and apoptosis. Here we describe the classic ERK1/2 cascade, and concentrate mainly on the properties of MEK1/2 and ERK1/2, including their mode of regulation and their role in various cellular processes and in oncogenesis. This cascade may serve as a prototype of the other MAPK cascades, and the study of this cascade is likely to contribute to the understanding of mitogenic and other processes in many cell lines and tissues.
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PMID:The ERK cascade: a prototype of MAPK signaling. 1617 Feb 16

Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent alpha4beta1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL.
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PMID:Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma. 1618 74

The basis of oncogenesis underlies the modification of the control of the cell cycle, which leads to disturb balance between proliferation and apoptosis. The MDM2 protein suppresses the ability of p53 to activate genes responsible for repairing or apoptosis, but also promotes p53 degradation by ubiquitination. MDM2 inhibits tumor suppressor property of pRb, by releasing E2F1, which stimulates DNA synthesis in S-phase. MDM2 influences on the neuronal and muscle differentiation. Quantity and stability of the MDM2 protein is regulated by p73, p53, TSG101, p14ARF and Ras-Raf-MEK-ERK pathway. Changes of the level of the MDM2 can disturb control of cell cycle and contribute to oncogenesis.
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PMID:[Significance of MDM2 protein in the cell cycle]. 1620 41

The Met receptor tyrosine kinase (RTK) regulates epithelial remodeling, dispersal, and invasion and is deregulated in many human cancers. It is now accepted that impaired down-regulation, as well as sustained activation, of RTKs could contribute to their deregulation. Down-regulation of the Met receptor involves ligand-induced internalization, ubiquitination by Cbl ubiquitin ligases, and lysosomal degradation. Here we report that a ubiquitination-deficient Met receptor mutant (Y1003F) is tumorigenic in vivo. The Met Y1003F mutant is internalized, and undergoes endosomal trafficking with kinetics similar to the wild-type Met receptor, yet is inefficiently targeted for degradation. This results in sustained activation of Met Y1003F and downstream signals involving the Ras-mitogen-activated protein kinase pathway, cell transformation, and tumorigenesis. Although Met Y1003F undergoes endosomal trafficking and localizes with the cargo-sorting protein Hrs, it is unable to induce phosphorylation of Hrs. Fusion of monoubiquitin to Met Y1003F is sufficient to decrease Met receptor stability and prevent sustained MEK1/2 activation. In addition, this rescues Hrs tyrosine phosphorylation and decreases transformation in a focus-forming assay. These results demonstrate that Cbl-dependent ubiquitination is dispensable for Met internalization but is critical to target the Met receptor to components of the lysosomal sorting machinery and to suppress its inherent transforming activity.
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PMID:Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation. 1622 11

Maf b-Zip transcription factors are involved in both terminal differentiation and oncogenesis. To investigate this apparent contradiction, we used two different primary cell types and performed an extensive analysis of transformation parameters induced by Maf proteins. We show that MafA and c-Maf are potent oncogenes in chicken embryo fibroblasts, while MafB appears weaker. We also provide the first evidence that MafA can confer growth factor independence and promote cell division at low density. Moreover, using MafA as a model, we identified several parameters that are critical for Maf transforming activities. Indeed, MafA ability to induce anchorage-independent cell growth was sensitive to culture conditions. In addition, the transforming activity of MafA was dependent on its phosphorylation state, since mutation on Ser65 impaired its ability to induce growth at low density and anchorage-independent growth. We next examined transforming activity of large Maf proteins in embryonic neuroretina cells, where they are known to induce differentiation. Unlike v-Jun, MafA, MafB and c-Maf did not show oncogenic activity in these cells. Moreover, they counteracted transformation induced by constitutive activation of the Ras/Raf/MEK pathway. Taken together, our results show that Maf proteins could display antagonistic functions in oncogenesis depending on the cellular context, and support a dual role for Maf as both oncogenes and tumor suppressor-like proteins.
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PMID:Cell context reveals a dual role for Maf in oncogenesis. 1624 50

The docking protein Gab2 is a proto-oncogene product that is overexpressed in primary breast cancers. To determine the functional consequences of Gab2 overexpression, we utilized the immortalized human mammary epithelial cell line MCF-10A. In monolayer culture, expression of Gab2 at levels comparable with those detected in human breast cancer cells accelerated epidermal growth factor (EGF)-induced cell cycle progression and was associated with increased basal Stat5 tyrosine phosphorylation and enhanced and/or more sustained EGF-induced Erk and Akt activation. Three-dimensional Matrigel culture of MCF-10A cells resulted in the formation of polarized, growth-arrested acini with hollow lumina. Under these conditions, Gab2 increased cell proliferation during morphogenesis, leading to significantly larger acini, an effect dependent on Gab2 binding to Grb2 and Shp2 and enhanced by recruitment of the p85 subunit of phosphatidylinositol 3-kinase. Pharmacological inhibition of MEK revealed that, in addition to direct activation of phosphatidylinositol 3-kinase, increased Erk signaling also contributed to Gab2-mediated enhancement of acinar size. In addition, Gab2 overcame the proliferative suppression that normally occurs in late stage cultures and conferred independence of the morphogenetic program from exogenous EGF. Finally, higher levels of Gab2 expression led to the formation of large disorganized structures with defective luminal clearance. These findings support a role for Gab2 in mammary tumorigenesis.
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PMID:Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein. 1625 90

NF-kappaB/Rel transcription factors are best known for their roles in innate and adaptive immunity and inflammation. They also play a central role in promoting cell survival. This latter activity of NF-kappaB antagonizes programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)alpha and plays an important role in immunity, lymphopoiesis, osteogenesis, tumorigenesis and radio- and chemoresistance in cancer. With regard to TNFalpha, the NF-kappaB-mediated inhibition of PCD seems to involve an attenuation of the c-Jun-N-terminal kinase (JNK) cascade mediated through the induction of select downstream targets such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase, Gadd45beta/Myd118. Notably, NF-kappaB also blunts accumulation of reactive oxygen species (ROS), which themselves are pivotal elements for induction of PCD by TNFalpha, and this suppression of ROS formation mediates an additional protective activity recently ascribed to NF-kappaB. The antioxidant activity of NF-kappaB has been shown to depend upon upregulation of both Ferritin heavy chain (FHC)--a component of Ferritin, the primary iron-storage protein complex found in cells--and of the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Indeed, the inductions of Mn-SOD and FHC represent another important means through which NF-kappaB controls proapoptotic JNK signaling triggered by TNFalpha. These findings might enable the development of new, more targeted approaches to treatment of diseases sustained by a deregulated activity of NF-kappaB, including some cancers and chronic inflammatory conditions.
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PMID:The NF-kappaB-mediated control of ROS and JNK signaling. 1626 88

Kaposi's sarcoma is an angioproliferative disseminated tumor of endothelial cells linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). AP-1 transcription factors are involved in diverse biological processes, including infection and replication of viruses, cell growth, oncogenesis, angiogenesis, and invasion of cancer cells. Here we show that KSHV activates AP-1 during primary infection. The activation of AP-1 at the early stage of KSHV infection is mainly mediated by virus entry events. Concurrently, KSHV infection strongly activates MEK, JNK, and to a lesser extent, p38 mitogen-activated protein kinase (MAPK) pathways. Specific inhibitors or dominant negative constructs of MEK and JNK completely abolish AP-1 activation by KSHV, while those of p38 reduce it by half. Furthermore, individual MAPK pathways differentially regulate KSHV activation of AP-1 components. KSHV activation of AP-1 leads to the transcriptional induction of interleukin 6 (IL-6), which is inhibited by inhibitors or dominant negative constructs of MAPK pathways. Together, these results demonstrate that KSHV induces AP-1 and IL-6 during primary infection by modulating multiple MAPK pathways. Because of the diverse roles of IL-6, AP-1, and MAPK pathways in viral infection and tumor induction and promotion, these results have important implications in the pathogenesis of KSHV-induced malignancies.
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PMID:Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. 1630 73

Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor-alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.
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PMID:PAK1 hyperactivation is sufficient for mammary gland tumor formation. 1633 Dec 48

Cyclooxygenase-2 (COX-2) expression is a marker of poor prognosis in gastric cancer patients, and its inhibition suppresses gastric tumorigenesis in experimental animal models. The mechanism that leads to COX-2 overexpression in this tumor type is unknown. We have now shown that inhibition of phosphatidylinositol 3-kinase by LY294002 suppresses both basal and phorbol myristate acetate-induced COX-2 expression in TMK-1 and MKN-28 gastric cancer cells. Furthermore, inhibition of glycogen synthase kinase-3beta (GSK-3beta) by SB415286 induced expression of COX-2 mRNA and protein as well as the enzyme activity in the gastric cancer cells. The effect of SB415286 was confirmed by the use of two additional GSK-3beta inhibitors, lithium chloride and SB216763. SB415286 had a modest 1.6-fold stimulatory effect on a 2-kb COX-2 promoter reporter construct, but more importantly, it was shown to block the decay of COX-2 mRNA. In contrast to modulation of phosphatidylinositol 3-kinase/Akt/GSK-3beta pathway, inhibitors of mitogen-activated protein kinases (MEK 1/2, p38, JNK) or the mammalian target of rapamycin did not alter COX-2 expression in gastric cancer cells. Our data show that inhibition of GSK-3beta stimulates COX-2 expression in gastric cancer cells, which seems to be primarily facilitated via an increase in mRNA stability and to a lesser extent through enhanced transcription.
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PMID:Expression of cyclooxygenase-2 is regulated by glycogen synthase kinase-3beta in gastric cancer cells. 1637 52


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