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)

Even though RAS usually acts as a dominant transforming oncogene, in primary fibroblasts and some established cell lines Ras inhibits proliferation. This can explain the virtual absence of RAS mutations in some types of tumors, such as chronic myeloid leukemia (CML). We report that in the CML cell line K562 Ras induces p21Cip1 expression through the Raf-MEK-ERK pathway. Because K562 cells are deficient for p15INK4b, p16INK4a, p14ARF, and p53, this would be the main mechanism whereby Ras up-regulates p21 expression in these cells. Accordingly, we also found that Ras suppresses K562 growth by signaling through the Raf-ERK pathway. Because c-Myc and Ras cooperate in cell transformation and c-Myc is up-regulated in CML, we investigated the effect of c-Myc on Ras activity in K562 cells. c-Myc antagonized the induction of p21Cip1 mediated by oncogenic H-, K-, and N-Ras and by constitutively activated Raf and ERK2. Activation of the p21Cip1 promoter by Ras was dependent on Sp1/3 binding sites in K562. However, mutational analysis of the p21 promoter and the use of a Gal4-Sp1 chimeric protein strongly suggest that c-Myc affects Sp1 transcriptional activity but not the binding of Sp1 to the p21 promoter. c-Myc-mediated impairment of Ras activity on p21 expression required a transactivation domain, a DNA binding region, and a Max binding region. Moreover, the effect was independent of Miz1 binding to c-Myc. Consistent with its effect on p21Cip1 expression, c-Myc rescued cell growth inhibition induced by Ras. The data suggest that in particular tumor types, such as those associated with CML, c-Myc contributes to tumorigenesis by inhibiting Ras antiproliferative activity.
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PMID:Myc antagonizes Ras-mediated growth arrest in leukemia cells through the inhibition of the Ras-ERK-p21Cip1 pathway. 1552 12

Cell signaling affects gene expression by regulating the activity of transcription factors. Here, we report that mitogen-activated protein kinase (MAPK) phosphorylation of Ets-1 and Ets-2, at a conserved site N terminal to their Pointed (PNT) domains, resulted in enhanced transactivation by preferential recruitment of the coactivators CREB binding protein (CBP) and p300. We discovered this phosphorylation-augmented interaction in an unbiased affinity chromatography screen of HeLa nuclear extracts by using either mock-treated or ERK2-phosphorylated ETS proteins as ligands. Binding between purified proteins demonstrated a direct interaction. Both the phosphoacceptor site, which lies in an unstructured region, and the PNT domain were required for the interaction. Minimal regions that were competent for induced CBP/p300 binding in vitro also supported MAPK-enhanced transcription in vivo. CBP coexpression potentiated MEK1-stimulated Ets-2 transactivation of promoters with Ras-responsive elements. Furthermore, CBP and Ets-2 interacted in a phosphorylation-enhanced manner in vivo. This study describes a distinctive interface for a transcription factor-coactivator complex and demonstrates a functional role for inducible CBP/p300 binding. In addition, our findings decipher the mechanistic link between Ras/MAPK signaling and two specific transcription factors that are relevant to both normal development and tumorigenesis.
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PMID:Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment. 1557 96

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is the most potent tumor promoter ever tested in rodents. Although it is known that most of the effects of TCDD are mediated by binding to the aryl hydrocarbon receptor (AhR), the mechanisms leading to tumor promotion remain to be elucidated. Loss of contact-inhibition is one characteristic hallmark in tumorigenesis. In WB-F344 cells, TCDD induces a release from contact-inhibition which is manifested by a twofold increase in DNA-synthesis and cell number when TCDD (1 nmol L-1) is given to confluent cells. Because TCDD leads to phosphorylation of the epidermal growth factor receptor and an increase in c-Src-activation in WB-F344 cells, we investigated the functional relevance of this observation. Pharmacological inhibition of c-Src using PP1 (10 micromol L-1) or genistein (10 micromol L-1) did not prevent TCDD-dependent release from contact-inhibition. In accordance, elevation of cyclin A-a previously identified target of TCDD and marker of S-phase entry-was not reduced in the presence of PP1 or genistein. Western blot analysis revealed that phosphorylation of the EGF-receptor downstream target ERK was not induced in response to TCDD. Furthermore, TCDD-dependent increase in DNA-synthesis was not inhibited by the MEK1/2 inhibitor U0126 (10 micromol L-1). Our data show that neither c-Src-activation, nor ERK-activation are required for TCDD-dependent release from contact-inhibition arguing against a functional role of EGF-receptor activation in response to TCDD in WB-F344 cells.
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PMID:Evaluation of the role of c-Src and ERK in TCDD-dependent release from contact-inhibition in WB-F344 cells. 1559 23

NF-kappaB/Rel transcription factors block apoptosis or programmed cell death (PCD) induced by tumor necrosis factor (TNF) alpha. The antiapoptotic activity of NF-kappaB is also crucial for immunity, lymphocyte development, tumorigenesis, and cancer chemoresistance. With respect to TNFalpha, the NF-kappaB-mediated suppression of apoptosis involves inhibition of the c-Jun-N-terminal kinase (JNK) cascade. This inhibitory activity of NF-kappaB depends upon transcriptional upregulation of blockers of the JNK cascade such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase Gadd45beta/Myd118. Moreover, NF-kappaB blunts accumulation of reactive oxygen species (ROS) induced by TNFalpha, and this antioxidant effect of NF-kappaB is also critical for inhibition of TNFalpha-induced JNK activation. Suppression of ROS by NF-kappaB is mediated by Ferritin heavy chain (FHC)--the primary iron-storage mechanism in cells--and possibly, by the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Thus, induction of FHC and Mn-SOD represents an additional, indirect means by which NF-kappaB controls proapoptotic JNK signaling. These findings identify potential new targets for anti-inflammatory and anti-cancer therapy.
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PMID:NF-kappaB and JNK: an intricate affair. 1561 22

Emerging evidence supports a role for p38 MAPK in negative regulation of tumorigenesis. Here we show that a subtle activation of p38 MAPK is sufficient to suppress tumorigenesis as measured by the ability to form tumors when MKK6-inducible cells were explanted into nude mice. On the other hand, this activation of p38 MAPK did not necessarily cause an immediate inhibition of cell growth in vitro as measured by standard MTS assay. This data uncovers a new methodology for anti-cancer drugs screening and suggests that a substantial number of potential anti-tumor compounds, such as activators of MKK6/p38 signaling, was missed out in previous high throughput screens based on conventional growth inhibition assays.
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PMID:A subtle change in p38 MAPK activity is sufficient to suppress in vivo tumorigenesis. 1561 62

Activation of the extracellular signal-regulated kinases (ERK1/2; p42/p44 mitogen-activated protein kinase (MAPK)) is one of the most extensively studied signaling pathways not least because it occurs downstream of oncogenic RAS. Here, we take advantage of the wealth of experimental data available on the canonical RAS/RAF/MEK/ERK pathway of Bhalla et al. to test the utility of a newly developed nonlinear analysis algorithm designed to predict likelihood of cellular transformation. By using ERK phosphorylation as an "output signal", the method analyzes experimentally determined kinetic data and predicts putative oncogenes and tumor suppressor gene products impacting the RAS/MAPK module using a purely theoretical approach. This analysis identified several modifiers of ERK/MAPK activation described previously. In addition, several novel enzymes are identified which are not previously described to affect ERK/MAPK phosphorylation. Importantly, the nonlinear analysis enables a ranking of modifiers of MAPK activation predicting their relative importance in RAS-dependent oncogenesis. The results are compared with a linearized analysis based on sensitivity analysis about the steady state or metabolic control analysis (MCA). The results are favorable, pointing to the utility of first-order sensitivity analysis and MCA in the analysis of complex signaling networks for oncogenes.
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PMID:Automated oncogene detection in complex protein networks with applications to the MAPK signal transduction pathway. 1562 May 13

NAG-1 (nonsteroidal anti-inflammatory drug-activated gene), a member of the transforming growth factor beta superfamily, is involved in cellular processes such as inflammation, apoptosis/survival, and tumorigenesis and is regulated by p53, Sp1, and Egr-1. In the current study, the regulation of NAG-1 expression in LNCaP human prostate carcinoma cells by 12-O-tetradecanoylphorbol-13-acetate (TPA) was examined. TPA treatment increased NAG-1 protein and mRNA levels in a time- and concentration-dependent manner as well as NF-kappa B binding/transcriptional activity in LNCaP cells. Pretreatment with protein kinase C (PKC) inhibitor blocked the TPA-induced increase in NAG-1 protein levels and NF-kappa B binding/transcriptional activity, whereas an inhibition of p38, JNK, MEK activity had no effect on TPA-induced NAG-1 levels and NF-kappa B transcriptional activity. Expression of constitutively active PKCs induced an increase in NF-kappa B transcriptional activity and NAG-1 protein levels in LNCaP cells. The expression of NF-kappa B p65 induced NAG-1 promoter activity, and chromatin immunoprecipitation assay for p65 showed that NF-kappa B binds the NAG-1 promoter in LNCaP cells. Inhibition of TPA-induced NAG-1 expression by NAG-1 short interfering RNA blocked TPA-induced apoptosis in LNCaP cells, suggesting induction of NAG-1 negatively affects LNCaP cell survival. These results demonstrate that NAG-1 expression is up-regulated by TPA in LNCaP cells through a PKC-dependent pathway involving the activation of NF-kappa B.
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PMID:Protein kinase C-dependent regulation of NAG-1/placental bone morphogenic protein/MIC-1 expression in LNCaP prostate carcinoma cells. 1575 99

The ras genes give rise to a family of related GTP-binding proteins that exhibit potent transforming potential. Mutational activation of Ras proteins promotes oncogenesis by disturbing a multitude of cellular processes, such as gene expression, cell cycle progression and cell proliferation, as well as cell survival, and cell migration. Ras signalling pathways are well known for their involvement in tumour initiation, but less is known about their contribution to invasion and metastasis. This review summarises the role and mechanisms of Ras signalling, especially the role of the Ras effector cascade Raf/MEK/ERK, as well as the phosphatidylinositol 3-kinase/Akt pathway in Ras-mediated transformation and tumour progression. In addition, it discusses the impact of Rho GTPases on Ras-mediated transformation and metastasis.
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PMID:Oncogenic Ras in tumour progression and metastasis. 1584 65

Chronic myeloid leukemia (CML) is caused by the constitutively active Bcr-Abl tyrosine kinase. This fusion protein is generated by the Philadelphia translocation t(9;22). CML is a progressive condition that invariably advances from a drug-sensitive to a drug-resistant, aggressive, acute leukemia. The mechanisms responsible for this progression are largely unknown; however, in many cases, progression is accompanied by an increase in Bcr-Abl expression. Osteopontin (OPN) expression has been shown to be involved in the progression and increased aggression and invasiveness of many solid tumors. Here, we demonstrate that OPN expression is induced in a model of leukemia, and we describe the identification of specific signaling pathways required for the induction of OPN expression by p210 Bcr-Abl. We have determined that high levels of Bcr-Abl activate a signaling cascade involving the sequential activation of Ras, phosphatidylinositol-3 kinase, atypical protein kinase C, Raf-1, and mitogen-activated protein kinase kinase, leading to the ultimate expression of OPN. Our results suggest that these molecules represent a single pathway and also that there is no redundancy in this pathway, as inhibition of any individual component results in a block in the induction of OPN. The data presented here define for the first time the ability of Bcr-Abl to stimulate the expression of OPN and also identify the signaling pathway involved. This may not only prove important in understanding the mechanisms of progression of CML but also highlights a pathway that may prove significant in many other cases of oncogenesis, where OPN expression is implicated.
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PMID:Bcr-Abl regulates osteopontin transcription via Ras, PI-3K, aPKC, Raf-1, and MEK. 1585 38

Mammalian Notch-1 is part of an evolutionarily conserved family of transmembrane receptors best known for involvement in cell fate decisions. Mutations that result in Notch-1 activation result in T-lineage oncogenesis. In other cell lineages, however, studies have indicated that cooperation with cellular signaling pathways, such as Ras, is necessary for Notch-mediated oncogenesis and in some settings, Notch-1 has been reported to function as a tumor suppressor. In order to test the hypothesis that the Notch-1 pathway exhibits cross-talk with Ras/Raf/MEK/ERK, the constitutively active cytoplasmic portion of Notch-1 was introduced into 293 HEK fibroblasts via retroviral transduction. ERK-1,-2 activation was markedly increased in cells expressing constitutively active Notch-1. These cells exhibited a more rounded morphology as compared to 293 cells transduced with an empty vector or parental 293 cells. These observations correlated with decreased total and phosphorylated focal adhesion kinase protein (FAK). Subsequent examination of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) revealed that total and phosphorylated PTEN protein was elevated in cells expressing constitutively active Notch-1. Loss of Akt phosphorylation was also observed in cells bearing activated Notch-1. Two potential binding sites for the Notch effector CBF-1 were identified in the human PTEN promoter sequence. A PTEN promoter luciferase reporter exhibited increased activity in the presence of Notch-1 signaling. These data indicate that Notch-1 can participate in cross-talk with other signaling pathways such as Ras/Raf/MEK/ERK through the regulation of the PTEN tumor suppressor.
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PMID:Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1. 1609 76


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