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)

Rel/NF-kappaB transcription factors regulate the division and survival of B lymphocytes. Here we show that B cells lacking NF-kappaB1 and c-Rel fail to increase in size upon mitogenic stimulation due to a reduction in induced c-myc expression. Mitogen-induced B cell growth, although not markedly impaired by FRAP/mTOR or MEK inhibitors, required phosphatidylinositol 3-kinase (PI3K) activity. Inhibition of PI3K-dependent growth coincided with a block in the nuclear import of NF-kappaB1/c-Rel dimers and a failure to upregulate c-myc. In addition, PI3K was shown to be necessary for a transcription-independent increase in c-Myc protein levels that accompanies mitogenic activation. Collectively, these findings establish a role for Rel/NF-kappaB signaling in the mitogen-induced growth of mammalian cells, which in B lymphocytes requires a PI3K/c-myc-dependent pathway.
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PMID:B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. 1250 5

IL-16 is a ligand and chemotactic factor for CD4+ T cells. IL-16 inhibits the CD3 mediated lymphocyte activation and proliferation. The effects of IL-16 on the target cells are dependent on the cell type, the presence of co-activators etc. To understand the regulation function and mechanism of IL-16 on target cells, we used a 130 a.a. recombinant IL-16 to study its effects on the growth of Jurkat T leukemia cells in vitro. We found that the rIL-16 stimulated the proliferation of Jurkat cells at low dose (10(-9)M), but inhibited the growth of the cells at higher concentration (10(-5)M). Results showed that 10(-5) M of rIL-16 treatment induced an enhanced apoptosis in Jurkat cells. The treatment blocked the expression of FasL, but up-regulated the c-myc and Bid expression in the cells. Pre-treatment of PKC inhibitor or MEK1 inhibitor markedly increased or decreased the rIL-16 induced growth-inhibiting effects on Jurkat cells, respectively. The results suggested that the rIL-16 might be a regulator for the growth or apoptosis of Jurkat cells at a dose-dependent manner. The growth-inhibiting effects of rIL-16 might be Fas/FasL independent, but, associated with the activation of PKC, up-regulated expression of c-Myc and Bid, and the participation of the ERK signal pathway in Jurkat cells.
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PMID:The associated regulators and signal pathway in rIL-16/CD4 mediated growth regulation in Jurkat cells. 1252 94

Avoidance of apoptosis and mitogen-independent growth are hallmarks of cancer. Mitogen-activated kinases (for example, ErbB1, Raf-1, MEK, PI-3-K, mTOR) can suppress chemotherapy-induced apoptosis in cancer cells. While kinase inhibitors restore susceptibility of cancer cells to apoptosis, they do not necessarily cause growth arrest in cancer cells harboring additional mutations in downstream signaling pathways such as inactivation of Rb and overexpression of c-myc. This article provides a conceptual basis for a novel use of inhibitors of mitogenic kinases. While arresting growth of normal cells, kinase inhibitors may not arrest cancer cells but instead can sensitize them to apoptosis. Following pretreatment with low doses of kinase inhibitors, the chemotherapy that predominantly induces apoptosis in cycling cells (cyclotherapy) will kill cancer cells while sparing normal cells.
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PMID:Cyclotherapy: protection of normal cells and unshielding of cancer cells. 1254 8

Lysyl oxidase (LO), which catalyzes the oxidation of lysine residues, was previously shown to have anti-oncogenic activity on ras-transformed cells. Since oncogenic Ras mediates transformation, in part, through the activation of the transcription factor nuclear factor-kappa B (NF-kappa B), we tested here the effects of LO on NF-kappa B activity. Expression of LO in ras-transformed NIH 3T3 cells led to decreased NF-kappa B binding and activity, as well as the expression of the NF-kappa B target gene c-myc. Importantly, ectopic expression of LO led to a dramatic decrease in colony formation by ras-transformed NIH 3T3 cells, a finding comparable to the expression of the I kappa B alpha dominant-negative mutant, which could be rescued by p65/p50 NF-kappa B subunit expression. LO was unable to directly inhibit the activity of ectopically expressed p65 and c-Rel NF-kappa B subunits, suggesting that LO affected an upstream signaling pathway(s) induced by Ras. Consistent with this hypothesis, LO expression decreased both the rate of I kappa B alpha turnover and the activities of IKK alpha and IKK beta. Moreover, the ectopic expression of a constitutively active version of either kinase reversed the negative effects of LO. Ras can induce NF-kappa B via both the phosphatidylinositol 3-kinase (PI3K)/Akt and Raf/MEK pathways. LO potently downregulated the PI3K and Akt kinases, while partially inhibiting MEK kinase activity. Expression of a constitutively activated, myristylated Akt or PDK1 was able to counteract the effect of LO on NF-kappa B, whereas constitutively activated Raf was only partially effective. Importantly, LO blocked membrane localization of Akt and PDK1 in Ras-transformed cells. Overall, these results strongly argue that the anti-oncogenic effects of LO on ras-mediated transformation are due to its ability to inhibit signaling pathways that lead to activation of NF-kappa B.
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PMID:Lysyl oxidase inhibits ras-mediated transformation by preventing activation of NF-kappa B. 1264 Jan 11

Among the inhibitors of apoptosis proteins (IAPs), survivin has attracted special attention through its involvement in human cancer. The mechanism underlying tumour-associated survivin re-expression is not known. We found a correlation between exogenous c-H-Ras oncoprotein and endogenous survivin in a series of rat cell lines, which expressed defined oncogenes. Moreover, human HaCat cells, transfected with a constitutively activated c-H-ras gene, had significantly increased survivin levels. To study the interdependence of the two proteins, we generated a rat cell line that expressed a dexamethasone-inducible c-H-ras construct. Induction of c-H-Ras expression was followed by rapid upregulation of survivin. Conversely, downregulation of the oncoprotein resulted in prompt reduction of survivin to baseline value. c-H-Ras-induced survivin was expressed constitutively and independent of cell cycle progression or proliferation. Compromising Ras-stimulated PI3-K activity and MEK1 by chemicals abolished survivin expression and was associated with apoptotic cell death. Upregulation of survivin appeared to be an important activity of c-H-Ras oncoprotein, since cotransfection of a survivin-antisense construct into c-myc/c-H-ras-transfected primary rat embryo cells resulted in profound reduction of transformed clones. It is tempted to speculate that the frequent presence of survivin in human cancer cells might be a consequence of activated Ras-signalling pathways.
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PMID:Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras. 1283 49

Cadmium exposure increases the risk of prostate cancer. We now describe the effects of Cd2+ on signalling and proliferation in 1LN prostate cells. Cd2+ increased [3H]thymidine uptake and cell number twofold. Cd2+ elevated intracellular IP3, cytosolic-free Ca2+, phosphorylated MEK1/2, ERK1/2, p38 MAPK and JNK two- to threefold. Increased PDK1 and phosphorylation of the 85-kDa regulatory subunit of PI 3-kinase, Akt and p70s6k were also observed. Cd2+ treatment increased transcription factors NFkappaB and CREB, and the expression of c-fos and c-myc. Cd2+-induced increased uptake of [3H]thymidine was abolished by translational and transcriptional inhibitors, and Ca2+ channel blockers. Inhibition of phospholipase C and of Ca2+ binding to IP3 receptors inhibited Cd2+-induced DNA synthesis as did inhibition of tyrosine kinases, protein kinase C, PI 3-kinase, farnesyl transferase, MEK1/2, ERK1/2 and p38MAPK. Thus signalling events, which are triggered on exposure of 1LN cells to submicromolar concentrations of Cd2+, induce increased proliferation of these cells.
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PMID:Induction of mitogenic signalling in the 1LN prostate cell line on exposure to submicromolar concentrations of cadmium+. 1449 49

Our previous studies have shown that the cell proliferation rate, mRNA levels of p450scc, p450c17, and 3betaHSD, and secretion of cortisol were significantly increased in human adrenocortical cells stably transfected with mutated K-ras expression plasmid "pK568MRSV" after being inducted with IPTG. In addition, the increased level was a time-dependent manner. However, the levels of p450, p450scc, p450c17, 3betaHSD, cortisol, and cell proliferation rate were inhibited by a MEK phospholation inhibitor, PD098059. The above results prove that mutated K-ras oncogene is able to regulate tumorigenesis and steroidogenesis through a Ras-RAF-MEK-MAPK signal transduction pathway. The aim of this study was to investigate regulated factors in this pathway and also examine whether the other signal transduction pathways or other moles involved in tumorigenesis or steroidogenesis. In the first year, we analyzed gene profiles of mutant K-ras-transfected adrenocortical cells by DNA microarray to determine the gene expression related to cell cycle, signal transduction, apoptosis, tumorigenesis, steroidogenesis, and other expressed sequence tag. After being affected by the K-ras mutant, gene expression was significantly increased in some upregulated genes. Human zinc-finger protein 22 increased by 28.5 times, Osteopontin increased by 5.8 times, LIM domain Kinase 2 (LIMK2) increased by 3.3 times, Homo sapiens dual-specificity tyrosine-(Y)-phosphorylation regulated Kinase 2 (DYRK2) increased by 2.2 times, and human syntaxin 3 increased by two times. On the other hand, significant decreases in gene expression were also observed in some downregulated genes. Retinoblastoma binding protein 1 (RBBP1) decreased by four times, Homo sapiens craniofacial development protein 1 (CFDP1) decreased by 2.4 times, DAP Kinase-related apoptosis-inducing protein Kinase 1 (DRAK1) decreased by 2.3 times, SKI-interacting protein (SKIP) decreased by 2.2 times, and human poly(A)-Binding protein (PABP) decreased by 2.1 times. In all significant differentially expressed genes, preliminary analysis by bioinformatics revealed that after induced K-ras mutant expression by isopropyl thiogalctoside (IPTG), the downregulation of RBBP1 gene was most correlated to cell proliferation. RBBP1 can bind with RB/E2F to form a mSIN3-HDAC complex, which induces cell cycle arrest in the G1/G0 stage by repressing transcription of E2F-regulated genes. The result of a Northern blot showed that RBBP1 were inhibited after an induction of IPTG for 36 h. Another Northern blot analysis proved that mRNA levels of cyclin D1 and c-myc increased in proportion to K-ras expression. Finally, Western blot was carried out, and the results showed that phosphorylated pRB also increased. Taken together, we infer that the mutant K-ras oncogene promoted the cells to proceed to the G1/S stage by the inhibiting the formation of RB/RBBP1-dependent repressor complex from binding with the SIN3-HDAC complex, which resulted in the acetylation of histone to active transcription of E2F-regulated genes. However, the roles of the other differentially expressed genes involved in cell proliferation, cell morphologic change, tumorigenesis, or steroidogenesis still need further investigation.
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PMID:Retinoblastoma protein (pRB) was significantly phosphorylated through a Ras-to-MAPK pathway in mutant K-ras stably transfected human adrenocortical cells. 1461 87

Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (+/-)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H(2)O(2)-stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1% fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 microM H(2)O(2), indicating that exogenous 500 microM H(2)O(2) was a growth stimulator of rat aortic smooth muscle cells. Exogenous H(2)O(2) significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 microM H(2)O(2)-stimulated rat aortic smooth muscle cells (IC(50): 200 microM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H(2)O(2) in a dose-dependent manner. In 500 microM H(2)O(2)-stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 microM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H(2)O(2)-stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.
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PMID:Antiproliferative mechanisms of raxofelast (IRFI-016) in H2O2-stimulated rat aortic smooth muscle cells. 1474 95

Stimulation of the erythropoietin (EPO) receptor triggers a cascade of signaling events. We reported that EPO upregulates c-myc expression through 2 pathways in BaF3-EpoR cells--a phosphatidylinositol 3-kinase (PI3K) pathway operating on transcriptional initiation and a Raf-1-mitogen-activated protein kinase (MAPK) pathway affecting elongation. We now show that EPO induces phosphorylation of Raf-1 at serine 338 and within the carboxy-terminal domain, resulting in an electrophoretic mobility change (hyperphosphorylation). Importantly, MEK 1 inhibitor PD98059 blocked only the hyperphosphorylation of Raf-1 but not the phosphorylation at serine 338. This inhibition of Raf-1 hyperphosphorylation resulted in increased kinase activity of Raf-1 and increased phosphorylation of MEK, suggesting that the hyperphosphorylation of Raf-1 inhibits its MEK kinase activity. Deletion of the first 184 amino acids of Raf-1, which are involved in its interaction with Ras, had no effect on EPO-induced phosphorylation. Introducing the dominant-negative N17Ras or GAP had no effect on EPO-induced kinase activity of Raf-1 and ELK activation. N17Ras failed to inhibit ELK activation in another cell line-Rauscher murine erythroleukemia- which expresses the EPO receptor endogenously and differentiates in response to the hormone. These results indicate the presence of a Ras-independent mechanism for Raf-1 and MEK activation in these cells.
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PMID:Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism. 1502 17

ACTH is the hormone known to control adrenal cortex function and maintenance in the intact animal but, in culture, it inhibits proliferation of adrenocortical cells from different mammalian species, a puzzle that has remained unsolved for nearly 30 years. In this paper we compare ACTH and fibroblast growth factor 2 (FGF2) antagonistic effects on the cell cycle in the Y1 cell line, a functional lineage of mouse adreno-cortical tumor cells. This cell line displays chronic high levels of c-Ki-Ras-GTP, high active constitutive levels of phosphatidylinositol 3-OH kinase/Protein Kinase B (PI3K/AKT) and low constitutive basal expression of c-Myc, which accounts for a minor deregulation of the cell cycle. In G0/G1-arrested Y1 cells, over-expression of the dominant negative mutant HaRasN17 drastically reduces c-Ki-Ras-GTP levels, eliminating basal c-Myc expression and basal S phase entry. PI3K/Akt seems to be the downstream pathway from c-Ki-ras for deregulation of c-Myc basal expression, since wortmannin abolishes c-Myc expression in serum-starved, G0/G1-arrested Y1 cells. FGF2 is a strong mitogen for Y1 cells, promoting -- in a manner dependent on the MEK/ERK pathway -- c-myc transcription induction, c-Myc protein stabilization and S phase entry in G0/G1-arrested Y1 cells. On the other hand, ACTH causes c-Myc protein destabilization, partially blocking S phase entry induced by FGF2, by a process dependent on the cAMP/protein kinase A (PKA) pathway. The whole pathway activated by ACTH to destabilize c-Myc protein in Y1 cells might comprise the following steps: ACTH receptor -->cAMP/PKA --> Akt deactivation -->GSK3 activity liberation --> c-Myc Thr58 phosphorylation. We demonstrate that c-Myc regulation is a central key in the cell cycle control by these factors, since enforced expression of c-Myc through the MycER chimera abrogates the ACTH inhibitory effect over FGF2-induced S phase entry.
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PMID:c-Myc protein is stabilized by fibroblast growth factor 2 and destabilized by ACTH to control cell cycle in mouse Y1 adrenocortical cells. 1559 Oct 23


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