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)

Amplification and mutation of Ha-ras has been shown to correlate with the malignancy of tumors that appear in chemically-induced mouse skin. Cell lines isolated from mouse skin tumors represent the evolutionary stages of tumor development. Due to the high Ha-ras levels the JNK and ERK modules are found elevated, contributing to the enhanced AP-1 activity in the more malignant cells. To examine the role of the transforming Ha-ras in controlling ERK signaling, transfection of an activated Ha-ras allele was tested in a squamous cell carcinoma cell line. The ERK1/2 signaling pathways were blocked pharmacologically by PD98059 MEK inhibitor, which inhibited cell proliferation and anchorage-independent growth of squamous and spindle carcinoma cells. In addition, treatment with PD98059 and introduction of the dominant negative ATF-2 mutant into the spindle carcinoma cells, partially reverted the spindle phenotype to squamous-like. These results suggest that ERK1/2 and A TF-2 play an important role in oncogenicity and in the degree of progression within the mouse skin carcinogenesis system.
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PMID:JNK and ERK signaling pathways in multistage mouse carcinogenesis: studies in the inhibition of signaling cascades as a means to understand their in vivo biological role. 1201 47

Cell dissociation and cell migration are the two main components of epithelium-mesenchyme transitions (EMT). We previously demonstrated that Ras is required for the accomplishment of both of these processes during the EGF-induced EMT of the NBT-II rat carcinoma cell line in vitro. In this study, we examined the downstream targets of Ras that are responsible for the dissociation and motility of NBT-II cells. Overexpression of activated forms of c-Raf and MEK1 (a component of the mitogen-activated protein kinase pathway, MAPK) led to cell dissociation, as inferred by the loss of desmosomes from the cell periphery. By contrast, active PI3K, RalA and RalB did not induce desmosome breakdown. The MEK1 inhibitor PD098059 inhibited EGF- and Ras-induced cell dispersion, whereas the PI3K inhibitor LY294002 had no effect. Accordingly, among the partial loss-of-function mutants of Ras (RasV12) that were used to distinguish between downstream targets of Ras, we found that the Raf-specific Ras mutants RasV12S35 and RasV12E38 induced cell dissociation. The PI3K- and RalGDS-activating Ras mutants had, in contrast, no effect on cell dispersion. However, MEK1 was unable to promote cell motility, whereas RasV12S35 and RasV12E38 induced cell migration, suggesting that another Ras effector was responsible for cell motility. We found that the small GTPase Rac is necessary for EGF-mediated cell dispersion since overexpression of a dominant-negative mutant of Rac1 (Rac1N17) inhibited EGF-induced NBT-II cell migration. All stimuli that promoted cell migration also induced Rac activation. Finally, coexpression of active Rac1 and active MEK1 induced the motility of NBT-II cells, suggesting that Ras mediates NBT-II cell scattering through the coordinate activation of Rac and the Raf/MAPK pathway.
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PMID:Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways. 1204 29

Interleukin-8 (IL-8) is known to contribute to human cancer progression through its potential function as a mitogenic, angiogenic, or motogenic factor. We found a high level of IL-8 production in SK-N-MC human primitive neuroectodermal tumor cells transfected with the human RET gene (SK-N-MC (RET) cells) in response to glial cell line-derived neurotrophic factor (GDNF) stimulation. IL-8 was also produced at high levels in TT human medullary thyroid carcinoma and TPC-1 human papillary thyroid carcinoma cell lines both of which express activated RET tyrosine kinase. To investigate which signaling pathways are responsible for IL-8 expression, we treated SK-N-MC (RET) cells with several kinase inhibitors before GDNF stimulation. The results showed that a MEK1 inhibitor, PD98059, a p38MAPK inhibitor, SB202190, and a protein kinase C (PKC) inhibitor, Calphostin C, markedly decreased the IL-8 secretion from SK-N-MC (RET) cells at 24 h after GDNF stimulation. In contrast, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002, increased its secretion. These results thus suggested that IL-8 production by RET tyrosine kinase is regulated by multiple signaling pathways.
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PMID:Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signaling pathways. 1205 17

Ionizing radiation (1-5 Gy) activates the epidermal growth factor receptor (EGFR), a major effector of the p42/44 mitogen-activated protein kinase (MAPK) pathway. MAPK and its downstream effector, p90 ribosomal S6 kinase (p90RSK), phosphorylate transcription factors involved in cell proliferation. To establish the role of the EGFR/MAPK pathway in radiation-induced transcription factor activation, MDA-MB-231 human breast carcinoma cells were examined using specific inhibitors of signaling pathways. Gel-shift analysis revealed three different profile groups: 1) transcription factors that responded to both radiation (2 Gy) and epidermal growth factor (EGF) (CREB, Egr, Ets, and Stat3); 2) factors that responded to radiation, but not EGF (C/EBP and Stat1); and 3) those that did not respond significantly to either radiation or EGF (AP-1 and Myc). Within groups 1 and 2, a two- to fivefold maximum stimulation of binding activity was observed at 30-60 min after irradiation. Interestingly, only transcription factors that responded to EGF had radiation responses significantly inhibited by the EGFR tyrosine kinase inhibitor, AG1478; these responses were also abrogated by farnesyltransferase inhibitor (FTI) or PD98059, inhibitors of Ras and MEK1/2, respectively. Moreover, radiation-induced increases in CREB and p90RSK phosphorylation and activation of Stat3 and Egr-1 reporter constructs by radiation were all abolished by AG1478. These data demonstrate a distinct radiation response profile at the transcriptional level that is dependent on enhanced EGFR/Ras/MAPK signaling.
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PMID:Epidermal growth factor receptor dependence of radiation-induced transcription factor activation in human breast carcinoma cells. 1213 64

Recent studies have shown that inhibition of stress-induced signaling via the mitogen activated protein kinase (MAPK) pathway can potentiate the toxic effects of chemotherapeutic drugs and ionizing radiation. Because of these observations, we have further investigated the impact upon growth and survival of mammary (MDA-MB-231, MCF7, T47D), prostate (DU145, LNCaP, PC3) and squamous (A431) carcinoma cells following irradiation and combined long-term exposure to MEK1/2 inhibitors. Exposure of carcinoma cells to ionizing radiation resulted in MAPK pathway activation initially (0-4 h) and modestly enhanced MAPK activity at later times (24 h-96 h). Inhibition of radiation-induced MAPK activation using MEK1/2 inhibitors potentiated radiation-induced apoptosis in two waves, at 21-30 h and 96-144 h after exposure. The potentiation of apoptosis was not observed in MCF7, LNCaP, or PC3 cells. At 24 h, the potentiation of apoptosis was independent of radiation dose whereas at 108 h, apoptosis correlated with increasing dose. Removal of the MEK1/2 inhibitor either 6 h or 12 h after exposure abolished the potentiation of apoptosis at 24 h. At this time, the potentiation of apoptosis correlated with cleavage of pro-caspases -8, -9 and -3, and with release of cytochrome c into the cytosol. Inhibition of caspase function using a pan-caspase inhibitor ZVAD blocked the enhanced apoptotic response at 24 h. Selective inhibition of caspase 9 with LEHD or caspase 8 with IETD partially blunted the apoptotic response in MDA-MB-231, DU145 and A431 cells, whereas inhibition of both caspases reduced the response by > 90%. Removal of the MEK1/2 inhibitor either 24 h or 48 h after exposure abolished the potentiation of apoptosis at 108 h. Incubation of cells with ZVAD for 108 h also abolished the potentiation of apoptosis. In general agreement with the finding that prolonged inhibition of MEK1/2 was required to enhance radiation-induced apoptosis at 108 h, omission of MEK1/2 inhibitor from the culture media during assessment of clonogenic survival resulted in either little or no significant alteration in radiosensitivity. Collectively, our data show that combined exposure to radiation and MEK1/2 inhibitors can reduce survival in some, but not all, tumor cell types. Prolonged blunting of MAPK pathway function following radiation exposure is required for MEK1/2 inhibitors to have any effect on carcinoma cell radiosensitivity.
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PMID:Pharmocologic inhibitors of the mitogen activated protein kinase cascade have the potential to interact with ionizing radiation exposure to induce cell death in carcinoma cells by multiple mechanisms. 1217 Jul 77

Overexpression of the growth factor receptor subunit c-erbB2, leading to its ligand-independent homodimerization and activation, has been implicated in the pathogenesis of mammary carcinoma. Here, we have examined the effects of c-erbB2 on the adhesive properties of a mammary epithelial cell line, HB2/tnz34, in which c-erbB2 homodimerization can be induced by means of a transfected hybrid "trk-neu" construct. trk-neu consists of the extracellular domain of the trkA nerve growth factor (NGF) receptor fused to the transmembrane and cytoplasmic domains of c-erbB2, allowing NGF-induced c-erbB2 homodimer signaling. Both spreading and adhesion on collagen surfaces were impaired on c-erbB2 activation in HB2/tnz34 cells. Antibody-mediated stimulation of alpha(2)beta(1) integrin function restored adhesion, suggesting a direct role for c-erbB2 in integrin inactivation. Using pharmacological inhibitors and transient transfections, we identified signaling pathways required for suppression of integrin function by c-erbB2. Among these was the MEK-ERK pathway, previously implicated in integrin inactivation. However, we could also show that downstream of phosphoinositide-3-kinase (PI3K), protein kinase B (PKB) acted as a previously unknown, potent inhibitor of integrin function and mediator of the disruptive effects of c-erbB2 on adhesion and morphogenesis. The integrin-linked kinase, previously identified as a PKB coactivator, was also found to be required for integrin inactivation by c-erbB2. In addition, the PI3K-dependent mTOR/S6 kinase pathway was shown to mediate c-erbB2-induced inhibition of adhesion (but not spreading) independently of PKB. Overexpression of MEK1 or PKB suppressed adhesion without requirement for c-erbB2 activation, suggesting that these two pathways partake in integrin inhibition by targeting common downstream effectors. These results demonstrate a major novel role for PI3K and PKB in regulation of integrin function.
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PMID:c-erbB2-induced disruption of matrix adhesion and morphogenesis reveals a novel role for protein kinase B as a negative regulator of alpha(2)beta(1) integrin function. 1218 54

We found that 12-O-tetradecanoylphorbol-13-acetate (TPA) promoted anchorage-independent growth but did not affect anchorage-dependent growth of MIA PaCa-2 human pancreatic carcinoma cells. TPA markedly activated mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase in an anchorage-independent manner. Two protein kinase C (PKC) isoforms, conventional PKC (cPKC) and novel PKC (nPKC), but not apical PKC, translocated from the cytosolic to the particulate fraction upon TPA treatment. To identify the PKC isoforms involved in the regulation of anchorage-independent growth, four PKC isoforms (alpha, delta, epsilon, and zeta) were forced to be expressed in MIA PaCa-2 cells with an adenovirus vector. Overexpression of nPKCdelta or nPKC epsilon activated MAPK and promoted anchorage-independent growth. Overexpression of cPKCalpha alone did not influence anchorage-independent growth but lowered the concentration of TPA that was required to enhance such growth. Expression of constitutively active MAPK kinase-1 (MEK1) also promoted anchorage-independent growth. Furthermore, PKC inhibitors or an MEK inhibitor completely suppressed both TPA-induced activation of MAPK and promotion of anchorage-independent growth, but a cPKC-selective inhibitor partially suppressed TPA-induced promotion of the growth. Based on these results, we suggest that MAPK activation, mediated by certain isoforms of PKC, plays a part in oncogenic growth of MIA PaCa-2 cells. In summary, our data indicated that specific inhibitors of the cPKC and nPKC signaling pathway might be selective anti-oncogenic growth agents for some types of human pancreatic cancer.
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PMID:Enhancement of anchorage-independent growth of human pancreatic carcinoma MIA PaCa-2 cells by signaling from protein kinase C to mitogen-activated protein kinase. 1220 69

Previous studies have shown that EGF can induce the tyrosine phosphorylation of caveolin-1 in murine fibroblasts following ErbB1 (EGF receptor) mutation or overexpression, but the cell signaling events linking EGF action with caveolin phosphorylation are not fully established. In this regard, we examined multiple human carcinoma cell lines that express various ErbB family members, including A431 epidermoid carcinoma cells and several squamous carcinoma cell lines. In all cases, EGF treatment induced the tyrosine phosphorylation of caveolin-1 in a time- and EGF dose-dependent manner, and immunoblotting analysis revealed that this phosphorylation occurred at tyrosine-14. The EGF-dependent phosphorylation of caveolin-1 was observed at low temperatures (4 degrees C) and was enhanced by caveolae-disrupting agents (cyclodextrin), suggesting that this EGF-dependent system is in a low temperature-stable arrangement that allows for their interaction under conditions where mobility in the membrane is altered. To further assess the events linking EGF action with caveolin phosphorylation, we evaluated the ligand specificity of these responses and their dependence on known effectors of EGF receptor function. We observed that EGF and HB-EGF, but not heregulin, promoted caveolin-1 phosphorylation in A431 cells, suggesting that these responses are linked to EGF receptor activation and not solely occurring via the activation of other endogenous ErbB family members. In addition, the EGF-induced phosphorylation of caveolin-1 in A431 cells was blocked by the Src kinase antagonists PP1 and PP2, but not by the MEK inhibitor PD98059, the phosphoinositide 3-kinase inhibitors LY294002 and wortmannin, or cytoskeleton-disrupting agents, such as cytochalasin D, colchicine, and nocadazole. Altogether, these data indicate that multiple human carcinoma cells exhibit an EGF receptor-dependent tyrosine phosphorylation of caveolin-1 and that this process is sensitive to Src family kinase inhibitors. These observations support a role for caveolin tyrosine phosphorylation in the profile of cellular responses by which Src potentiates cancer progression following EGF receptor overexpression.
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PMID:Caveolin-1 phosphorylation in human squamous and epidermoid carcinoma cells: dependence on ErbB1 expression and Src activation. 1237 46

Changes in glucose metabolism during diabetes are linked to an increased risk for the development of cancer. Increased activity of aldose reductase, the rate-limiting polyol pathway enzyme that converts glucose into sorbitol, mediates pathologies associated with diabetes and is thought to be involved in increased resistance to chemotherapeutic drugs. Thus, increased intracellular sorbitol levels may serve a protective function in cancer cells. In these studies we determined whether an inhibitor of aldose reductase could enhance the effectiveness of anticancer agents. Our findings indicate that treatment with the aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (EBPC), enhances the cytotoxic effects of the anticancer agents doxorubicin and cisplatin in HeLa cervical carcinoma cells. To establish a mechanistic basis for the increased cytotoxicity by EBPC, we examined the activity of the extracellular signal-regulated kinase (ERK) pathway, which is an important regulator of cell growth. Interestingly, treatment with EBPC in combination with the chemotherapeutic drugs increased ERK activity as compared to treatment with the chemotherapeutic drugs, suggesting a possible role for the ERK pathway in mediating doxorubicin- or cisplatin-induced cell death. Consistent with this possibility, inhibition of ERK activation by the MEK inhibitor, U0126, reversed the EBPC-mediated enhancement of cell death. In summary, these data provide evidence that adjuvant therapy with aldose reductase inhibitors improves the effectiveness of chemotherapeutic drugs, possibly through an ERK pathway-mediated mechanism.
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PMID:Inhibition of aldose reductase enhances HeLa cell sensitivity to chemotherapeutic drugs and involves activation of extracellular signal-regulated kinases. 1239 72

Recent studies have suggested that inhibition of the mitogen activated protein kinase (MAPK) pathway as well as abrogation of cell cycle check-point control can potentiate the lethal actions of chemotherapeutic drugs and radiation. We therefore investigated the impact of combined exposure to the check-point abrogator (UCN-01) in conjunction with MEK1/2 inhibitors upon survival of breast and prostate carcinoma cells. Treatment of cells with UCN-01 alone resulted in prolonged activation of the MAPK pathway. Inhibition of MEK1/2 caused modest reductions in basal MAPK activity and transiently suppressed UCN-01-stimulated MAPK activity below that of MEK1/2 inhibitor alone. Significantly, combined, but not individual, exposure of cells to UCN-01 and MEK1/2 inhibitors enhanced BAX association with mitochondria and triggered release of cytochrome c into the cytosol, accompanied by activation of effector pro-caspases, resulting in a greater than additive potentiation of apoptosis within 1 8-24h. Radiation exposure of drug treated cells did not further enhance apoptosis. Treatment of cells with both caspase 9 and caspase 8 inhibitors was required to completely inhibit apoptosis in carcinoma cells. Overexpression of Bcl-(xL) blocked cytochrome c release and cell killing induced by the drug combination. Colony forming assays demonstrated that cells exposed to both agents exhibited a substantial reduction in clonogenic survival compared to either drug alone; moreover, radiation further reduced clonogenic survival despite failing to promote additional apoptosis. Collectively, these data demonstrate that combined exposure of carcinoma cells to UCN-01 and MEK1/2 inhibitors induces apoptosis and interacts with radiation to further reduce clonogenic survival.
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PMID:Inhibitors of MEK1/2 interact with UCN-01 to induce apoptosis and reduce colony formation in mammary and prostate carcinoma cells. 1243 72


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