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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As the obligate heterodimer partner to class II nuclear receptors, the retinoid X receptor alpha (RXRalpha) plays a vital physiological role in the regulation of multiple hepatic functions, including bile formation, intermediary metabolism, and endobiotic/xenobiotic detoxification. Many RXRalpha-regulated genes are themselves suppressed in inflamed liver via unknown mechanisms, which constitute a substantial component of the negative hepatic acute phase response. In this study we show that RXRalpha, generally considered a stable nuclear resident protein, undergoes rapid nuclear export in response to signals initiated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta), a central activator of the acute phase response. Within 30 min of exposure to IL-1beta, nuclear levels of RXRalpha are markedly suppressed in human liver-derived HepG2 cells, temporally coinciding with its appearance in the cytoplasm. The nuclear residence of RXRalpha is maintained by inhibiting c-jun N-terminal kinase (JNK, curcumin or SP600125) or CRM-1-mediated nuclear export (Leptomycin B). Pretreatment with the proteasome inhibitor MG132 blocks IL-1beta-mediated reductions in nuclear RXRalpha levels while increasing accumulation in the cytoplasm. Mutational studies identify one residue, serine 260, a JNK phosphoacceptor site whose phosphorylation status had an unknown role in RXRalpha function, as critical for IL-1beta-mediated nuclear export of transfected human RXRalpha-green fluorescent fusion constructs. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear RXRalpha levels, via a multistep, JNK-dependent mechanism involving Ser260, nuclear export, and proteasomal degradation. Thus, inflammation-meditated cell signaling targets RXRalpha for nuclear export and degradation; a potential mechanism that explains the broad suppression of RXRalpha-dependent gene expression in the inflamed liver.
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PMID:Nuclear export of retinoid X receptor alpha in response to interleukin-1beta-mediated cell signaling: roles for JNK and SER260. 1655 33

Our previous work demonstrated that the proteasome is central to most of genes induced by lipopolysaccharide. In this study, we evaluated the role of the proteasome in response to two other microbial stimuli, CpG DNA (bacterial DNA) and peptidoglycan (PG), by measuring the effect of proteasome inhibition on cytokine secretion, induction of inflammatory gene expression, and activation of mitogen-activated protein kinases (MAPK) in murine macrophages. Pretreatment of macrophage cultures with lactacystin, a well-established proteasome inhibitor, significantly repressed tumor necrosis factor alpha secretion and tumor necrosis factor alpha and interleukin 1 beta gene expression, blocked the degradation of IkappaB, and dysregulated phosphorylation of MAPK induced by CpG DNA or PG. With respect to MAPK, lactacystin blocked expression of PG- or CpG-induced phosphorylated ERK1 and ERK2 and increased expression of phosphorylated c-Jun amino-terminal kinase but had no significant effect on phosphorylated p38. Increased expression of phoshorylated c-Jun amino-terminal kinase did not lead to an increase in AP-1 binding activity. Collectively, these data strongly support the conclusion that the proteasome is a key regulator of the CpG DNA- and PG-induced signaling pathways.
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PMID:Proteasome-mediated regulation of CpG DNA- and peptidoglycan-induced cytokines, inflammatory genes, and mitogen-activated protein kinase activation. 1672 Dec 67

Paxillin is a substrate of the Src tyrosine onco-kinase and is involved in cell transformation, cell spreading, migration, and cancer development mediated through the mitogen-activated protein kinase signaling cascades. Here, we showed that paxillin plays a key role in skin cell transformation induced by epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA). To investigate the mechanism of paxillin's role in cell transformation, we established a paxillin knockdown stably transfected cell line by introducing small interfering RNA-paxillin (si-paxillin). The si-paxillin cells displayed a dramatic suppression of cell proliferation and anchorage-independent cell transformation induced by EGF or TPA compared with si-mock control cells. In si-paxillin cells, decreased activator protein-1 (AP-1)-dependent luciferase activity corresponded with suppressed AP-1 DNA binding activity. Importantly, knockdown of paxillin inhibited EGF- or TPA-induced c-Jun phosphorylation at Ser(63) and Ser(73). Furthermore, total c-Jun protein level was dramatically decreased in si-paxillin cells and was dependent on serum deprivation time. The down-regulation of c-Jun was restored in si-paxillin cells by treatment with the proteasome inhibitor lactacystin but not by the lysosome inhibitor leupeptin. These results clearly provided evidence that paxillin regulates c-Jun protein level and plays a key role in cell transformation most likely through the regulation of c-Jun stability.
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PMID:Involvement of the paxillin pathway in JB6 Cl41 cell transformation. 1674 Jul 38

Chemoresistance has been one of the major problems in anticancer therapy. In our effort to find a potential molecular target for overcoming the chemoresistance in prostate cancer, a promising anticancer drug trichostatin A (TSA) induced cell death was found to be compromised by enhanced NF-kappaB activation in 267B1/K-ras human prostate epithelial cancer cells. However, both the NF-kappaB activation and chemoresistance were reduced by pretreatment with proteasome inhibitor-I (ProI), accompanied by accumulations of both IkappaBalpha and p65/RelA (but not p50/NF-kappaB1) in the cytoplasm. Clonogenic cell survival and soft agar assays further confirmed the increased TSA chemosensitivity of 267B1/K-ras cells by ProI treatment. Moreover, dominant negative mutant of IKKbeta, IkappaBalpha and p65 enhanced the chemosensitization, too. Unexpectedly, using LY294002 and PD98059, phosphatidylinositol-3-kinase and mitogen-activated protein kinase were also implied in TSA chemoresistance through NF-kappaB activation, while these compounds had showed no effect on radiosensitization in the cells. On the other hand, together with TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay, activations of caspase-8 and caspase-3 by TSA and ProI were noticed, suggesting the involvement of apoptotic process in chemosensitization of 267B1/K-ras cells. Altogether, these results suggest that blocking the NF-kappaB activation pathway could be an efficient target for improving the TSA chemosensitization and applying to the development of anticancer therapeutics in Ki-Ras-overexpressing tumorigenic cells, including prostate cancer.
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PMID:NF-kappaB inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells. 1677 37

Cyclic AMP response element binding protein (CREB) content is diminished in smooth muscle cells (SMCs) in remodeled pulmonary arteries from animals with pulmonary hypertension and in the SMC layers of atherogenic systemic arteries and cardiomyocytes from hypertensive individuals. Loss of CREB can be induced in cultured SMCs by chronic exposure to hypoxia or platelet-derived growth factor BB (PDGF-BB). Here we investigated the signaling pathways and mechanisms by which PDGF elicits depletion of SMC CREB. Chronic PDGF treatment increased CREB ubiquitination in SMCs, while treatment of SMCs with the proteasome inhibitor lactacystin prevented decreases in CREB content. The nuclear export inhibitor leptomycin B also prevented depletion of SMC CREB alone or in combination with lactacystin. Subsequent studies showed that PDGF activated extracellular signal-regulated kinase, Jun N-terminal protein kinase, and phosphatidylinositol 3 (PI3)-kinase pathways in SMCs. Inhibition of these pathways blocked SMC proliferation in response to PDGF, but only inhibition of PI3-kinase or its effector, Akt, blocked PDGF-induced CREB loss. Finally, chimeric proteins containing enhanced cyan fluorescent protein linked to wild-type CREB or CREB molecules with mutations in several recognized phosphorylation sites were introduced into SMCs. PDGF treatment reduced the levels of each of these chimeric proteins except for one containing mutations in adjacent serine residues (serines 103 and 107), suggesting that CREB loss was dependent on CREB phosphorylation at these sites. We conclude that PDGF stimulates nuclear export and proteasomal degradation of CREB in SMCs via PI3-kinase/Akt signaling. These results indicate that in addition to direct phosphorylation, proteolysis and intracellular localization are key mechanisms regulating CREB content and activity in SMCs.
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PMID:Platelet-derived growth factor BB induces nuclear export and proteasomal degradation of CREB via phosphatidylinositol 3-kinase/Akt signaling in pulmonary artery smooth muscle cells. 1678 81

CXCL8 (IL-8) plays an important role in the pathogenesis of a variety of inflammatory diseases. However, little is known about the signaling pathways that regulate CXCL8-induced chemotaxis. Here, we found that CXCL8 treatment of CXCR1- and CXCR2-over-expressing L1.2 cells (CXCR1-L1.2 and CXCR2-L1.2, respectively) induced the phosphorylation of Cbl and Akt. The tyrosine kinase inhibitor Tyrphostin A9, phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 as well as proteasome inhibitors significantly blocked the CXCL8-induced chemotaxis of L1.2 cells and human neutrophils. We further found that stimulation with CXCL8 enhanced the association of the PI3K subunit p85 with Cbl. Additionally, over-expression of wild-type Cbl and G306E-Cbl (mutation in the tyrosine kinase-binding domain) inhibited chemotaxis by approximately 50% as compared with the vector control, whereas the 70Z mutant (deletion in the RING finger domain) did not reduce migration. However, wild-type Cbl or its mutants had no effect on the CXCL8-induced activation of MAPK, indicating that Cbl specifically modulated CXCL8-induced chemotaxis. Furthermore, over-expression of the kinase-dead Akt mutant decreased CXCL8-induced chemotaxis by 60% and diminished Cbl phosphorylation as compared with the vector control. The CXCL8-induced phosphorylation of Cbl was also reduced when cells were pre-treated with the PI3K inhibitor LY294002. Lastly, we have shown that pre-treatment of L1.2 cells with the proteasome inhibitor Lactacystin blocks CXCL8-induced internalization of the CXCR1 and CXCR2 receptors. These studies provide new information regarding CXCL8-induced signaling pathways that may regulate chemotaxis and receptor internalization.
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PMID:Cbl and Akt regulate CXCL8-induced and CXCR1- and CXCR2-mediated chemotaxis. 1679 38

Proteasome inhibitors represent a novel class of anti-tumor agents that have clinical efficacy against hematologic malignancies, but single-agent activity against solid tumors such as breast cancer has been disappointing, perhaps due to activation of anti-apoptotic survival signals. To evaluate a possible role for the p38 mitogen-activated protein kinase (MAPK), A1N4-myc human mammary epithelial, and BT-474 and MDA-MB-231 breast carcinoma cells, were studied. Exposure of these lines to pharmacologic p38 blockade enhanced proteasome inhibitor-mediated apoptosis, as did overexpression of dominant negative (DN)-p38-alpha and -beta-MAPK isoforms. Inhibition of p38 resulted in suppression of induction of anti-apoptotic MAPK phosphatase (MKP)-1, in association with enhanced activation of the pro-apoptotic c-Jun-N-terminal kinase (JNK). Moreover, infection of cells treated with a proteasome inhibitor/p38 inhibitor combination with Adenovirus (Ad) inducing over-expression of MKP-1 suppressed apoptosis compared with controls. Further targets of p38 MAPK were also studied, and proteasome inhibition activated phosphorylation of MAPK-activated protein kinase-2, heat shock protein (HSP)-27, and the AKT8 virus oncogene cellular homolog (Akt). Inhibition of p38 MAPK resulted in decreased phospho-HSP-27 and phospho-Akt, while down-regulation of HSP-27 with a small interfering RNA decreased phosphorylation of Akt, directly linking activation of p38 to Akt. Finally, inhibition of Akt with phosphatidylinositol-3-kinase inhibitors increased apoptosis, as did over-expression of DN-Akt. These studies support the hypothesis that proteasome inhibitors activate an anti-apoptotic survival program through p38 MAPK that involves MKP-1 and Akt. Further, they suggest that strategies targeting MKP-1 and Akt could enhance the anti-tumor efficacy of proteasome inhibitors against breast cancer.
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PMID:Proteasome inhibitors induce a p38 mitogen-activated protein kinase (MAPK)-dependent anti-apoptotic program involving MAPK phosphatase-1 and Akt in models of breast cancer. 1680 78

Previous work has demonstrated that epidermal growth factor family ligands, signaling through the MAPK/ERK pathway, prevent hen granulosa cell differentiation, in vitro, even in the presence of factors that promote differentiation (e.g. TGFbeta and FSH). The working hypothesis is that a release from tonic inhibitory ERK signaling is prerequisite for the initiation of hen granulosa cell differentiation. Initial results demonstrate that the ERK signaling pathway is desensitized after treatment with TGFalpha or betacellulin. Thus, studies were conducted to evaluate a role for MAPK phosphatases in the termination of ERK signaling in undifferentiated granulosa cells. Subsequent to ligand-induced translocation of ERK to the nucleus, de novo transcription and translation of one or more protein tyrosine or dual-specificity phosphatases results in dephosphorylation and localization of inactivated ERK within the nucleus. RT-PCR amplification reveals expression of the MAPK-selective phosphatases (MKP), MKP-1, -3, and dual-specificity phosphatase 5, in granulosa cells. TGFalpha induces expression (within 3 h) of mRNA encoding the ERK-selective nuclear phosphatase, dual-specificity phosphatase 5, and subsequently (by 20 h) induces mRNA encoding the cytoplasmic phosphatase, MKP-3. Increased expression of phosphatases is associated with the intracellular localization and dephosphorylation of ERK and is inhibited by the selective ERK inhibitor, U0126. In turn, regulation of phosphatase activity occurs via the ubiquitin-proteasome degradation pathway because treatment of cells with the proteasome inhibitor, Z-LLF-CHO, markedly promotes ERK dephosphorylation. These data provide direct evidence for ERK-mediated negative feedback due to regulation of phosphatase activity in undifferentiated granulosa cells.
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PMID:Phosphatase activation by epidermal growth factor family ligands regulates extracellular regulated kinase signaling in undifferentiated hen granulosa cells. 1684 May 44

Exposure to sublethal stress can trigger endogenous protection against subsequent, higher levels of stress. We tested for this preconditioning phenomenon in a model of Parkinson's disease by applying 6-hydroxydopamine to the dopaminergic MN9D cell line. Exposure to sublethal concentrations of 6-hydroxydopamine (5-10 microM) protected against the toxic effects of a subsequent exposure to a higher concentration (50 microM), as measured by the Hoechst assay for nuclear viability. This was accompanied by little or no protection against 6-hydroxydopamine-induced lactate dehydrogenase release, decline in ATP, or reduction in (3)H-dopamine uptake. The antioxidant, N-acetyl cysteine (20 mM), when applied during preconditioning, abolished protection, as did the protein synthesis inhibitor, cycloheximide (0.2 microM). Preconditioning did not affect superoxide dismutase or glutathione peroxidase enzymes, or levels of heat shock protein-72. However, Bcl-2 protein levels rose with preconditioning. Preconditioning rapidly increased phosphorylation of kinases ERK1/2, Akt and JNK, and was abolished by pharmacological inhibitors of their activity. Finally, sublethal 6-hydroxydopamine preconditioned against the toxicity of proteasome inhibitor, MG-132 (1 microM). Thus, exposure of a dopaminergic cell line to sublethal oxidative stress can protect against additional oxidative stress due to translational and post-translational modifications, as well as confer 'cross-tolerance' against a different insult, proteasome inhibition.
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PMID:Effect of sublethal 6-hydroxydopamine on the response to subsequent oxidative stress in dopaminergic cells: evidence for preconditioning. 1695 75

In matured rat oocytes, spontaneous activation from the metaphase-II (MII) stage occurred after collection from the oviducts. It is well known that the mitogen-activated protein kinase (MAPK) pathway and p34(cdc2) kinase play an important role in the arrest at MII in other species. However, there is no information about the difference in these factors among strains of rats. In the present study, in spontaneously activated oocytes from the Wistar rat, the Mos protein level and the activity of MAPK kinase (MEK)/MAPK were decreased at 120 min (13.8, 25.7, and 19.3, respectively, P<0.05), whereas Sprague-Dawley (SD) oocytes, which were not spontaneously activated, had a high level of Mos protein and MEK/MAPK activity (75.9, 76.2, and 87.9, respectively, P<0.05). Phosphorylation of MAPK in the SD oocytes was significantly suppressed by MEK inhibitor, U0126 at 60 min; this treatment decreased p34(cdc2) kinase activity via cyclin B1 degradation in a time-dependent manner. The treatment with proteasome inhibitor, MG132 or Ca2+-chelator, BAPTA-AM, overcame the spontaneous degradation of both Mos and cyclin B1 in a dose-dependent manner in Wistar oocytes. More than 90% of Wistar oocytes treated with BAPTA-AM were arrested at MII until 120 min. In conclusion, SD oocytes carrying Mos/MEK/MAPK, maintained a high activity of p34(cdc2) kinase by stabilizing cyclin B1, thus involved in their meiotic arrest. In contrast, Wistar oocytes had a relatively low cytostatic factor activity; rapid decrease of Mos/MEK/MAPK failed to stabilize both cyclin B1 and Mos, and these oocytes were likely to spontaneously activate.
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PMID:Involvement of Ca2+-dependent proteasome in the degradation of both cyclin B1 and Mos during spontaneous activation of matured rat oocytes. 1702 76


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