Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF alpha) can function as both an autocrine and a paracrine growth factor and may therefore play a role in ovarian tumor progression. TNF alpha initiates multiple cellular responses, many of which are mediated through the mitogen-activated protein kinase pathways, which transduce signals from the TNF alpha receptors through the cytoplasm to the nucleus, resulting in regulation of gene expression. We examined the role of c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinase (ERK) 1 and 2 in the cellular growth response to TNF alpha in the ovarian carcinoma cell line UCI 101. JNK1 activity was increased to a maximum level ninefold above the basal level after 10-20 min of treatment with 10 ng/mL TNF alpha. A maximum threefold induction of ERK1/2 activity was observed after 1 min of treatment. At concentrations up to 100 ng/mL, TNF alpha had neither a stimulatory nor an inhibitory effect on growth of UCI 101 cells. However, inhibition of TNF alpha-induced ERK1/2 activity by the MAP/ERK kinase 1 inhibitor PD 98059 resulted in 60% inhibition of cell growth in TNF alpha-treated UCI 101 cells. This decrease in cell growth was accompanied by apoptosis, as demonstrated by the presence of a 180-bp DNA ladder. Thus, the inhibition of TNF alpha-induced ERK1/2 activity was associated with induction of apoptosis in the TNF alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subsequent transient increase in TNF alpha-induced JNK1 activity. The significance of this increase with respect to apoptosis induction remains to be determined. These findings demonstrated that ERK1/2 activity can modulate cellular sensitivity to TNF alpha and suggested that the balance between the levels of ERK1/2 and JNK1 activation may be critical in the cellular growth response to TNF alpha.
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PMID:Association of apoptosis with the inhibition of extracellular signal-regulated protein kinase activity in the tumor necrosis factor alpha-resistant ovarian carcinoma cell line UCI 101. 1033 40

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
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PMID:[New therapy developments in rheumatoid arthritis]. 1175 32

To investigate the mechanism of the glucocorticoids-induced augmentation of skin response, we have recently reported the modulatory effect of glucocorticoids on the regulation of cytokines production in keratinocytes stimulated with various chemicals in vitro through both NF-kappaB and AP-1 activation. Further to clarify the mechanism in the glucocorticoids-induced augmentation of cytokines production from keratinocytes, we examined the effect of glucocorticoids to keratinocytes without chemical stimulation. Glucocorticoids 10(-4) M inhibited the production of IL-1alpha from Pam 212 cells. However, lower concentration (10(-8)-10(-10) M) of glucocorticoids significantly enhanced the production of IL-1alpha by Pam 212 cells at both the protein and mRNA levels. In contrast, glucocorticoids had no effect on the production of either TNF-alhpa, IL-6, nor GM-CSF by Pam 212 cells cultured for 6 h. Electrophoretic mobility shift assays (EMSA) revealed that 10(-10)-10(-12) M glucocorticoids induced the NF-kappaB activation in Pam 212 cells, however, augmented AP-1 activation by 10(-8)-10(-10) M of glucocorticoids was observed in Pam 212 cells. Furthermore, pyrrolidine dithiocarbamate (PDTC) partially inhibited the IL-1alpha production and completely inhibited NF-kappaB expression by Pam 212 cells. On the other hand, MAP-kinase inhibitors (PD98059, SB202190) completely abrogated not only AP-1 activation but the low concentration glucocorticoids-induced IL-1alpha production. These data indicated that lower concentration of glucocorticoids induced the augmentation of IL-1alpha production from keratinocytes mediated through the AP-1 pathway and partially through NF-kappaB pathway.
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PMID:Glucocorticoids induced the production and gene expression of IL-1alpha through AP-1 and partially NF-kappaB activation in murine epidermal cells. 1216 Feb 24

Recent investigations have provided important insights into how signaling through the antigen receptors determines whether a cell survives or dies. In T cells, Grb2 and MAP kinases play essential roles in differentiating between apoptotic and survival signals. The PTEN phosphatase and Bim, a pro-apoptotic Bcl-2 family member, regulate apoptosis in both T and B cells. In B cells, antigen receptor-mediated death can be rescued by co-stimulation, in which the roles of protein kinase C and BAFF, a TNF family member, have been recently elucidated. In a recently identified mechanism of regulating inflammation, receptors such as c-mer and glycoproteins such as MFG-E8 were found to participate in the clearance of apoptotic cells.
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PMID:Apoptosis during lymphoid development. 1263 72

Gap junction channels are essential for intercellular communication. Among the most abundant gap junction channel proteins is connexin 43 (Cx43). The goal of our study was to find out, whether Cx43 content may be regulated via adenylyl cyclase (AC)/cAMP/protein kinase A (PKA), protein kinase C (PKC) pathways or by a tyrosine kinase coupled pathway, i.e. TNF alpha-receptor dependent pathway. Therefore, we used HeLa cells transfected with Cx43 and exposed these cells for 24 h to either db-cAMP (10(-4)M), forskolin (10(-5)M), the phorbolester phorbol-12,13-didecanoate PDD (10(-7)M) (or its inactive form 4 alpha-PDD), TNF alpha (10 U/ml) with or without additional treatment with the MAP kinase inhibitors SB203580 (10(-5) M, p38 MAP-kinase inhibitor) or the MEK1-inhibitor PD98059 (10(-5)M). Cx43 content was analysed using Western blot analysis. All results were confirmed by a second series of identical experiments using Cx43 immunohistochemistry. We found significantly enhanced Cx43 content in cells treated with db-cAMP, forskolin, PDD or TNF alpha (p<0.05), while 4 alpha-PDD or the solvent DMSO exerted no effect. These increases in Cx43 content could be completely suppressed by SB203580 (p<0.05) but not by PD98059. In absence of a stimulating drug, these inhibitors (SB203580 or PD98059) did not affect Cx43 content. Additional PCR experiments revealed increases in Cx43-mRNA under the influence of db-cAMP, forskolin, PDD or TNFalpha (p<0.05), which all could be completely suppressed by SB203580. From these results we conclude that 1.Cx43 content can be regulated via AC/cAMP/PKA, PKC and TNF alpha-receptor-dependent pathways 2. Activation of p38 MAP kinase is a common pathway for regulation of Cx43 content in HeLa cells
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PMID:Chronic regulation of the expression of the gap junction protein connexin 43 in transfected HeLa cells. 1282 13

Inflammatory osteolysis induced by implant-derived wear debris is associated with infiltration of various cell-types to the implant-bone interface leading to abundant secretion of pro-inflammatory cytokines and activation of proteinases that together lead to propagation of the localized inflammatory response and periprosthetic bone erosion. Tumor necrosis factor family members are considered to be direct mediators of inflammation and osteolysis. These cytokines exert their osteoclastic effects via activation of the transcription factor NF-kappaB and certain MAP kinases, including c-Jun, Erks and p38, all known to be essential for the development of osteoclasts. We have recently documented that the osteoclastogenic cytokines TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that PMMA particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of the transcription factor NF-kappaB. More importantly, our data indicate that inhibitors of the osteoclastogenic factors, TNF and RANKL abrogate particle-induced osteoclastogenesis. In the current study, we investigated if PMMA particles activate MAP kinases, and the potential role of these kinases as mediators of osteolysis. Using kinase assays, we show that in osteoclast precursors, PMMA particles markedly and rapidly activate p38 and ERK MAP kinases. This activation was specific, evident by complete blockade with specific inhibitory compounds. Similarly, we show that PMMA particles activate the JNK pathway, which is known to be involved in inflammatory and osteoclastogenic events. We also show that p38 MAP kinase regulates PMMA-activation of NF-kappaB, thus providing a possible mechanism for particle action in osteoclast precursors. Finally, we provide evidence that specific inhibitors of MAP kinases are capable of inhibiting PMMA-stimulated osteoclastogenesis. These data provide evidence that MAP kinases are potent mediators of particle-induced osteoclastogenesis.
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PMID:Mitogen-activated protein (MAP) kinases mediate PMMA-induction of osteoclasts. 1455 17

Airway epithelial cells are often the sites of targeted adenovirus vector delivery. Activation of the host inflammatory response and modulation of signal transduction pathways by adenovirus vectors have been previously documented, including activation of MAP kinases and phosphatidylinositol 3-kinase (PI3-kinase). The effect of activation of these pathways by adenovirus vectors on cell survival has not been examined. Both the PI3-kinase/Akt and ERK/MAP kinase signaling pathways have been linked to cell survival. Akt has been found to play a role in cell survival and apoptosis through its downstream effects on apoptosis-related proteins. Constitutive activation of either PI3-kinase or Akt blocks apoptosis induced by c-Myc, UV radiation, transforming growth factor-beta, Fas, and respiratory syncytial virus infection. We examined the effect of adenovirus vector infection on activation of these prosurvival pathways and its downstream consequences. Airway epithelial cells were transduced with replication-deficient adenoviral vectors containing a nonspecific transgene, green fluorescent protein driven by the cytomegalovirus promoter, or an empty vector with no transgene. They were then exposed to the proapoptotic stimulus actinomycin D plus TNF-alpha, and evidence of apoptosis was evaluated. Compared with the cells treated with actinomycin/TNF alone, the adenovirus vector-infected cells had a 50% reduction in apoptosis. When we examined induction of the prosurvival pathways, ERK and AKT, in the viral vector-infected cells, we found that there was significant activation of both Akt and ERK.
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PMID:Adenovirus vectors activate survival pathways in lung epithelial cells. 1510 95

Rheumatoid arthritis is characterised by the interaction of multiple mediators, among the most important of which are cytokines. In recent years, extensive data demonstrates a pivotal role for one cytokine, macrophage migration inhibitory factor (MIF), in fundamental events in innate and adaptive immunity. MIF has now been demonstrated to be involved in the pathogenesis of many diseases, but in the case of RA the evidence for a role of MIF is very strong. MIF is abundantly expressed in the serum of RA patients, and in RA synovial tissue where it correlates with disease activity. MIF induces synoviocyte expression of key proinflammatory genes including TNF, IL-1, IL-6, IL-8, cPLA2, COX2 and MMPs. MIF also regulates the function of endothelial cells and B cells. Moreover, MIF is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumor suppressor protein p53. In multiple rat and mouse models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. MIF -/- mice further demonstrate increases in synovial apoptosis. That the human Mif gene is encoded by different functional alleles in subjects with inflammatory disease also provides evidence for the role of MIF in RA. The mechanism of action of MIF is becoming better understood. MIF appears to interact with cell surface CD74, with consequent activation of MAP kinases but possibly not NFkappaB intracellular signal transduction. This apparent selectivity may be implicated in the ability of MIF to antagonise the effects of glucocorticoids. As MIF expression is induced by glucocorticoids, inhibition of its antagonistic effects may permit enhanced therapeutic effect of glucocorticoids, or "steroid sparing". To date there are no clinical trials of MIF antagonism in any disease, but exploitation of antibody, soluble receptor, or small molecule approaches enabled by the unique crystal structure of MIF, may soon lead to the ability to test in the clinic the importance of this cytokine in human RA.
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PMID:Macrophage migration inhibitory factor in rheumatoid arthritis. 1557 36

Conventional therapy for inflammatory bowel diseases rely on corticosteroids and 5-aminosalicylates combined with immunosuppressive agents for maintenance. These drugs are not always effective and may inflict serious side effects. Other therapies are therefore awaited. Infliximab, a monoclonal antibody against the pro-inflammatory cytokine TNF-alpha has been successfully applied as a treatment for Crohn's disease. The mechanism of action of this drug extends beyond the level of TNF-alpha scavenging and includes induction of apoptosis of effector cells. Numerous anti-TNF antibodies have been developed and are currently evaluated in clinical trials. Other targets for monoclonal antibodies include integrins and cytokines involved in T-cell differentiation and activation. Likewise recombinant proteins that moderate TNF bioactivity and lymphocyte function have been developed. The therapeutic effect of recombinant interleukin-10 seems to be dependent on local delivery of the protein. Antisense therapy targeting lymphocyte migration has also been tested in IBD. Finally, the conventional drug thalidomide and possibly MAP-kinase inhibitors may become novel treatment entities for IBD.
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PMID:New cytokine therapeutics for inflammatory bowel disease. 1558 91

The exposure of cells to TGF-beta1 can trigger a variety of cellular responses including the inhibition of cell growth, migration, differentiation and apoptosis. TGF-beta1-regulated apoptosis is cell type and context-dependent, indeed TGF-beta1 provides signals for both cell survival or apoptosis. The molecular mechanisms underlying the role of TGF-beta1 in apoptosis remains unclear. The proteins that primarily mediate the intracellular signaling of TGF-beta1 are the members of the Smad family. Nevertheless, TGF-beta1 signaling can also cooperate with the death receptor apoptotic pathway (Fas, TNF), with the intracellular modulators of apoptosis JNK and p38 MAP kinases, Akt, NF-kappaB, and with the mitochondrial apoptotic pathway mediated by members of the Bcl-2 family. Moreover, the involvement of TGF-beta1 in the production of oxidative stress and in preventing the inflammatory processes required for the clearance of apoptotic bodies is further evidence of its integration into apoptotic pathways. The interaction and balance between different stimuli provides the basis for the pro- or anti-apoptotic output of TGF-beta1 signaling in a given cell.
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PMID:Dual role for TGF-beta1 in apoptosis. 1573 30


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