Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell motility is a complex biological process, involved in development, inflammation, homeostasis, and pathological processes such as the invasion and metastatic spread of cancer. Here, we describe a genomic screen designed to identify inhibitors of cell migration. A library of 10,996 small interfering RNAs (targeting 5,234 human genes) was screened for their ability to block the migration of a highly motile ovarian carcinoma cell line, SKOV-3, by using a 384-well wound-healing assay coupled with automated microscopy and wound quantification. Two or more small interfering RNAs against four genes, CDK7, DYRK1B, MAP4K4 (NIK/HGK) (MAP4K4, mitogen-activated protein 4 kinase 4), and SCCA-1 (SerpinB3), potently blocked the migration of SKOV-3 cells, concordant with reduced transcript levels. Further studies of the promigratory role of MAP4K4 showed that the knockdown of this transcript inhibited the migration of multiple carcinoma cell lines, indicating a broad role in cell motility and potently suppressed the invasion of SKOV-3 cells in vitro. The effect of MAP4K4 on cellular migration was found to be mediated through c-Jun N-terminal kinase, independent of AP1 activation and downstream transcription. Accordingly, small molecule inhibition of c-Jun N-terminal kinase suppressed SKOV-3 cell migration, underscoring the potential therapeutic utility of mitogen-activated protein kinase pathway inhibition in cancer progression.
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PMID:A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. 1653 54

Baicalin is a flavonoid isolated from Scutellaria baicalensis and is known to affect multiple biological functions, including the inhibition of aldose reductase, HIV infection, and nitric oxide producing activity. Oxidative stress is considered a major cause of aging and various age-related diseases, and among the key cellular components exquisitely sensitive to oxidative stress is the transcription factor, nuclear factor-kappaB (NF-kappaB). In the present study, we attempted to elucidate the mechanisms underlying the suppression of age-related NF-kappaB activation by baicalin in kidney tissue from old rats. Results showed NF-kappaB activation and the upregulation of NF-kappaB targeting genes, hemoxygenase-1, inducible nitric oxide synthase (iNOS), and COX-2 with age. In contrast, the increased expression of these NF-kappaB targeting genes was effectively inhibited by baicalin. Baicalin was shown to inhibit the NF-kappaB cascade via three signal transduction pathways, NIK/IKK, extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK). Our results clearly indicated the anti-oxidative effects of baicalin on age-related redox imbalance. Thus, the significance of the current study is the new information revealing the anti-oxidative properties of baicalin and the role it plays in the regulation of age-related alterations.
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PMID:Short-term feeding of baicalin inhibits age-associated NF-kappaB activation. 1676 19

Nuclear factor-kappaB (NF-kappaB), a redox-sensitive transcription factor, plays an important role in the aging process. Thus, developing and identifying specific components that modulate NF-kappaB without adverse side-effects would be of major importance. Hesperetin, a flavanone abundant in citrus fruits, has a variety of pharmacological properties being antioxidant, cholesterol-lowering, and anti-inflammatory. In this study, we investigated how hesperetin fed to 6- and 24-month-old rats modulates NF-kappaB in their kidneys. Results showed that hesperetin suppressed NF-kappaB activation and related gene expressions. An even more interesting finding is that hesperetin suppressed NF-kappaB through four signal transduction pathways, NIK/IKK, ERK, p38, and JNK. Further evidence showed the remarkable efficacy of hesperetin to suppress the translocation of Trx/Ref-1, indicating its beneficial effect on the redox status. The most significant findings of the current study report new information on the use of hesperetin as a potential anti-aging agent.
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PMID:Modulation of the age-related nuclear factor-kappaB (NF-kappaB) pathway by hesperetin. 1693 86

The primary objective of this study was to evaluate the ability and mechanism of action of kaempferol, which is contained in extracts from Nelumbo nucifera, a well-known Oriental herb used in traditional medicine, with regard to the inhibition of iNOS and TNF-alpha expression in aged rat gingival tissues. We conducted an investigation into the age-related effects of kaempferol on reactive oxygen species (ROS) and GSH oxidative status in samples of aged gingival tissues. Western blotting was conducted in order to determine the expression of iNOS, TNF-alpha, p38 MAPK, NIK/IKK, p65 and IkappaBalpha in the sample tissues. Electrophoretic mobility shift assays (EMSA) were conducted in an effort to characterize the binding activities of NF-kappaB transcription factors in the aged rat gingival nuclear extracts. Our results indicate that kaempferol reduced ROS levels and augmented GSH levels in a dose-dependent manner in the aged gingival tissues. Kaempferol was shown to effect a significant reduction in iNOS and TNF-alpha protein levels, as compared to control gingival tissue samples. The results of Western blot analysis revealed that kaempferol treatment effected the reduction of iNOS and TNF-alpha expression, decreased nuclear p65 and increased cytosolic p65, down-regulation of Erk, p38, JNK and NIK/IKK expression. The EMSA results also indicated that kaempferol, when administered to the rat tissues, attenuated the NF-kappaB nuclear binding activity. Kaempferol may inhibit ROS generation via the inhibition of iNOS and TNF-alpha expression in aged gingival tissues, via the modulation of the NF-kappaB and mitogen-activated protein kinase (MAPK) pathways.
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PMID:Down-regulation of iNOS and TNF-alpha expression by kaempferol via NF-kappaB inactivation in aged rat gingival tissues. 1727 14

Redox sensitive, pro-inflammatory nuclear transcription factor NF-kappaB plays a key role in both inflammation and aging processes. In a redox state disrupted by oxidative stress, pro-inflammatory genes are upregulated by the activation of NF-kappaB through diverse kinases. Thus, the search and characterization of new substances that modulate NF-kappaB are of recent research interest. Cinnamaldehyde (CNA) is the major component of cinnamon bark oil, which has been widely used as a flavoring agent in foodstuffs such as beverages and ice cream. In the present study, CNA was examined for its molecular modulation of inflammatory NF-kappaB activation via the redox-related NIK/IKK and MAPK pathways through the reduction of oxidative stress. Results show that age-related NF-kappaB activation upregulated NF-kappaB targeting genes, inflammatory iNOS, and COX-2, all of which were inhibited effectively by CNA. Our study further shows that CNA inhibited the activation of NF-kappaB via three signal transduction pathways, NIK/IKK, ERK, and p38 MAPK. Our results indicate that CNA's antioxidative effect and the restoration of redox balance were responsible for its anti-inflammatory action. Thus, the significance of the current study is the new information revealing the anti-inflammatory properties of CNA and the role it plays in the regulation of age-related alterations in signal transduction pathways.
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PMID:Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. 1748 22

Epstein-Barr Virus (EBV) Latent Infection Membrane Protein 1 (LMP1) is expressed in all the EBV related malignancies. LMP1 expression is critical for transformation of human B-cells by EBV. LMP1 expression in human B cells induces activation and adhesion molecule expression and cell dumping, which are characteristic of CD40 activated B lymphocytes. In immortalized fibroblasts, LMP1 mimics aspects of activated ras in enabling serum, contact, and anchorage independent growth. Reverse genetic analyses implicate six transmembrane domains (TM), TM1-6, and two C-terminal cytosolic domains, transformation effector sites 1 and 2 (TES1 and 2) or C-terminal activation regions 1 and 2 (CTAR1 and 2) as the essential domains for LMP1 effects. The 6 transmembrane domains cause intermolecular interaction, whereas the C-terminal domains signal through tumor necrosis factor receptor (TNFR) associated factors (TRAFs) or TNFR associated death domain proteins (TRADD) and activate NF-kappaB, JNK, and p38. LMP1 TES1/CTAR1 directly recruits TRAFs 1, 2, 3 and 5 whereas LMP1 TES2/CTAR2 indirectly recruits TRAF6 via BS69. LMP1 TES1/CTAR1 activates TRAF2, NIK, IKKalpha and p52 mediated noncanonical NF-KB pathway and LMP1 TES2/CTAR2 activates TRAF6, TAB1, TAK1, IKKalpha/ IKKbeta/ IKKgamma mediated canonical NF-KB pathway. Interestingly, TRAF3 is a negative regulator of noncanonical NF-kappaB activation, although a positive role in LMP1 signaling has also been described. LMP1 mediated JNK activation is predominantly TES2/CTAR2 dependent and requires TRAF6. LMP1 specifically increases TRAF3 partitioning into lipid rafts and interestingly does not induce degradation of any of the TRAFs upon NF-kappaB activation. Studies of the chemistry and biology of LMP1-TRAF interaction mediated activation of signaling pathways are important for controlling EBV infected cell survival and growth.
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PMID:LMP1 TRAFficking activates growth and survival pathways. 1763 26

MAPK kinase 4 (MKK4) is a dual-specificity kinase that activates both JNK and p38 MAPK. However, the mechanism by which MKK4 regulates TNF-induced apoptosis is not fully understood. Therefore, we used fibroblasts derived from MKK4 gene-deleted (MKK4-KO) mice to determine the role of this kinase in TNF signaling. We found that when compared with the wild-type cells, deletion of MKK4 gene enhanced TNF-induced apoptosis, and this correlated with down-regulation of TNF-induced cell-proliferative (COX-2 and cyclin D1) and antiapoptotic (survivin, IAP1, XIAP, Bcl-2, Bcl-x(L), and cFLIP) gene products, all regulated by NF-kappaB. Indeed we found that TNF-induced NF-kappaB activation was abrogated in MKK4 gene-deleted cells, as determined by DNA binding. Further investigation revealed that TNF-induced I kappaB alpha kinase activation, I kappaB alpha phosphorylation, I kappaB alpha degradation, and p65 nuclear translocation were all suppressed in MKK4-KO cells. NF-kappaB reporter assay revealed that NF-kappaB activation induced by TNF, TNFR1, TRADD, TRAF2, NIK, and I kappaB alpha kinase was modulated in gene-deleted cells. Overall, our results indicate that MKK4 plays a central role in TNF-induced apoptosis through the regulation of NF-kappaB-regulated gene products.
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PMID:Targeted deletion of MKK4 gene potentiates TNF-induced apoptosis through the down-regulation of NF-kappa B activation and NF-kappa B-regulated antiapoptotic gene products. 1764 Oct 59

Enterovirus 71 (EV71) is a widespread virus that causes severe and fatal diseases in patients, including circulation failure. The mechanisms underlying EV71-initiated intracellular signaling pathways to influence host cell functions remain unknown. In this study, we identified a requirement for PDGFR, PI3-K/Akt, p38 MAPK, JNK, and NF-kappaB in the regulation of VCAM-1 expression by rat vascular smooth muscle cells (VSMCs) in response to viral infection. EV71 induced VCAM-1 expression in a time- and viral concentration-dependent manner. Infection of VSMCs with EV71 stimulated VCAM-1 expression and phosphorylation of PDGFR, Akt, and p38 MAPK which were attenuated by AG1296, wortmannin, and SB202190, respectively. The phosphorylation of JNK stimulated by EV71 was not detected under present conditions. In contrast, JNK inhibitor SP600125 inhibited EV71-induced VCAM-1 expression. Furthermore, VCAM-1 expression induced by EV71 was significantly attenuated by a selective NF-kappaB inhibitor (helenalin). Consistently, EV71-stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaB-alpha as well as VCAM-1 mRNA expression was blocked by helenalin, AG1296, SB202190, SP600125, wortmannin, and LY294002. Moreover, the involvement of p38 MAPK, PI3-K/Akt, and NF-kappaB in EV71-induced VCAM-1 expression was reveled by that transfection with dominant negative plasmids of p38 MAPK, p85, Akt, NIK, IKK-alpha, and IKK-beta attenuated these responses. These findings suggest that in VSMCs, EV71-induced VCAM-1 expression was mediated through activation of PDGFR, PI3-K/Akt, p38 MAPK, JNK, and NF-kappaB pathways.
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PMID:EV71 induces VCAM-1 expression via PDGF receptor, PI3-K/Akt, p38 MAPK, JNK and NF-kappaB in vascular smooth muscle cells. 1766 26

We examined the role of osteopontin (OPN) in NIK- and MEKK1-dependent MMP-9 activation, melanoma growth and lung metastasis and its clinical significance in malignant melanoma. Here we report that OPN induces alphavbeta3 integrin-mediated MEKK1-dependent JNK1 phosphorylation. OPN stimulates NIK- or JNK1-dependent c-Jun expression. In contrast, OPN induces MEKK1-dependent JNK1 activation that leads to downregulation of ERK1/2 activation. OPN triggers NIK- and MEKK1-dependent AP-1 activation whereas NIK-dependent AP-1 activation is independent of JNK1 that leads to pro-MMP-9 activation. In vivo studies indicate that the levels of pNIK and MMP-9 are significantly higher in the OPN-induced primary tumor and metastasized lung compared to control. Clinical data revealed that the enhanced level of OPN and pNIK expression in the skin biopsies correlates with Clark's level and Breslow thickness. Altogether, OPN regulates negative cross-talk between NIK/ERK and MEKK1/JNK1 pathways that controls melanoma progression.
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PMID:Osteopontin stimulates melanoma growth and lung metastasis through NIK/MEKK1-dependent MMP-9 activation pathways. 1778 54

We have investigated the effect of tumor necrosis factor-alpha (TNF-alpha) on the production of extracellular matrix-degrading proteases in skeletal muscles. Using microarray, quantitative PCR, Western blotting, and zymography, we found that TNF-alpha drastically increases the production of matrix metalloproteinase (MMP)-9 from C2C12 myotubes. In vivo administration of TNF-alpha in mice increased the transcript level of MMP-9 in skeletal muscle tissues. Although TNF-alpha activated all the three MAPKs (i.e. ERK1/2, JNK, and p38), inhibition of ERK1/2 or p38 but not JNK blunted the TNF-alpha-induced production of MMP-9 from myotubes. Inhibition of Akt also inhibited the TNF-alpha-induced production of MMP-9. TNF-alpha increased the activation of transcription factors NF-kappaB and AP-1 but not SP-1 in myotubes. Overexpression of a dominant negative inhibitor of NF-kappaB or AP-1 blocked the TNF-alpha-induced expression of MMP-9 in myotubes. Similarly, point mutations in AP-1- or NF-kappaB-binding sites in MMP-9 promoter inhibited the TNF-alpha-induced expression of a reporter gene. TNF-alpha increased the activity of transforming growth factor-beta-activating kinase-1 (TAK1). Furthermore, overexpression of a dominant negative mutant of TAK1 blocked the TNF-alpha-induced expression of MMP-9 and activation of NF-kappaB and AP-1. Our results also suggest that TNF-alpha induces MMP-9 expression in muscle cells through the recruitment of TRAF-2, Fas-associated protein with death domain, and TNF receptor-associated protein with death domain but not NIK or TRAF-6 proteins. We conclude that TAK1-mediated pathways are involved in TNF-alpha-induced MMP-9 production in skeletal muscle cells.
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PMID:Tumor necrosis factor-alpha augments matrix metalloproteinase-9 production in skeletal muscle cells through the activation of transforming growth factor-beta-activated kinase 1 (TAK1)-dependent signaling pathway. 1789 57


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