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)

CD40 is a 48kDa phosphorylated transmembrane glycoprotein that belongs to the tumor necrosis factor receptor superfamily and may play a role in formation of atherosclerotic plaques. Here, we investigated the effect of chylomicron remnants on CD40 expression in the human premonocytic cell line, THP-1 cells. Chylomicron remnants upregulated the expression of CD40 protein and mRNA in a dose- and time-dependent manner. Further, chylomicron remnants increased the generation of reactive oxygen species as determined by an increasing level of 2',7'-dichlorofluorescein. Pretreatment with the antioxidant, N-acetylcysteine, inhibited chylomicron remnant-induced CD40 protein expression by 60%. On the other hand, chylomicron remnants transiently increased the phosphorylation of extracellular signal-regulated kinase (ERK 1/2) and p38 mitogen-activated protein kinase (MAPK). Pretreatment with the MAPK kinase inhibitor, U0126, completely inhibited chylomicron remnants-induced CD40 protein expression, whereas the p38 MAPK inhibitor, SB203580, had no effect. Pretreatment with N-acetylcysteine had no effect on chylomicron remnant-induced ERK 1/2 phosphorylation. These data suggest that CD40 expression stimulated by chylomicron remnants in THP-1 cells is dependent on ERK 1/2-mediated pathway, which is followed by redox-sensitive mechanism-dependent and independent pathway. Thus, chylomicron remnants may contribute to the formation of atherosclerotic plaques via their immunological and proinflammatory effects.
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PMID:Chylomicron remnants upregulate CD40 expression via the ERK pathway and a redox-sensitive mechanism in THP-1 cells. 1635 5

Poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation-induced necrosis has been implicated in several pathophysiological conditions. Although mitochondrial dysfunction and apoptosis-inducing factor translocation from the mitochondria to the nucleus have been suggested to play very important roles in PARP-1-mediated cell death, the signaling events downstream of PARP-1 activation in initiating mitochondria dysfunction are not clear. Here we used the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine, a potent PARP-1 activator, to study PARP-1 activation-mediated cell death. We found, based on genetic knockouts and pharmacological inhibition, that c-Jun N-terminal kinase (JNK), especially JNK1, but not the other groups of mitogen-activated protein kinase, is required for PARP-1-induced mitochondrial dysfunction, apoptosis-inducing factor translocation, and subsequent cell death. We reveal that receptor-interacting protein 1 (RIP1) and tumor necrosis factor receptor-associated factor 2 (TRAF2), are upstream of JNK in PARP-1 hyperactivated cells, because PARP-1-induced JNK activation was attenuated in RIP1-/- and TRAF2-/- mouse embryonic fibroblast cells. Consistently, knockouts of RIP1 and TRAF2 caused a resistance to PARP-1-induced cell death. Therefore, our study uncovers that RIP1, TRAF2, and JNK comprise a pathway to mediate the signaling from PARP-1 overactivation to mitochondrial dysfunction.
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PMID:Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. 1644 54

Epstein-Barr virus latent membrane protein 1 (LMP1) activates NF-kappaB and c-Jun N-terminal kinase (JNK), which is essential for LMP1 oncogenic activity. Genetic analysis has revealed that tumor necrosis factor receptor-associated factor 6 (TRAF6) is an indispensable intermediate of LMP1 signaling leading to activation of both NF-kappaB and JNK. However, the mechanism by which LMP1 engages TRAF6 for activation of NF-kappaB and JNK is not well understood. Here we demonstrate that TAK1 mitogen-activated protein kinase kinase kinase and TAK1-binding protein 2 (TAB2), together with TRAF6, are recruited to LMP1 through its N-terminal transmembrane region. The C-terminal cytoplasmic region of LMP1 facilitates the assembly of this complex and enhances activation of JNK. In contrast, IkappaB kinase gamma is recruited through the C-terminal cytoplasmic region and this is essential for activation of NF-kappaB. Furthermore, we found that ablation of TAK1 resulted in the loss of LMP1-induced activation of JNK but not of NF-kappaB. These results suggest that an LMP1-associated complex containing TRAF6, TAB2, and TAK1 plays an essential role in the activation of JNK. However, TAK1 is not an exclusive intermediate for NF-kappaB activation in LMP1 signaling.
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PMID:TAK1 is a component of the Epstein-Barr virus LMP1 complex and is essential for activation of JNK but not of NF-kappaB. 1644 57

Human glutathione S-transferase P1-1 (GSTP1-1) is an ubiquitously expressed protein that plays an important role in the detoxification and xenobiotics metabolism. It has been shown that GSTP1-1 interacts with c-Jun NH(2)-terminal kinase (JNK) and suppresses its activity. Here, we report a novel function of GSTP1-1 in regulating tumor necrosis factor-alpha (TNF-alpha)-triggered signaling. The present experiments showed that GSTP1-1 physically associated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in vivo and in vitro. Overexpression of GSTP1-1 inhibited TRAF2-induced activation of both JNK and p38 but not of nuclear factor-kappaB (NF-kappaB). Glutathione S-transferase P1-1 also attenuated TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and inhibited TRAF2-ASK1-induced cell apoptosis by suppressing the interaction of TRAF2 and ASK1. Conversely, silencing of GSTP1-1 expression through RNA interference (RNAi) resulted in increase of TNF-alpha-dependent TRAF2-ASK1 association followed by hyper-activation of ASK1 and JNK. A mutant GSTP1-1 lacking TRAF domain-binding motif exhibited a significant decline of capacity to bind TRAF2 and block TRAF2-ASK1 signaling compared with the wild type of GSTP1-1. Moreover, the glutathione-conjugating activity of GSTP1-1 was not involved in the regulation of TRAF2 signaling. These findings indicate that GSTP1-1 plays an important regulatory role in TNF-alpha-induced signaling by forming ligand-binding interactions with TRAF2, which provides a new insight for analysing the protective effects of GSTP1-1 in tumor cells.
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PMID:Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals. 1663 64

A member of the tumor necrosis factor receptor superfamily, TROY, is expressed in the CNS of embryonic and adult mice. In the present study, we characterized TROY-expressing cells in the embryonic and postnatal forebrain. In the early embryonic forebrain, TROY was highly expressed in nestin-positive neuroepithelial cells and radial glial cells, but not in microtubule-associated protein 2-positive postmitotic neurons. During the late embryonic and postnatal development, expression of TROY was observed in radial glial cells and astrocytes, whereas its expression was not detected in neuronal lineage cells. In addition, TROY was exclusively expressed in Musashi-1-positive multipotent/glial progenitors in the postnatal subventricular zone. To investigate the functions of TROY in neural development, we overexpressed TROY in PC12 cells and established stably expressing cell clones. As expected, the signals from overexpressed TROY were constitutively transduced via the activation of the nuclear factor-kappaB and the c-Jun N-terminal kinase pathways in such clones. In addition, upregulation of negative basic helix-loop-helix transcription factors, HES-5 and Id2 proteins, was observed in the TROY-overexpressing clones. Interestingly, the overexpression of TROY in PC12 cells strongly inhibited nerve growth factor-induced neurite outgrowth with reduction of some markers of differentiated neurons, such as neurofilament 150 kDa and neuron-specific beta-tubulin. These findings suggest that the signaling from TROY regulates neuronal differentiation at least in part.
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PMID:Characterization of TROY-expressing cells in the developing and postnatal CNS: the possible role in neuronal and glial cell development. 1682 5

Kaposi's sarcoma-associated herpesvirus (KSHV) contains several open reading frames (ORFs) encoding proteins capable of initiating signal transduction pathways. Among them is the K15 ORF, which consists of eight exons encoding a protein with 12 predicted transmembrane domains and a cytoplasmic C terminus. When transiently expressed, the 8-exon K15 transcript gives rise to a protein with an apparent molecular mass of 45 kDa. K15 interacts with cellular proteins, TRAF (tumor necrosis factor receptor-associated factor) and Src kinases, and activates AP-1, NF-kappaB, and the mitogen-activated protein kinases (MAPKs) c-jun-N-terminal kinase and extracellular signal-regulated kinase. This signaling activity of K15 is related to phosphorylation of Y(481) of the K15 SH2-B motif Y(481)EEV. In this study we demonstrate the expression of an endogenous 45-kDa K15 protein in KSHV BAC36-infected epithelial cells. This endogenous K15 protein shows the same intracellular localization as transiently expressed K15, and expression kinetic studies suggest it to be a lytic gene. We have further determined the downstream target genes of K15 signaling using DNA oligonucleotide microarrays. We demonstrate that K15 is capable of inducing expression of multiple cytokines and chemokines, including interleukin-8 (IL-8), IL-6, CCL20, CCL2, CXCL3, and IL-1alpha/beta, as well as expression of Dscr1 and Cox-2. In epithelial cells, K15-induced upregulation of most genes was dependent on phosphorylation of Y(481), whereas in endothelial cells mutation of Y(481) did not result in a complete loss of Dscr1 and Cox-2 expression and NFAT-activity. Our study establishes K15 as one of the KSHV lytic genes that are inducing expression of multiple cytokines, which have been shown to play an important role in KSHV-associated pathogenesis.
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PMID:Modulation of host gene expression by the K15 protein of Kaposi's sarcoma-associated herpesvirus. 1705 Jun 9

EBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH(2)-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IkappaB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor-associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor kappaB and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1.
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PMID:Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. 1717 61

The blood brain barrier (BBB) is composed of specialized endothelial cells tightly anastomosed to one another and surrounded by a thick extracellular matrix, the basement membrane. Together these components restrict the diffusion of cells and molecules from the periphery into the central nervous system (CNS), providing immune privilege and homeostasis. Dysregulation of the BBB and trans-endothelial migration of immune cells are amongst the earliest CNS changes partaking in lesion formation in multiple sclerosis (MS). Death receptors are members of the tumor necrosis factor receptor (TNFR) super-family. They are expressed on a variety of tissues including endothelium, but the consequence of their triggering appears to be cell type specific. In this study, we describe the expression of death receptors TNFR1, Fas and DR5 on primary cultures of human BBB-derived endothelial cells (ECs), as well as the effects of receptor activation on human brain endothelial cell (HBEC) function. We show that HBECs are resistant to cell death mediated via TNFalpha, FasL and TRAIL and that neither receptor ligation induces cellular proliferation of HBECs. TNFR1 ligation induces NFkappaB activation and the upregulation of chemokines MCP-1 and IL-8, as well as adhesion molecules ICAM-1 and VCAM-1, while Fas and DR5 triggering activate the extracellular signal regulated kinases-1 and -2 (Erk 1/2, p42/44 MAPK) inducing the release of matrix metalloproteinase 9 (MMP9) by BBB-derived ECs.
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PMID:Death receptor expression and function at the human blood brain barrier. 1739 9

Kaposi's sarcoma herpesvirus oncoprotein vFLIP K13 is a potent activator of NF-kappaB and plays a key role in viral pathogenesis. K13 contains a putative TRAF-interacting motif, which is reportedly required for its interaction with TRAF2. The K13-TRAF2 interaction is believed to be essential for the recruitment of K13 to the I-kappaB kinase (IKK) complex and for K13-induced NF-kappaB and JNK activation. In addition, TRAF3 has been reported to be required for K13-induced NF-kappaB and JNK activation. We have re-examined the role of the TRAFs in K13 signaling and report that mutations in the putative TRAF-interacting motif of K13 have no deleterious effect on its ability to interact with the IKK complex or activation of the NF-kappaB pathway. Furthermore, endogenously expressed TRAF2 and TRAF3 do not interact with K13 and play no role in K13-induced NF-kappaB activation or its interaction with the IKK complex. Finally, K13 does not activate the JNK pathway. Our results support a model in which K13 bypasses the upstream components of the tumor necrosis factor receptor signaling pathway and directly interacts with the IKK complex to selectively activate the NF-kappaB pathway without affecting the JNK pathway. Selective NF-kappaB activation by K13 might represent a novel strategy employed by the virus to promote latency.
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PMID:Kaposi's sarcoma-associated herpesvirus (KSHV) oncoprotein K13 bypasses TRAFs and directly interacts with the IkappaB kinase complex to selectively activate NF-kappaB without JNK activation. 1759 77

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) gene is considered the EBV oncogene as it is necessary for EBV-mediated transformation of B lymphocytes and itself transforms rodent fibroblasts. LMP1 activates the NF-kappaB, phosphatidylinositol 3-kinase (PI3K)-Akt, mitogen-activated protein kinase, and Jun N-terminal protein kinase signaling pathways through its two signaling domains, carboxyl-terminal activating regions 1 and 2 (CTAR1 and CTAR2). CTAR1 and CTAR2 induce signal transduction pathways through their direct (CTAR1) or indirect (CTAR2) recruitment of tumor necrosis factor receptor-associated factors (TRAFs). CTAR1 is necessary for LMP1-mediated transformation as well as activation of PI3K signaling and induction of cell cycle markers associated with G(1)/S transition. In this study, activation of PI3K-Akt signaling and deregulation of cell cycle markers were mapped to the TRAF-binding domain within CTAR1 and to the residues between CTAR1 and CTAR2. LMP1 CTAR1 also activated the MEK1/2-extracellular signal-regulated kinase 1/2 signaling pathway, and this activation was necessary for LMP1-induced transformation of Rat-1 fibroblasts. Dominant-negative forms of TRAF2 and TRAF3 inhibited but did not fully block LMP1-mediated transformation. These findings identify a new signaling pathway that is uniquely activated by the TRAF-binding domain of LMP1 and is required for transformation.
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PMID:Unique signaling properties of CTAR1 in LMP1-mediated transformation. 1762 74


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