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)

The putative core protein of hepatitis C virus (HCV) regulates cellular growth and a number of cellular promoters. To further understand its effect, we investigated the role of the core protein in the endogenous regulation of two distinct transcription factors, nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1), and the related mitogen-activated protein kinase kinase (MAPKK) and c-Jun N-terminal kinase (JNK). Stable cell transfectants expressing the HCV core protein suppressed tumor necrosis factor (TNF)-induced NF-kappaB activation. Supershift analysis revealed that NF-kappaB consists of p50 and p65 subunits. This correlated with inhibition of the degradation of IkappaBalpha, the inhibitory subunit of NF-kappaB. The effect was not specific to TNF, as suppression in core protein-expressing cells was also observed in response to a number of other inflammatory agents known to activate NF-kappaB. In contrast to the effect on NF-kappaB, the HCV core protein constitutively activated AP-1, which correlated with the activation of JNK and MAPKK, which are known to regulate AP-1. These observations indicated that the core protein targets transcription factors known to be involved in the regulation of inflammatory responses and the immune system.
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PMID:Ectopic expression of hepatitis C virus core protein differentially regulates nuclear transcription factors. 981 6

Our previous study indicated that the core protein of hepatitis C virus (HCV) can associate with tumor necrosis factor receptor (TNFR)-related lymphotoxin-beta receptor (LT-betaR) and that this protein-protein interaction plays a modulatory effect on the cytolytic activity of recombinant form LT-betaR ligand (LT-alpha1beta2) but not tumor necrosis factor alpha (TNF-alpha) in certain cell types. Since both TNF-alpha/TNFR and LT-alpha1beta2/LT-betaR are also engaged in transcriptional activator NF-kappaB activation or c-Jun N-terminal kinase (JNK) activation, the biological effects of the HCV core protein on these regards were elucidated in this study. As demonstrated by the electrophoretic mobility shift assay, the expression of HCV core protein prolonged or enhanced the TNF-alpha or LT-alpha1beta2-induced NF-kappaB DNA-binding activity in HuH-7 and HeLa cells. The presence of HCV core protein in HeLa or HuH-7 cells with or without cytokine treatment also enhanced the NF-kappaB-dependent reporter plasmid activity, and this effect was more strongly seen with HuH-7 cells than with HeLa cells. Western blot analysis suggested that this modulation of the NF-kappaB activity by the HCV core protein was in part due to elevated or prolonged nuclear retention of p50 or p65 species of NF-kappaB in core protein-producing cells with or without cytokine treatment. Furthermore, the HCV core protein enhanced or prolonged the IkappaB-beta degradation triggering by TNF-alpha or LT-alpha1beta2 both in HeLa and HuH-7 cells. In contrast to that of IkappaB-beta, the increased degradation of IkappaB-alpha occurred only in LT-alpha1beta2-treated core-producing HeLa cells and not in TNF-alpha-treated cells. Therefore, the HCV core protein plays a modulatory effect on NF-kappaB activation triggering by both cytokines, though the mechanism of NF-kappaB activation, in particular the regulation of IkappaB degradation, is rather cell line and cytokine specific. Studies also suggested that the HCV core protein had no effect on TNF-alpha-stimulated JNK activity in both HeLa and HuH-7 cells. These findings, together with our previous study, strongly suggest that among three signaling pathways triggered by the TNF-alpha-related cytokines, the HCV core protein potentiates NF-kappaB activation in most cell types, which in turn may contribute to the chronically activated, persistent state of HCV-infected cells.
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PMID:Hepatitis C virus core protein enhances NF-kappaB signal pathway triggering by lymphotoxin-beta receptor ligand and tumor necrosis factor alpha. 988 79

The human nerve growth factor receptor (TrkA) contains four potential N-glycosylation sites that are highly conserved within the Trk family of neurotrophin receptors, and nine additional sites that are less well conserved. Using a microscale deglycosylation assay, we show here that both conserved and variable N-glycosylation sites are used during maturation of TrkA. Glycosylation at these sites serves two distinct functions. First, glycosylation is necessary to prevent ligand-independent activation of TrkA. Unglycosylated TrkA core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules Shc and PLC-gamma. Second, glycosylation is required to localize TrkA to the cell surface, where it can trigger the Ras/Raf/MAP kinase cascade. Using confocal microscopy, we show that unglycosylated active Trk receptors are trapped intracellularly. Furthermore, the unglycosylated active TrkA receptors are unable to activate kinases in the Ras-MAP kinase pathway, MEK and Erk. Consistent with these biochemical observations, unglycosylated TrkA core protein does not promote neuronal differentiation in Trk PC12 cells even at high levels of constitutive catalytic activity.
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PMID:TrkA glycosylation regulates receptor localization and activity. 1023 85

To investigate the transforming potential of hepatitis C virus (HCV), HCV core protein was produced in BALB/3T3 A31-I-1 cells. The cells expressing HCV core gene cooperatively with the v-H-ras gene showed loss of contact inhibition, morphological alterations, and anchorage-independent and serum-independent growth. The cells producing HCV core protein showed enhanced growth against stimulus of growth factor. In addition, antisense oligodeoxynucleotides against mRNA encoding HCV core protein suppressed the growth of HCV core-producing cells. Furthermore, HCV core protein activated mitogen-activated protein kinase and serum response element, which respond to growth stimuli. From these results, we concluded that HCV core protein is involved in the acquisition of cell growth advantage.
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PMID:Hepatitis C virus core protein regulates cell growth and signal transduction pathway transmitting growth stimuli. 1032 72

Histone H3 is the core protein of the nucleosome. Phosphorylation of H3 involves immediate early gene expression, chromatin remodeling, and chromosome condensation during mitosis. Very recently, Rsk2 or MSK1 kinase-mediated phosphorylation of H3 at serine 10 was reported. In the present study, we show that both ERKs and p38 kinase may mediate ultraviolet B-induced phosphorylation of H3 at serine 10. PD 98059, a MEK1 inhibitor, and SB 202190, a p38 kinase inhibitor, efficiently inhibited ultraviolet B-induced phosphorylation of H3. Phosphorylation of H3 was also inhibited in cells expressing dominant negative mutant (DNM) ERK2 and DNM p38 kinase. In contrast, no inhibition of H3 phosphorylation in Jnk1 or Jnk2 knockout cells (Jnk1(-/-) or Jnk2(-/-)) and cells expressing DNM JNK1 was observed. More importantly, incubation of active ERK2 or p38 kinase with H3 protein resulted in phosphorylation of H3 at serine 10 in vitro. These results suggest that ERK and p38 kinase are at least two important mediators of phosphorylation of H3 at serine 10.
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PMID:ERKs and p38 kinases mediate ultraviolet B-induced phosphorylation of histone H3 at serine 10. 1080 18

Persistent hepatitis C virus (HCV) infection is associated with the development of human hepatocellular carcinoma (HCC), although the mechanism of HCV-related hepatocarcinogenesis remains unclear. Recently, however, the close relationships between the development of HCC and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) cascade have been described. In the present study, we investigated the effects of HCV core protein on this MAPK/ERK cascade. HCV core protein significantly activated the MAPK/ERK cascade, including Elk1. We also examined whether HCV core protein acted synergistically along with hepatocyte mitogen-mediated MAPK/ERK activation. Interestingly, Elk-1 activities were further enhanced by the tumor promoter, 12-O-tetradecanoyl phorbol 13-acetate (TPA), but not by hepatocyte mitogens (epidermal growth factor [EGF] and transforming growth factor alpha [TGF-alpha]) in NIH3T3 cells and HepG2 cells expressing HCV core protein. Moreover, the MAPK/ERK activation by HCV core protein was blocked in the presence of the specific MEK1 inhibitor, PD98059. These results indicate that ERK activation by HCV core protein may be independent of hepatocyte mitogen-mediated signaling but synergistic with TPA, and HCV core protein may function at MEK1 or farther upstream of that component.
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PMID:Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha. 1105 45

The hepatitis C virus (HCV) core protein is a multifunctional viral nucleocapsid protein. Previously, it has been demonstrated that the HCV core protein interacts with the cytoplasmic domain of tumor necrosis factor receptor 1 (TNFR1). Since the TNFR1 is engaged in stimulation of transcriptional factor NF-kappaB and AP-1 through activation of IkappaB kinase and c-Jun N-terminal kinase (JNK, or stress-activated protein kinase), respectively, we have examined whether the interaction between core protein and TNFR1 can modulate JNK. In this study, we demonstrate that the HCV core protein synergistically activates TNFalpha-induced JNK at a core concentration dependent manner in human embryonic kidney (HEK) 293 cells. HCV core-mediated synergism of JNK activation was also detected in stable cells expressing HCV core protein. Furthermore, we demonstrate that HCV core protein does not compete with TNF receptor-associated death domain (TRADD) for its interaction with the death domain of TNFR1. Our in vivo data show that HCV core and TRADD form a ternary complex with TNFR1. These findings suggest that the HCV core protein modulates TNFR1 signaling and may, thus, play a role in chronic infection of HCV patients.
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PMID:Hepatitis C virus core protein potentiates c-Jun N-terminal kinase activation through a signaling complex involving TRADD and TRAF2. 1122 77

Hepatitis C virus (HCV) core protein has been shown to interact with the death domain (DD) of tumor necrosis factor receptor-1 (TNFR1). In this study, we further examined the interaction of the core protein with the signaling molecules of TNFR1, including FADD, TRADD, and TRAF2, in a human embryonic kidney cell line, HEK-293, that overexpresses the HCV core protein. This core protein-expressing cell line exhibited enhanced sensitivity to TNF-induced apoptosis. By in vitro binding and in vivo coimmunoprecipitation assays, we showed that the HCV core protein interacted with the DD of FADD and enhanced apoptosis induced by FADD overexpression. This enhancement could be blocked by a dominant-negative mutant of FADD. In contrast, the core protein did not directly interact with the DD of TRADD, but could disrupt the binding of TRADD to TNFR1. TRAF2 recruitment to the TNFR1 signaling complex was also disrupted by the core protein. Correspondingly, TRAF2-dependent activation of the protein kinase JNK was suppressed in the core protein-expressing cells. However, NF kappa B activation by TNF was not significantly altered by the HCV core protein, suggesting the existence of TRAF2-independent pathways for NF kappa B activation. These results combined indicate that the HCV core protein sensitizes cells to TNF-induced apoptosis primarily by facilitating FADD recruitment to TNFR1. The inhibition of JNK activation by the HCV core protein may also contribute to the increased propensity of cells for apoptosis. These results, in comparison with other published studies, suggest that the effects of the HCV core protein and their underlying mechanisms vary significantly among cells of different origins.
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PMID:Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor. 1133 43

Complement proteins are involved in early innate immune responses against pathogens and play a role in clearing circulating viral Ags from the blood of infected hosts. We have previously demonstrated that hepatitis C virus (HCV) core, the first protein to be expressed and circulating in the blood of infected individuals, inhibited human T cell proliferative response through interaction with the complement receptor, globular domain of C1q receptor (gC1qR). To investigate the mechanisms of HCV core/gC1qR-induced inhibition of T cell proliferation, we examined the effect of core protein on the early events in T cell activation. We found that HCV core inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated ERK kinase (MEK). HCV core-induced impairment of ERK/MEK mitogen-activated protein kinase resulted in the inhibition of IL-2 and IL-2Ralpha gene transcription, which led to the inhibition of IL-2 production and high-affinity IL-2R expression. Importantly, the ability of anti-gC1qR Ab treatment to reverse HCV core-induced inhibition of ERK/MEK phosphorylation reveals that the interaction between HCV core and gC1qR is linked to the interference of ERK/MEK mitogen-activated protein kinase activation. These results imply that HCV core-induced blockage of intracellular events in T cell activation by a complement-dependent regulatory pathway may play a critical role in the establishment of HCV persistence during the acute phase of viral infection.
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PMID:Hepatitis C virus core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway. 1167 41

Hepatitis C virus (HCV) core protein is a multifunctional protein interacting with cellular and viral proteins and promoters. A tetracycline-regulated system was used to generate a HepG2 Tet-Off cell line allowing regulated expression of a full-length (191 aa) and an N(c)-truncated core protein (160 aa). In this system HCV core protein expression activates extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 mitogen-activated protein (MAP) kinase, induces MAP kinase phosphatase MKP-1 expression, and increases cell proliferation. This was accompanied by an activation of c-Jun and ATF-2, but not Elk-1 and c-Fos. Furthermore, AP-1 activation was independent of c-Fos. Full-length and N(c)-truncated HCV core proteins exerted similar effects.
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PMID:Hepatitis C virus core protein induces cell proliferation and activates ERK, JNK, and p38 MAP kinases together with the MAP kinase phosphatase MKP-1 in a HepG2 Tet-Off cell line. 1187 30


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