Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human HepaRG cells are liver progenitors which possess hepatocyte-like functionality. We investigated the effects of double-stranded (ds) RNA on interferon (IFN)-beta and chemokine (CK) expression in these cells. By microarray and ELISA, we showed strong induction of CXCL10 and interleulin (IL)-8 besides IFN-beta and other CK ligands. RNA interference directed silencing of TLR3, RIG-I, IRF3, NFkappaB or MAP kinases (p38, ERK, JNK) was carried out. Knockdown of all these molecules, except ERK and JNK, blocked IFN-beta production. Both TLR3 and RIG-I are required for CXCL10 expression. Silencing of TLR3 completely impaired the IL-8 expression. dsRNA-conditioned medium from HepaRG cells exerted a drastic antiviral effect in HCV replicons, and in the JFH-1-based HCV production cell culture system. The IFN-beta knockdown in HepaRG cells removed this antiviral effect but did not enhance their capacity to initiate HCV RNA replication. We conclude that dsRNA induces antiviral and pro-inflammatory status in HepaRG cells.
 ...
PMID:Characterization of the double-stranded RNA responses in human liver progenitor cells. 1825 84

Transcription factor CCAAT/enhancer-binding protein (C/EBP)-beta is crucial for regulating transcription of genes involved in a number of diverse cellular processes, including those involved in some cytokine-induced responses. However, the mechanisms that contribute to its diverse transcriptional activity are not yet fully understood. To gain an understanding into its mechanisms of action, we took a proteomic approach and identified cellular proteins that associate with C/EBP-beta in an interferon (IFN)-gamma-dependent manner. Transcriptional mediator (Mediator) is a multisubunit protein complex that regulates signal-induced cellular gene transcription from enhancer-bound transcription factor(s). Here, we report that the Med1 subunit of the Mediator as a C/EBP-beta-interacting protein. Using gene knock-out cells and mutational and RNA interference approaches, we show that Med1 is critical for IFN-induced expression of certain genes. Med1 associates with C/EBP-beta through a domain located between amino acids 125 and 155 of its N terminus. We also show that the MAPK, ERK1/2, and an ERK phosphorylation site within regulatory domain 2, more specifically the Thr(189) residue, of C/EBP-beta are essential for it to bind to Med1. Last, an ERK-regulated site in Med1 protein is also essential for up-regulating IFN-induced transcription although not critical for binding to C/EBP-beta.
 ...
PMID:The Med1 subunit of transcriptional mediator plays a central role in regulating CCAAT/enhancer-binding protein-beta-driven transcription in response to interferon-gamma. 1833 25

Pancreatic beta-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of beta-cell mass loss by pro-inflammatory cytokine-induced apoptosis, influences of a pro-inflammatory environment on beta-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic beta cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-bromo-2'-deoxyuridine label respectively, in the presence-absence of varying concentrations of glucose, pro-inflammatory cytokines, and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines interleukin (IL)-1beta, interferon (IFN)-gamma, and tumour necrosis factor-alpha (TNF-alpha) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in beta-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased beta-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and beta-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic beta cells as well as to delay the development of overt diabetes.
 ...
PMID:Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1. 1848 29

The endometrium undergoes marked functional changes during estrous cycle and pregnancy. As the adjacent environment of the conceptus, it represents the maternal interface for embryo-maternal communication, which is essential to maintain pregnancy. Transcriptome studies provide the unique opportunity to assess molecular profiles changing in response to endocrine or metabolic stimuli or to embryonic pregnancy recognition signals. Here we review the current state of transcriptome profiling techniques and the results of a series of transciptome studies comparing bovine endometrium samples during the estrous cycle or endometrium samples from pregnant vs. non-pregnant animals. These studies revealed specific mRNA profiles which are characteristic for the functional status of the endometrium. Transcriptome studies of endometrial samples recovered during the pre-attachment period identified many interferon-stimulated genes, genes that are possibly involved in embryo-maternal immune modulation ( C1S, C1R, C4, SERPING1, UTMP, CD81, IFITM1, BST2), as well as genes affecting cell adhesion ( AGRN, CD81, LGALS3BP, LGALS9, GPLD1, MFGE8, and TGM2) and remodeling of the endometrium ( CLDN4, MEP1B, LGMN, MMP19, TIMP2, TGM2, MET, and EPSTI1). The results of these transcriptome studies were compared to those of similar microarray analyses in human, mouse and Rhesus monkey to identify similarities in endometrial biology between mammalian species and species-specific differences. Future studies will cover dynamic transcriptome changes between different stages of early pregnancy, the relationship between metabolic problems in dairy cows and the functionality of reproductive tissues as well as endometrium transcriptome profiles in recipients of somatic cell nuclear transfer embryos.
 ...
PMID:Transcriptome studies of bovine endometrium reveal molecular profiles characteristic for specific stages of estrous cycle and early pregnancy. 1856 Oct 91

The propensity of T cells to generate coordinated cytokine responses is critical for the host to develop resistance to pathogens while maintaining the state of immunotolerance to self-antigens. The exact mechanisms responsible for preventing the overproduction of proinflammatory cytokines including interferon (IFN)-gamma are not fully understood, however. In this study, we examined the role of a recently described Ras GTPase effector and repressor of the Raf/MEK/ERK cascade called impedes mitogenic signal propagation (Imp) in limiting the induction of T-cell cytokines. We found that stimulation of the T cell receptor complex leads to the rapid development of a physical association between Ras and Imp. Consistent with the hypothesis that Imp inhibits signal transduction, we also found that disengagement of this molecule by the Ras(V12G37) effector loop mutant or RNA interference markedly enhances the activation of the NFAT transcription factor and IFN-gamma secretion. A strong output of IFN-gamma is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of Ras(V12G37) caused T cells to accumulate preferentially in the lymph nodes and delayed their escape from the lymphoid tissue, respectively. Together, our results describe a hitherto unrecognized negative regulatory role for Imp in the production of IFN-gamma in T cells and point to Ras-Imp binding as an attractive target for therapeutic interventions in conditions involving the production of this inflammatory cytokine.
 ...
PMID:p21 Ras/impedes mitogenic signal propagation regulates cytokine production and migration in CD4 T cells. 1857 12

Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus that can cause life-threatening disease in the fetus and the immunocompromised host. Upon attachment to the cell, the virus induces robust inflammatory, interferon- and growth-factor-like signalling. The mechanisms facilitating viral entry and gene expression are not clearly understood. Here we show that platelet-derived growth factor-alpha receptor (PDGFR-alpha) is specifically phosphorylated by both laboratory and clinical isolates of HCMV in various human cell types, resulting in activation of the phosphoinositide-3-kinase (PI(3)K) signalling pathway. Upon stimulation by HCMV, tyrosine-phosphorylated PDGFR-alpha associated with the p85 regulatory subunit of PI(3)K and induced protein kinase B (also known as Akt) phosphorylation, similar to the genuine ligand, PDGF-AA. Cells in which PDGFR-alpha was genetically deleted or functionally blocked were non-permissive to HCMV entry, viral gene expression or infectious virus production. Re-introducing human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFR-alpha blocking antibody (IMC-3G3) or targeted inhibition of its kinase activity with a small molecule (Gleevec) completely inhibited HCMV viral internalization and gene expression in human epithelial, endothelial and fibroblast cells. Viral entry in cells harbouring endogenous PDGFR-alpha was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-alpha, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies inhibit HCMV-induced PDGFR-alpha phosphorylation. Taken together, these data indicate that PDGFR-alpha is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.
 ...
PMID:Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection. 1870 89

Cytokine-based therapeutic approaches using interferon (IFN) and interleukin 2 (IL-2) were conventionally applied for the treatment of progressive RCC. Caused by the limited effectiveness of cytokine-based approaches in advanced renal cell carcinoma, new substances were needed. Among these, the "targeted therapies", particularly the group of the tyrosine kinase inhibitors, are of main interest. At present, multikinase inhibitors and antiangiogenic agents (VEGFR, PDGFR-beta, and mTOR) are used in first- and second-line therapies of metastatic RCC in various clinical studies. This review presents and discusses the effectiveness of the most frequently used substances in mono- or combination regimes based on current data of the ASCO 2007.
 ...
PMID:Novel therapeutic options in metastatic renal cancer - review and post ASCO 2007 update. 1878 79

Tenascin-C (TN-C) is a key component of extracellular matrix (ECM) and its expression process is poorly understood during rheumatic heart valvular disease (RHVD). In this study, we found that interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and TN-C concentrations in patients with RHVD were significantly higher than in normal controls. More IFN-gamma receptors and TNF receptors were found being expressed on rheumatic aortic valves interstitial cells than on non-rheumatic ones and their expression was patients' sera dependent. Antibodies neutralizing IFN-gamma or TNF-alpha could attenuate patients' sera-induced TN-C transcription by isolated rheumatic aortic valves interstitial cells. By application with different protein kinase inhibitors, we found that combined with cyclic strain, TNF-alpha and IFN-gamma induced TN-C transcription through the RhoA/ROCK signalling pathway. At the same time, p38 mitogen-activated protein kinase was involved in TNF-alpha and IFN-gamma induced TN-C transcription. TNF-alpha also increased TN-C mRNA level by additional PKC and ERK 1/2 activation. Our finding revealed a new insight into ECM remodelling during RHVD pathogenesis and new mechanisms involved in the clinical anti-IFN-gamma and anti-TNF-alpha therapy.
 ...
PMID:Synergistic effects of cyclic strain and Th1-like cytokines on tenascin-C production by rheumatic aortic valve interstitial cells. 1904 Jun 16

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), a genetic aberration that codes for bcrabl, which plays a key role in disease pathophysiology. The first oral inhibitor of Brc-Abl was imatinib, which also targets KIT and platelet-derived growth factor receptor kinase and has demonstrated improved outcomes when compared with interferon, the previous standard of care. Imatinib resistance and intolerance have been an issue for patients, and as a result, new therapeutic approaches have been evaluated. Dose-escalated imatinib (800 mg daily) has shown some limited activity in patients with imatinib-resistant CML, but the development of second-generation tyrosine kinase inhibitors has broadened the treatment options. Dasatinib is also an oral kinase inhibitor, but it has increased potency for Brc-Abl compared with imatinib. Dasatinib has demonstrated activity in all phases of CML and Ph+ acute lymphocytic leukemia and is approved for the treatment of adults in this setting. Recent phase III data have demonstrated that, in patients with chronic-phase CML, dasatinib 100 mg once daily is equally effective, with improved tolerability, compared with the previously approved 70-mg twice-daily dose. Nilotinib, which has been recently approved, has increased potency for Brc-Abl compared with imatinib and has demonstrated activity in patients with imatinib-resistant and -intolerant chronic- and accelerated-phase CML. As experience with these agents continues to mature, we might optimize the treatment efficacy and safety profiles by altering dose regimens.
 ...
PMID:Optimizing treatment with Bcr-Abl tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia: focus on dosing schedules. 1925 84

The role of early to intermediate Plasmodium falciparum-induced cellular responses in the development of clinical immunity to malaria is not well understood, and such responses have been proposed to contribute to both immunity and risk of clinical malaria episodes. To investigate whether P. falciparum-induced cellular responses are able to function as predictive correlates of parasitological and clinical outcomes, we conducted a prospective cohort study of children (5 to 14 years of age) residing in a region of Papua New Guinea where malaria is endemic Live, intact P. falciparum-infected red blood cells were applied to isolated peripheral blood mononuclear cells obtained at baseline. Cellular cytokine production, including production of interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor (TNF) (formerly tumor necrosis factor alpha), and gamma interferon (IFN-gamma), was measured, and the cellular source of key cytokines was investigated. Multicytokine models revealed that increasing P. falciparum-induced IL-6 production was associated with an increased incidence of P. falciparum clinical episodes (incidence rate ratio [IRR], 1.75; 95% confidence interval [CI], 1.20 to 2.53), while increasing P. falciparum-induced TNF and IFN-gamma production was associated with a reduced incidence of clinical episodes (IRR for TNF, 0.55 [95% CI, 0.38 to 0.80]; IRR for IFN-gamma, 0.71 [95% CI, 0.55 to 0.90]). Furthermore, we found that monocytes/macrophages and gammadelta-T cells are important for the P. falciparum-induced production of IL-6 and TNF. Early to intermediate cellular cytokine responses to P. falciparum may therefore be important correlates of immunity and risk of symptomatic malaria episodes and thus warrant detailed investigation in relation to the development and implementation of effective vaccines.
 ...
PMID:Cellular tumor necrosis factor, gamma interferon, and interleukin-6 responses as correlates of immunity and risk of clinical Plasmodium falciparum malaria in children from Papua New Guinea. 1938 Apr 68


<< Previous 1 2 3 4 5 6 7 8 9 10