Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

JNK is a key regulator of matrix metalloproteinase production in rheumatoid arthritis. It is regulated by two upstream kinases known as MKK4 and MKK7. Previous studies demonstrated that only MKK7 is required for cytokine-mediated JNK activation and matrix metalloproteinase expression in cultured fibroblast-like synoviocytes (FLS). However, the functions of MKK4 and MKK7 in synoviocyte innate immune responses have not been determined. TNF, peptidoglycan (PGN), and LPS stimulation led to higher and more prolonged MKK7 phosphorylation compared with MKK4 in FLS. However, this pattern was reversed in poly(I-C) stimulated cells. siRNA knockdown studies showed that TNF, PGN, and LPS-induced JNK and c-Jun phosphorylation are MKK7 dependent, while poly(I-C) responses require both MKK4 and MKK7. Poly(I-C)-induced expression of IP-10, RANTES, and IFN-beta mRNA was decreased in MKK4- or MKK7-deficient FLS. However, MKK4 and MKK7 deficiency did not affect phosphorylation of IkappaB kinase-related kinases in the TLR3 signaling pathway. MKK7, but not MKK4 deficiency, significantly decreased poly(I-C)-mediated IRF3 dimerization, DNA binding, and IFN-sensitive response element-mediated gene transcription. These results were mimicked by the JNK inhibitor SP600125, indicating that JNK can directly phosphorylate IRF3. In contrast, deficiency of either MKK4 or MKK7 decreased AP-1 transcriptional activity. Therefore, JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 requires both MKK4 and MKK7, with the former activating c-Jun and the latter activating both c-Jun and IRF3 through JNK-dependent mechanisms.
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PMID:Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases. 1871 96

TLR 4 stimulation of innate immune cells induces a MyD88-independent signaling pathway that leads to the production of IFN-beta. In this study, we demonstrate glycogen synthase kinase 3-beta (GSK3-beta) plays a fundamental role in this process. Suppression of GSK3-beta activity by either pharmacological inhibition, small interfering RNA-mediated gene silencing, or ectopic expression of a kinase-dead GSK3-beta mutant enhanced IFN-beta production by TLR4-stimulated macrophages. Conversely, ectopic expression of a constitutively active GSK3-beta mutant severely attenuated IFN-beta production. GSK3-beta was found to negatively control the cellular levels of the transcription factor c-Jun and its nuclear association with ATF-2. Small interfering RNA-mediated knockdown of c-Jun levels abrogated the ability of GSK3-beta inhibition to augment IFN-beta, demonstrating that the ability of GSK3 to control IFN-beta production was due to its ability to regulate c-Jun levels. The ability of GSK3 inhibition to control IFN-beta production was confirmed in vivo as mice treated with a GSK3 inhibitor exhibited enhanced systemic levels of IFN-beta upon LPS challenge. These findings identify a novel regulatory pathway controlling IFN-beta production by TLR4-stimulated innate immune cells.
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PMID:IFN-beta production by TLR4-stimulated innate immune cells is negatively regulated by GSK3-beta. 1898 Oct 97

We describe a novel basic leucine zipper containing type I IFN-inducible early response gene SARI (Suppressor of AP-1, Regulated by IFN). Steady-state SARI mRNA expression was detected in multiple lineage-specific normal cells, but not in their transformed/tumorigenic counterparts. In normal and cancer cells, SARI expression was induced 2 h after fibroblast IFN (IFN-beta) treatment with 1 U/ml of IFN-beta. Antisense inhibition of SARI protected HeLa cells from IFN-beta-mediated growth inhibition. As a corollary, overexpression of SARI inhibited growth and induced apoptosis in cancer cells, but not in normal cells. SARI interacted with c-Jun via its leucine zipper, resulting in inhibition of DNA binding of activator protein (AP-1) complex and consequently AP-1-dependent gene expression. Transformed cells relying on AP-1 activity for proliferative advantage demonstrated increased susceptibility to SARI-mediated growth inhibition. These findings uncover a novel mode of IFN-induced anti-tumor growth suppression and suggest potential gene therapy applications for SARI.
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PMID:Cloning and characterization of SARI (suppressor of AP-1, regulated by IFN). 1907 69

Interferon regulatory factors (IRF)-3 and IRF-7 are master transcriptional factors that regulate type I IFN gene (IFN-alpha/beta) induction and innate immune defenses after virus infection. Prior studies in mice with single deletions of the IRF-3 or IRF-7 genes showed increased vulnerability to West Nile virus (WNV) infection. Whereas mice and cells lacking IRF-7 showed reduced IFN-alpha levels after WNV infection, those lacking IRF-3 or IRF-7 had relatively normal IFN-b production. Here, we generated IRF-3(-/-)x IRF-7(-/-) double knockout (DKO) mice, analyzed WNV pathogenesis, IFN responses, and signaling of innate defenses. Compared to wild type mice, the DKO mice exhibited a blunted but not abrogated systemic IFN response and sustained uncontrolled WNV replication leading to rapid mortality. Ex vivo analysis showed complete ablation of the IFN-alpha response in DKO fibroblasts, macrophages, dendritic cells, and cortical neurons and a substantial decrease of the IFN-beta response in DKO fibroblasts and cortical neurons. In contrast, the IFN-beta response was minimally diminished in DKO macrophages and dendritic cells. However, pharmacological inhibition of NF-kappaB and ATF-2/c-Jun, the two other known components of the IFN-beta enhanceosome, strongly reduced IFN-beta gene transcription in the DKO dendritic cells. Finally, a genetic deficiency of IPS-1, an adaptor involved in RIG-I- and MDA5-mediated antiviral signaling, completely abolished the IFN-beta response after WNV infection. Overall, our experiments suggest that, unlike fibroblasts and cortical neurons, IFN-beta gene regulation after WNV infection in myeloid cells is IPS-1-dependent but does not require full occupancy of the IFN-beta enhanceosome by canonical constituent transcriptional factors.
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PMID:Induction of IFN-beta and the innate antiviral response in myeloid cells occurs through an IPS-1-dependent signal that does not require IRF-3 and IRF-7. 1979 31

Activation of interferon-beta transcription is a highly ordered process beginning with the delivery of NF-kappaB to the IFN-beta enhancer through a process involving stochastic interchromosomal interactions between the IFN-beta enhancer and specialized Alu elements. NF-kappaB delivery is followed by the binding of ATF-2/c-Jun and IRF proteins in a highly cooperative fashion. The assembled "enhanceosome" then recruits PCAF/GCN5 which acetylates the histone tails of the adjacent nucleosomes. The transcriptional coactivator CBP, which binds in a complex with the RNA polymerase II holoenzyme is recruited by the enhanceosome replacing PCAF/GCN5. Next, SWI/SNF, which is part of the holoenzyme complex, induces a conformational change in a nucleosome positioned over the transcriptional start site allowing TFIID to bind, which promotes the sliding of this nucleosome to a new downstream position. At this point the full pre-initiation complex is assembled and transcription commences. This detailed picture of the IFN-beta transcription program gathered through years of rigorous studies, now serves as a paradigm for understanding complex transcriptional switches in eukaryotic systems.
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PMID:The transcriptional code of human IFN-beta gene expression. 2011 63

Innate immune responses contribute to synovial inflammation in rheumatoid arthritis. The present study was designed to investigate the contribution of IFN regulatory factor (IRF)3 and IRF7 to type I IFN-regulated gene expression in synoviocytes. Fibroblast-like synoviocytes were stimulated with polyinosinic-polycytidylic acid (poly [I-C]) after transfection with IRF3 or IRF7 small interfering RNA to knockdown transcription factor expression. Western blots, luciferase assay after transfection with reporter constructs, quantitative PCR, and AP-1 DNA binding ELISA were performed to evaluate the role of IRF3 and IRF7 in poly (I-C)-induced signaling and synoviocyte gene expression. IRF3 regulates IFN-stimulated response element (ISRE) promoter activity as well as IFN-beta, IRF5, IRF7, RANTES, IFN-inducible protein-10, MCP-1, and MIP1alpha gene expression in response to poly (I-C). IRF7 knockdown modestly decreased a subset of genes and ISRE activity, although the results were not statistically significant. Surprisingly, IRF3 knockdown almost completely blocked expression of additional genes in which the ISRE is not traditionally considered a dominant promoter site in fibroblast-like synoviocytes, including matrix metalloproteinase (MMP)3, MMP9, IL-6, and IL-8. Transcription factor activation studies demonstrated a role for IRF3 in regulation of c-Jun phosphorylation and AP-1 binding. IRF3 rather than IRF7 regulates poly (I-C)-induced type I IFN responses in human synoviocytes by increasing ISRE promoter activity. IRF3 also partially regulates expression of other cytokines and MMP through activation of c-Jun and the AP-1 promoter site. Targeting synoviocyte IRF3 represents a potential approach to suppress diverse mediators while limiting suppression of IRF7-mediated immune responses.
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PMID:Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3. 2048 55

Enhanced expression of the CCN family of secretory integrin-binding proteins correlates with many essential components of the cancerous state, including tumor cell adhesion, proliferation, invasion and migration. Consequently, CCN1 expression is elevated in various cancers, including breast cancer, and its expression directly correlates with poor patient prognosis. Using subtraction-hybridization, combined with induction of cancer cell terminal differentiation, we cloned SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN)), an IFN-beta-inducible, potent tumor suppressor gene that exerts cancer-selective growth inhibitory effects. Forced expression of SARI using an adenovirus (Ad.SARI) inhibits AP-1 function and downregulates CCN1 expression in multiple cancer lineages, resulting in a profound inhibition in anchorage-independent cell growth and tumor cell invasion. Overexpression of SARI reduces CCN1-promoter activity through inhibition of AP-1 binding. Accordingly, SARI selectively blocks expression of the transformed state in rat embryo fibroblast cells that stably overexpress c-Jun. These results illustrate that SARI inhibits AP-1 transactivating factor binding to the cis-element of the CCN1 promoter, possibly through its interaction with c-Jun. Overall, SARI can directly inhibit CCN1-induced transformation by inhibiting the transcription of CCN1, as well as indirectly by inhibiting the expression of c-Jun (and hence blocking AP-1 activity). In these contexts, transformed cells 'addicted' to AP-1 activity are rendered susceptible to SARI-mediated inhibition of expression of the transformed phenotype.
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PMID:Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1. 2053 1

Viral infection induces type I interferons (IFN-alpha and IFN-beta) that recruit unexposed cells in a self-amplifying response. We report that the transcription factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1-like sites. Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.
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PMID:The transcription factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor IRF3. 2064 78

LPS stimulation of macrophages production of IFN-beta plays a key role in innate immunity defending the microbial invasion. In this study, the effect of S632A3 promoting LPS-induced IFN-beta production and the underlying mechanism were investigated, mRNA level was measured by real-time PCR, cytokine production was determined by ELISA, GSK-3beta activity was investigated by kinase assay, protein phosphorylation and expression were evaluated by Western blotting. The results revealed that S632A3 significantly augmented IFN-beta production by LPS-stimulated macrophages. S632A3 inhibition of the activation of GSK-3beta, reduced the threonine 239 phosphorylation of transcription factor c-Jun but increased the total level of c-Jun in LPS-stimulated macrophages. Moreover, small interfering RNA-mediated knockdown of c-Jun level abrogated the ability of S632A3 to augment IFN-beta. The study thus demonstrates S632A3 being a new anti-inflammation lead compound and provides a molecular mechanism by which S632A3 promoted LPS-induced IFN-beta production in macrophages through inhibiting the activation of GSK-3beta.
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PMID:[S632A3 promotes LPS-induced IFN-beta production through inhibiting the activation of GSK-3beta]. 2413 77


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