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

African swine fever virus (ASFV) is able to inhibit TNF-alpha-induced gene expression through the synthesis of A238L protein. This was shown by the use of deletion mutants lacking the A238L gene from the Vero cell-adapted Ba71V ASFV strain and from the virulent isolate E70. To further analyze the molecular mechanism by which the viral gene controls TNF-alpha, we have used Jurkat cells stably transfected with the viral gene to identify the TNF-alpha regulatory elements involved in the induction of the gene after stimulation with PMA and calcium ionophore. We have thus identified the cAMP-responsive element and kappa3 sites on the TNF-alpha promoter as the responsible of the gene activation, and demonstrate that A238L inhibits TNF-alpha expression through these DNA binding sites. This inhibition was partially reverted by overexpression of the transcriptional factors NF-AT, NF-kappaB, and c-Jun. Furthermore, we present evidence that A238L inhibits the activation of TNF-alpha by modulating NF-kappaB, NF-AT, and c-Jun trans activation through a mechanism that involves CREB binding protein/p300 function, because overexpression of these transcriptional coactivators recovers TNF-alpha promoter activity. In addition, we show that A238L is a nuclear protein that binds to the cyclic AMP-responsive element/kappa3 complex, thus displacing the CREB binding protein/p300 coactivators. Taken together, these results establish a novel mechanism in the control of TNF-alpha gene expression by a viral protein that could represent an efficient strategy used by ASFV to evade the innate immune response.
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PMID:The viral protein A238L inhibits TNF-alpha expression through a CBP/p300 transcriptional coactivators pathway. 1636 38

Through its transcriptional activities, the proto-oncoprotein c-Jun can regulate cellular proliferation, survival, and differentiation. We have established a novel yeast assay that screens for repressors of c-Jun transcriptional activity. This screen led to the identification of a ubiquitously expressed novel RING zinc finger protein, termed Makorin RING zinc finger protein 1 (MKRN1), recently shown to act as an E3 ubiquitin ligase. Overexpression of MKRN1 in mammalian cells inhibited the transcriptional activities of not only c-Jun, but also the nuclear receptors, the androgen receptor, and the retinoic acid receptors. Truncation analysis indicates that both the amino and carboxy termini are required for this transrepression activity. Surprisingly, when fused to the heterologous DNAbinding domain of GAL4, MKRN1 activates, rather than inhibits, a GAL4-responsive reporter plasmid. In addition, truncation of either the amino- or carboxy-terminal half of MKRN1 disrupts its transactivation activity, the same observation that was made on its transrepression activity. These results demonstrate that MKRN1 has transcriptional activity and suggest that its transrepression and transactivation functions are mediated by the same mechanism. Interestingly, disruption of MKRN1's ubiquitin ligase activity does not affect its inhibitory transcriptional activity. Thus, MKRN1 may represent a nuclear protein with multiple nuclear functions, including regulating RNA polymerase II-catalyzed transcription.
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PMID:Makorin RING finger protein 1 (MKRN1) has negative and positive effects on RNA polymerase II-dependent transcription. 1678 14

The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however, some activity was seen against all HMCLs and primary MM cells with at least 0.5 microM PKC412. PARP cleavage and decreased PKC activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced apoptosis is a JNK-dependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of NFkappaB and increased expression of the heat shock proteins HSP70 and HSP90. Consistent with the former, sequential inhibition of NFkappaB activation with bortezomib or SN50 synergistically enhanced cell killing. Our results demonstrate that PKC412 induces JNK-dependent apoptosis of HMCLs and primary MM cells and that this effect is enhanced by NFkappaB inhibition. The further evaluation of PKC412 in the treatment of MM is justified.
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PMID:PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells. 1703 22

Nuclear receptor coregulator (NRC) is a 250-kDa nuclear protein involved in transcriptional activation of nuclear hormone receptors, nuclear factor-kappaB, c-Jun, c-Fos, and cAMP response element-binding protein. NRC is organized into a modular structure consisting of two activation domains (AD1 and AD2), two nuclear hormone receptor-interacting motifs, LxxLL-1 and LxxLL-2, and a C-terminal regulatory region rich in serines, threonines, and leucines. The LxxLL-1 motif of NRC binds to a broad spectrum of nuclear hormone receptors with high affinity whereas LxxLL-2 interacts with a very limited number of receptors. In this study we present further evidence that NRC can act as a dimer and have identified a dimerization region of 146 amino acids including LxxLL-1. Mutation of the core LxxLL-1 motif, however, indicates that it is not involved in the dimerization of NRC. AD2, just C-terminal of LxxLL-1, was found to play a central role in ligand-dependent activation by nuclear receptors even though AD1 exhibits more potent intrinsic activity. Thus, a short region of approximately 300 amino acids including and flanking LxxLL-1 plays an important role in NRC dimerization and nuclear receptor binding and transcriptional activation. In addition, consistent with its role as a cointegrator for transcriptional activation, NRC also functions as a coactivator for signal transducer and activator of transcription 2 (STAT-2) and p53. Activation of p53 by NRC appears to involve a novel mechanism where NRC interacts indirectly with p53 through Trap80, a member of the mediator complex, which binds NRC interacting factor-1 (NIF-1), which interacts with and potentiates the effect of NRC.
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PMID:Nuclear receptor coregulator (NRC): mapping of the dimerization domain, activation of p53 and STAT-2, and identification of the activation domain AD2 necessary for nuclear receptor signaling. 1753 6

Kaposi's sarcoma-associated herpesvirus encodes numerous regulatory proteins capable of modulating viral and cellular gene expression and affecting host cell functions. K-bZIP, a leucine zipper-containing transcription factor encoded by ORFK8, is one such protein. During infection, transcription of the ORFK8 early gene is turned on by the immediate-early replication and transcription factor activator (RTA). One described function of the K-bZIP nuclear protein is to interact with and repress RTA-mediated transactivation of viral promoters, including that of the K8 gene. In the present work, we provide evidence that the expression of K-bZIP results in the activation of the ifn-beta gene. Of interest, ifn-beta gene activation by K-bZIP is independent of interferon (IFN)-responsive factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB) activation. Using a DNA binding affinity assay and electromobility shift assay, we report that K-bZIP binds efficiently to the PRDIII-I region of the beta IFN (IFN-beta) promoter, and, in doing so, it prevents the attachment of activated IRF-3 but not that of NF-kappaB or ATF2/c-Jun to the IFN-beta promoter sequence. As a consequence, ifn-beta gene activation in response to IFN inducers such as Sendai virus infection or expression of retinoic acid-inducible gene I, mitochondrial antiviral signaling protein, or TANK-binding kinase 1 (TBK-1) is severely impaired (>90%) by the presence of K-bZIP. K-bZIP also prevents the activation of RANTES and CXCL11, whose promoters are also regulated by IRF-3. Lysine 158 (target for SUMO conjugation), threonine 111, and serine 167 (targets for phosphorylation) mutants of K-bZIP were equally effective as wild-type K-bZIP in mediating the repression of TBK-1-activated ifn-beta gene expression. Lastly, the overexpression of CREB binding protein could not reverse the K-bZIP repression of TBK-1-activated ifn-beta gene expression. In all, our results indicate that K-bZIP binds directly to the PRDIII-I region of the IFN-beta promoter and, as a consequence, causes a low level of ifn-beta gene transcription. In doing so, K-bZIP prevents IRF-3 from binding to the IFN-beta promoter and precludes the formation of the enhanceosome, which is required for maximal ifn-beta gene transcription. A new role for K-bZIP as a protein involved in immune evasion is therefore uncovered.
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PMID:Binding of Kaposi's sarcoma-associated herpesvirus K-bZIP to interferon-responsive factor 3 elements modulates antiviral gene expression. 1765 96

We provide a comprehensive analysis on c-Jun N-terminal kinase (JNK) actions leading to death or differentiation in postnatal hippocampal and cortical neurons. Stimulation with glutamate or 6-hydroxy-dopamine caused activation of caspase-3 and apoptotic neuronal death which were both attenuated by JNK-inhibition. In cortical neurons, stress-induced nuclear JNK distribution was rather complex. We observed a decrease of activated and total JNK in the nucleus after stimulation, but an increase of the phosphorylated transcription factor c-Jun. Isoform-analysis revealed a nuclear translocation of JNK2, while nuclear protein levels of JNK1 decreased. This activation pattern differed from neurite formation. In hippocampal and cortical neurons, JNK activity continuously increased during neuritogenesis, whereas levels of phosphorylated c-Jun gradually declined. Despite these similarities, JNK inhibition by SP600125 only affected neurite outgrowth in hippocampal cells. Furthermore, experiments in JNK-deficient mice demonstrated that all JNK isoforms contributed to neuritogenesis. Summarizing, JNKs are involved in both neuritogenesis and death of primary neurons with differentially regulated nuclear translocation of specific isoforms after degenerative stress, while neuritogenesis is supported by all JNK isoforms.
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PMID:c-Jun N-terminal kinases trigger both degeneration and neurite outgrowth in primary hippocampal and cortical neurons. 1797 77

FIAT is a leucine zipper protein whose name was coined for its interaction with ATF4 and the subsequent blockage of ATF4-directed osteocalcin gene transcription. FIAT is a nuclear protein that lacks a basic DNA-binding domain but contains three identifiable leucine zipper domains. FIAT heterodimerizes with ATF4 through one of these zippers and thereby prohibits ATF4 from binding to its cognate DNA sequence. We tested whether FIAT also interacts with additional basic domain-leucine zipper transcriptional regulators of osteoblast activity, such as the Fos family member Fra-1 or one of its dimerization partners, c-Jun. Transient transfection assays in osteoblastic MC3T3-E1 cells with the heterologous AP-1-tk-luciferase reporter revealed that FIAT does not affect c-Jun-mediated transcription, even in the presence of the c-Jun coactivator alphaNAC. However, FIAT inhibited transcriptional activation by a c-Jun~Fra-1 heterodimer. Thus FIAT specifically inhibits Fra-1 transcriptional activity. These data identify a second target of the FIAT transcriptional repressor activity and suggest that FIAT can modulate early osteoblast activity by interacting with ATF4, as well as regulate later osteoblast function through inhibition of Fra-1.
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PMID:Identification of additional dimerization partners of FIAT, the factor inhibiting ATF4-mediated transcription. 1808 29

Photodynamic therapy (PDT), using the porphyrin photosensitizer Photofrin (PH), is approved for the clinical treatment of solid tumors. In addition to the direct cytotoxic responses of PH-PDT-mediated oxidative stress, this procedure also induces expression of angiogenic and prosurvival molecules including cyclooxygenase-2 (COX-2). In vivo treatment efficacy is improved when PH-PDT is combined with inhibitors of COX-2. In the current study we evaluated the signaling pathways involved with PH-PDT-mediated COX-2 expression in a mouse fibrosarcoma cell line. COX-2 promoter reporter constructs with mutated transcription elements documented that the nuclear factor kappa B (NFkappaB) element, cyclic-AMP response element 2 (CRE-2), CCAAT/enhancer binding protein (C/EBP) element and activator binding protein-1 (AP-1) element were responsive to PH-PDT. Transcription factor binding assays demonstrated that nuclear protein binding to NFkappaB, CRE-2, c-fos and c-jun elements were elevated following PH-PDT. Kinase phosphorylation upstream of COX-2 expression was also examined following PH-PDT. Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and c-Jun were phosphorylated following PH-PDT but the SAPK/JNK inhibitor SP600125 failed to attenuate COX-2 expression. In contrast, p38 mitogen-activated protein kinase (MAPK), which activates CRE-2 binding, was phosphorylated following PH-PDT and inhibitors of p38 MAPK, SB203580 and SB202190, decreased PH-PDT-induced COX-2 expression at both the mRNA and protein levels. Extracellular signal-regulated kinase (ERK1/2) phosphorylation, which also increases CRE-2 binding activity, was initially high in untreated cells, decreased immediately following PH-PDT and then rapidly increased. MEK1/2 is immediately upstream of ERK1/2 and the MEK1 inhibitor PD98059 failed to attenuate COX-2 expression while the MEK1/2 inhibitor U0126 induced a slight decrease in COX-2 expression. The NFkappaB inhibitor SN50 failed to reduce COX-2 expression. These results demonstrate that multiple protein kinase cascades can be activated by oxidative stress and that the p38 MAPK signaling pathway and CRE-2 binding are involved in COX-2 expression following PH-PDT.
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PMID:Cyclooxygenase-2 expression induced by photofrin photodynamic therapy involves the p38 MAPK pathway. 1828 82

High-mobility group box protein 1 (HMGB1) is a non-histone nuclear protein that acts as a pro-inflammatory cytokine and is released by monocytes and macrophages. Necrotic cells also release HMGB1 at the site of tissue damage which induces a variety of cellular responses, including the expression of pro-inflammatory mediators. This study investigated the secretion of HMGB1 in mycobacterial infection by macrophages in vitro and in the lungs of infected guinea pigs. We observed that infection by mycobacterium effectively induced HMGB1 release in both macrophage and monocytic cell cultures. Culture filtrate proteins from Mycobacterium tuberculosis induced maximum release of HMGB1 compared with different subcellular fractions of mycobacterium. We demonstrated that HMGB1 is released in lungs during infection of M. tuberculosis in guinea pigs and increased HMGB1 secretion in lungs of guinea pigs was delayed by prior vaccination with Mycobacterium bovis BCG. The secretion of cytokines like tumour necrosis factor alpha (TNF-alpha) and Interleukin-1beta was significantly increased when M. bovis BCG-infected cultures of J774A.1 cells were incubated with HMGB1. Among different mycobacterial toll-like receptor ligands, heat-shock protein 65 (HSP65) was found to be more potent in inducing HMGB1 secretion in RAW 264.7 cells. Pharmacological suppression of p38 or extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases with specific inhibitors failed to inhibit HSP65-induced HMGB1 release, but inhibition of c-Jun NH(2)-terminal kinase activation attenuated HMGB1 release. Inhibition of the inducible NO synthase and neutralizing antibodies against TNF-alpha also reduced HMGB1 release stimulated by HSP65. We conclude that HMGB1 is secreted by macrophages during tuberculosis and it may act as a signal of tissue or cellular injury and enhances immune response.
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PMID:Mycobacterial infection induces the secretion of high-mobility group box 1 protein. 1833 66

Copper is an essential metal that is able to produce reactive oxygen species and to induce intracellular oxidative stress. Several studies have examined the effects of excessive copper and oxidative stress on various organisms and tissues, but few have addressed the molecular mechanisms by which copper affects transcription. Our results demonstrated that, in COS-7 cells, copper treatment caused an increase in the binding of nuclear proteins to activating protein-1 and antioxidant response elements. The level of copper-inducible nuclear protein binding was modulated by increasing or decreasing the level of intracellular oxidative stress. Copper exposure also led to an increase in the steady-state levels of c-fos, c-jun, and c-myc mRNAs. Exposure to copper resulted in an increase in the levels of phosphorylation and activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 pathways. The activation of these pathways resulted in a concomitant increase in c-Jun phosphorylation. We investigated the hypothesis that copper-induced oxidative stress leads to the formation of stable lipid peroxidation by-products that activate mitogen-activated protein kinase (MAPK) pathways, ultimately affecting transcription. While exposure did result in the production of 4-hydroxynonenal, the timing of the increased levels of proto-oncogene mRNA, phosphorylation of c-jun, and phosphorylation and activation of MAPKs, as well as the inability of the lipophilic antioxidant vitamin E to abrogate MAPK phosphorylation, suggest that the formation of stable lipid peroxidation by-products may not be the primary mechanism by which copper activates MAPKs. These results further elucidate the effects of copper on signal transduction pathways to alter gene expression.
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PMID:Mechanism of copper-activated transcription: activation of AP-1, and the JNK/SAPK and p38 signal transduction pathways. 1879 45


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