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)

Tumor cells recruit inflammatory cells to the tumor site and transform them into tumor-supportive cells which in turn release numerous cytokines, including Transforming Growth Factor-beta that enhances tumor proliferation, invasion, angiogenesis and induces immune paralysis. Activation of JNK/c-Jun signaling pathway by various stimuli often leads to a formation of the AP-1 transcriptional complex, which is a critical regulator of a complex program of gene expression that defines the invasive phenotype. Recent studies on JNK/c-Jun phosphorylation have been carried out using phospho-specific antibodies, which have greatly facilitated analysis of signal transduction. The electrophoretic mobility shift assay (EMSA, gel shift) helps in determining the transcription factor activation and is based on the observation that complexes of protein and DNA migrate through a non-denaturing polyacrylamide gel more slowly than free DNA fragments or double-stranded oligonucleotides. The specificity of the DNA-binding protein is established by competition experiments and the protein composition of DNA binding activity can be analyzed with specific antibodies in a supershift assay. EMSA provides a sensitive and quantitative measure of a particular DNA binding activity under various experimental conditions.
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PMID:Molecular characterization of inflammation-induced JNK/c-Jun signaling pathway in connection with tumorigenesis. 1934 81

Streptococcus pneumoniae are commensals of the human nasopharynx with the capacity to invade mucosal respiratory cells. PspC, a pneumococcal surface protein, interacts with the human polymeric immunoglobulin receptor (pIgR) to promote bacterial adherence to and invasion into epithelial cells. Internalization of pneumococci requires the coordinated action of actin cytoskeleton rearrangements and the retrograde machinery of pIgR. Here, we demonstrate the involvement of Src protein-tyrosine kinases (PTKs), focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) but not p38 mitogen-activated protein kinases (MAPK) in pneumococcal invasion via pIgR. Pharmacological inhibitors of PTKs and MAPKs and genetic interference with Src PTK and FAK functions caused a significant reduction of pIgR-mediated pneumococcal invasion but did not influence bacterial adhesion to host cells. Furthermore, pneumococcal ingestion by host cells induces activation of ERK1/2 and JNK. In agreement with activated JNK, its target molecule and DNA-binding protein c-Jun was phosphorylated. We also show that functionally active Src PTK is essential for activation of ERK1/2 upon pneumococcal infections. In conclusion, these data illustrate the importance of a coordinated signaling between Src PTKs, ERK1/2, and JNK during PspC-pIgR-mediated uptake of pneumococci by host epithelial cells.
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PMID:Polymeric immunoglobulin receptor-mediated invasion of Streptococcus pneumoniae into host cells requires a coordinate signaling of SRC family of protein-tyrosine kinases, ERK, and c-Jun N-terminal kinase. 2082 50

Several key transcription factors and coregulators important to peripheral nerve myelination have been identified, but the contributions of specific chromatin remodeling complexes to peripheral nerve myelination have not been analyzed. Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complex. Previous studies have shown Chd4 interacts with Nab (NGFI-A/Egr-binding) corepressors, which are required for early growth response 2 (Egr2/Krox20), to direct peripheral nerve myelination by Schwann cells. In this study, we examined the developmental importance of the NuRD complex in peripheral nerve myelination through the generation of conditional Chd4 knock-out mice in Schwann cells (Chd4(loxP/loxP); P0-cre). Chd4 conditional null mice were found to have delayed myelination, radial sorting defects, hypomyelination, and the persistence of promyelinating Schwann cells. Loss of Chd4 leads to elevated expression of immature Schwann cell genes (Id2, c-Jun, and p75), and sustained expression of the promyelinating Schwann cell gene, Oct6/Scip, without affecting the levels of Egr2/Krox20. Furthermore, Schwann cell proliferation is upregulated in Chd4-null sciatic nerve. In vivo chromatin immunoprecipitation studies reveal recruitment of Chd4 and another NuRD component, Mta2, to genes that are positively and negatively regulated by Egr2 during myelination. Together, these results underscore the necessity of Chd4 function to guide proper terminal differentiation of Schwann cells and implicate the NuRD chromatin remodeling complex as a requisite factor in timely and stable peripheral nerve myelination.
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PMID:The nucleosome remodeling and deacetylase chromatin remodeling (NuRD) complex is required for peripheral nerve myelination. 2230 95

Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The contribution of the upregulation of TDP-43 expression to the pathogenesis has been strongly suggested by the observation that the level of TDP-43 expression is increased in both ALS and FTLD-U patients. We previously found that the low-grade (twice to five times more than the endogenous level) overexpression of TDP-43 induces neuronal cell death through the upregulation of Bim and CHOP expression and the downregulation of Bcl-xL expression. In this study, we further show that the low-grade overexpression of TDP-43 increases the level of phosphorylated c-Jun N-terminal kinase (JNK) and the co-incubation with a JNK inhibitor, the expression of a dominant-negative JNK, or the expression of a dominant-negative c-Jun inhibited the TDP-43-induced death in NSC34 motor neuronal cells. These data together suggest that the JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death.
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PMID:The JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death. 2300 69

High mobility group box 1 (HMGB1) is a DNA-binding protein that facilitates gene transcription and may act extracellularly as a late mediator of inflammation. The roles of HMGB1 in the pathogenesis of the spiral ganglion neurons (SGNs) of the cochlea are currently unknown. In the present study, we tested the hypothesis that early phenotypical changes in the SGNs of the amikacin-poisoned rat cochlea are mediated by HMGB1. Our results showed that a marked downregulation of HMGB1 had occurred by completion of amikacin treatment, coinciding with acute damage at the dendrite extremities of the SGNs. A few days later, during the recovery of the SGN dendrites, the protein was re-expressed and transiently accumulated within the nuclei of the SGNs. The phosphorylated form of the transcription factor c-Jun (p-c-Jun) was concomitantly detected in the nuclei of the SGNs where it often co-localized with HMGB1, while the anti-apoptotic protein BCL2 was over-expressed in the cytoplasm. In animals co-treated with amikacin and the histone deacetylase inhibitor trichostatin A, both HMGB1 and p-c-Jun were exclusively found within the cytoplasm. The initial disappearance of HMGB1 from the affected SGNs may be due to its release into the external medium, where it may have a cytokine-like function. Once re-expressed and translocated into the nucleus, HMGB1 may facilitate the transcriptional activity of p-c-Jun, which in turn may promote repair mechanisms. Our study therefore suggests that HMGB1 can positively influence the survival of SGNs following ototoxic exposure via both its extracellular and intranuclear functions.
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PMID:High mobility group box 1 (HMGB1): dual functions in the cochlear auditory neurons in response to stress? 2770 12


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