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)

The 92-kDa type IV collagenase (MMP-9) contributes to tumor invasion and metastases and strategies to down-regulate its expression could ultimately be of clinical utility. Although the expression of this collagenase is regulated by numerous growth factors, the signaling pathways that transduce these signals are fewer in number and therefore represent pharmacological targets. In this regard, we previously reported that MMP-9 expression was regulated by the c-jun amino terminal kinase (JNK) signaling cascade. Therefore, we undertook a study to determine the efficacy of a novel compound (SP600125), which binds to the ATP binding site of all known JNKs, in repressing MMP-9 expression. In OVCAR-3 cells, SP600125 inhibited the PMA-dependent secretion of MMP-9 in a time-dependent manner and over a dose range that blocked c-Jun phosphorylation and AP-1 binding. SP600125 repressed the activity of a PMA-stimulated MMP-9 promoter-driven luciferase reporter, suggesting that diminished secretion of this collagenase reflected reduced transcription. Further, the activity of a GAL4-driven reporter in PMA-treated cells, co-transfected with an expression construct encoding the trans-activation domain of c-Jun fused to the DNA binding domain of GAL4, was repressed by SP600125. These findings indicate the efficacy of SP600125 in inhibiting c-Jun activation, DNA-binding and the PMA-dependent induction of MMP-9 expression.
 ...
PMID:An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression. 1203 98

Telomerase activity is present in >90% of all tumors and appears to be regulated by the phosphatidylinositol 3-kinase signaling pathway. Here we demonstrate that Akt is not involved in the signaling cascade for telomerase regulation in ovarian surface epithelial cells. However, we showed that c-Jun NH2-kinase induces telomerase activity, that inhibition of JNK by JIP abrogates telomerase activity, and that JNK expression activates transcription of a reporter gene fused to the hTERT promoter sequence. Consequently, our data show that JNK is a key regulator of telomerase activity and, hence, may provide new perspectives on tumorigenesis that could be exploited for novel therapeutic strategies.
 ...
PMID:Telomerase is regulated by c-Jun NH2-terminal kinase in ovarian surface epithelial cells. 1218 9

The interactions between biomolecules and human glutathione transferase M2-2 (GST M2-2) were probed by using 9- and 15-mer combinatorial peptide libraries displayed on phage. The peptide libraries were based on random DNA sequences fused to gIII, a gene that expresses a phage coat protein and thus causes the peptides to be displayed on the surface of phage particles. A peptide sequence was enriched through binding to GST M2-2, which indicated a successful selection. Binding studies with the peptide displayed on phage showed binding specificity. The sequence of the peptide had similarities to segments of proteins in the Swiss-Prot Database, to c-Jun N-terminal kinase (JNK), and to the protein Bcl3. JNK is linked to the regulation of the transcription factor AP-1. Use of cell-based assays of the transcriptional activity of AP-1 allowed a novel coactivation function of GST M2-2 to be demonstrated. Specificity in the activation was indicated by the lack of effect of GST A1-1. No coactivator function of GST M2-2 could be demonstrated in assays with Bcl3. These results suggest that GST M2-2 has biological roles in addition to catalysis of detoxication reactions, and demonstrate the potential of phage display in functional genomics research.
 ...
PMID:Probing biomolecular interactions of glutathione transferase M2-2 by using peptide phage display. 1221 Sep 82

The mitogen-activated kinases are structurally related proline-directed serine/threonine kinases that phosphorylate similar phosphoacceptor sites and yet, in vivo, they exhibit stringent substrate specificity. Specific targeting domains (kinase docking domains) facilitate kinase-substrate interaction and play a major role in substrate specificity determination. The c-Jun N-terminal kinase (JNK) consensus docking domain comprises of a KXXK/RXXXXLXL motif located in the delta-domain of the c-Jun N-terminal to the phosphoacceptor site. The c-Jun dimerization protein 2 is phosphorylated by JNK on Thr-148. Activating transcription factor 3 (ATF3) is a basic leucine zipper protein which is highly homologous to c-Jun dimerization protein 2 (JDP2), especially within the threonine/proline phosphoacceptor site, Thr-148. Nevertheless, ATF3 does not serve as a JNK substrate in vitro or in vivo. Using ATF3 and JDP2 protein chimaeras, we mapped the JNK-docking domain within JDP2. Although a JNK consensus putative docking site is located within the JDP2 leucine zipper motif, this domain does not function to recruit JNK to JDP2. A novel putative docking domain located C-terminally to the JDP2 phosphoacceptor site was identified. This domain, when fused to the ATF3 heterologous phosphoacceptor site, can direct its phosphorylation by JNK. In addition, although the novel JNK-docking domain was found to be necessary for p38 phosphorylation of JDP2 on Thr-148, it was not sufficient to confer JDP2 phosphorylation by the p38 kinase.
 ...
PMID:Differential targeting of the stress mitogen-activated protein kinases to the c-Jun dimerization protein 2. 1222 89

Fluorescence resonance energy transfer (FRET) between two GFP variants is a powerful technique to describe protein-protein interaction in a biological system. However, it has a limitation that the two variants tethered to the respective proteins have to be in sufficient proximity upon binding, which is often difficult to attain by simple N- or C-terminal fusions. Here we describe a novel method to significantly enhance FRET between GFP variant-tagged proteins with the use of leucine zippers. For the homogeneous sandwich immunoassay of a high molecular weight antigen human serum albumin (HSA), two separate single-chain Fvs recognizing distant epitopes of HSA were respectively fused with fluorescence donor ECFP or acceptor EYFP, and FRET between the two was analyzed by fluorescence spectrometry. Because these two proteins did not give any detectable FRET uponantigen addition, we tethered each protein with a leucine zipper motif (c-Jun or FosB) at the C-terminus to help the neighborhood of the GFP variants. Upon antigen addition, the new pairs showed significant antigen-dependent FRET. By exchanging the binding domains, the method will find a range of applications for the assay of other proteins and their interactions in vitro or in vivo.
 ...
PMID:A homogeneous and noncompetitive immunoassay based on the enhanced fluorescence resonance energy transfer by leucine zipper interaction. 1246 62

The antigen stimulation of RBL-2H3 cells induced interleukin 13 (IL-13) production, which was inhibited by the steroidal anti-inflammatory drug dexamethasone and by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Dexamethasone did not inhibit the antigen-induced phosphorylation of JNK but inhibited that of c-Jun. In a cell-free system, the phosphorylation of glutathione S-transferase-fused c-Jun by recombinant JNK was not inhibited by dexamethasone but was inhibited by the addition of recombinant glucocorticoid receptor (GR). These findings suggest that the inhibition of antigen-induced IL-13 production by dexamethasone is due to the GR-mediated inhibition of c-Jun phosphorylation induced by JNK.
 ...
PMID:Inhibition by dexamethasone of interleukin 13 production via glucocorticoid receptor-mediated inhibition of c-Jun phosphorylation. 1462 17

The expression of A-type lamins, subdivided into lamin A and C, is developmentally regulated. Retinoic acid (RA)-induced differentiation of P19 embryonic carcinoma cells, in which A-type lamins are absent, increases the expression of lamin A/C. We previously showed, using P19 cells as a model system, that the lamin A/C promoter has a retinoic acid-responsive element (L-RARE), and that Sp1 and Sp3 bind the CACCC box of the L-RARE. In this study, we report that Sp1, Sp3, and c-Jun increase transactivation of the L-RARE during RA treatment. Sp1 and Sp3 regulate the lamin A/C promoter in Sp1-deficient SL2 cells and contribute to RA-dependent activation in GAL4-based transcriptional assays. Overexpression of c-Jun causes transactivation of a chimeric promoter consisting of four tandem L-RARE repeats fused with the luciferase gene in P19 cells. c-Jun also transactivates a reporter construct with five tandem GAL4-binding sites, only when co-expressed with either GAL4-Sp1 or Sp3 fusion proteins. Furthermore, we detect a physiological interaction between c-Jun with Sp1/Sp3 in RA-treated cells. Our data suggest that Sp1, Sp3, and c-Jun play an important role in gene expression through the L-RARE during RA treatment.
 ...
PMID:c-Jun and Sp1 family are critical for retinoic acid induction of the lamin A/C retinoic acid-responsive element. 1521 55

The activator protein-1 (AP-1) and runt domain binding (Runx/RD/Cbfa) sites and their respective binding proteins, c-Fos/c-Jun and Runx2 (Cbfa1), regulate the rat matrix metalloproteinase-13 (MMP-13) promoter in both parathyroid hormone (PTH)-treated and differentiating osteoblastic cells in culture. To determine the importance of these regulatory sites in the expression of MMP-13 in vivo, transgenic mice containing either wild-type (-456 or -148) or AP-1 and Runx/RD/Cbfa sites mutated (-148A3R3) MMP-13 promoters fused with the E. coli lacZ reporter were generated. The wild-type transgenic lines expressed higher levels of bacterial beta-galactosidase in bone, teeth, and skin compared to the mutant and non-transgenic lines. Next, we investigated if overexpression of Runx2 directed by the MMP-13 promoter regulated expression of bone specific genes in vivo, and whether this causes morphological changes in these animals. Real time RT-PCR experiments identified increased mRNA expression of bone forming genes and decreased MMP-13 in the tibiae of transgenic mice (14 days and 6 weeks old). Histomorphometric analyses of the proximal tibiae showed increased bone mineralization surface, mineral apposition rate, and bone formation rate in the transgenic mice which appears to be due to decreased osteoclast number. Since MMP-13 is likely to play a role in recruiting osteoclasts to the bone surface, decreased expression of MMP-13 may cause reduced osteoclast-mediated bone resorption, resulting in greater bone formation in transgenic mice. In summary, we show here that the 148 bp upstream of the MMP-13 transcriptional start site is sufficient and necessary for gene expression in bone, teeth, and skin in vivo and the AP-1 and Runx/RD/Cbfa sites are likely to regulate this. Overexpression of Runx2 by these regulatory elements appears to alter the balance between the bone formation-bone resorption processes in vivo.
 ...
PMID:Overexpression of Runx2 directed by the matrix metalloproteinase-13 promoter containing the AP-1 and Runx/RD/Cbfa sites alters bone remodeling in vivo. 1663 21

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.
 ...
PMID:Makorin RING finger protein 1 (MKRN1) has negative and positive effects on RNA polymerase II-dependent transcription. 1678 14

Focusing on the final step of osteoclastogenesis, we studied cell fusion from tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells into multinuclear cells. TRAP-positive mononuclear cells before generation of multinuclear cells by cell fusion were differentiated from RAW264.7 cells by treatment with receptor activator of nuclear factor kappa B ligand (RANKL), and then the cells were treated with lipopolysaccharide (LPS), followed by culturing for further 12 h. LPS-induced cell fusion even in the absence of RANKL. Similarly, tumor necrosis factor (TNF)-alpha and peptidoglycan (PGN) induced cell fusion, but M-CSF did not. The cell fusion induced by RANKL, TNF-alpha, and LPS was specifically blocked by osteoprotegerin (OPG), anti-TNF-alpha antibody, and polymyxin B, respectively. LPS- and PGN-induced cell fusion was partly inhibited by anti-TNF-alpha antibody but not by OPG. When TRAP-positive mononuclear cells fused to yield multinuclear cells, phosphorylation of Akt, Src, extracellular signal-regulated kinase (ERK), p38MAPK (p38), and c-Jun NH2-terminal kinase (JNK) was observed. The specific chemical inhibitors LY294002 (PI3K), PP2 (Src), U0126 (MAPK-ERK kinase (MEK)/ERK), and SP600125 (JNK) effectively suppressed cell fusion, although SB203580 (p38) did not. mRNA of nuclear factor of activated T-cells c1 (NFATc1) and dendritic cell-specific transmembrane protein (DC-STAMP) during the cell fusion was quantified, however, there was no obvious difference among the TRAP-positive mononuclear cells treated with or without M-CSF, RANKL, TNF-alpha, LPS, or PGN. Collectively, RANKL, TNF-alpha, LPS, and PGN induced cell fusion of osteoclasts through their own receptors. Subsequent activation of signaling pathways involving PI3K, Src, ERK, and JNK molecules was required for the cell fusion. Although DC-STAMP is considered to be a requisite for cell fusion of osteoclasts, cell fusion-inducing factors other than DC-STAMP might be necessary for the cell fusion.
 ...
PMID:Molecular analysis of RANKL-independent cell fusion of osteoclast-like cells induced by TNF-alpha, lipopolysaccharide, or peptidoglycan. 1717 44


<< Previous 1 2 3 4 5 6 7 Next >>