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)

Laminin, a basement membrane glycoprotein, has diverse biological activities including cell adhesion, growth, and differentiation. However, little is known concerning the signal transduction and active site involved in cell growth. In this study, we have shown that laminin and a 19-mer peptide (PA22-2) from the carboxyl-terminal end of the long arm of the laminin A chain, which was previously shown to promote cell adhesion and neurite outgrowth, stimulate thymidine incorporation and cell growth of PC12 cells. Laminin and PA22-2 (PA) were also found to induce a rapid and transient mRNA expression of c-fos and c-jun protooncogenes in PC12 cells. Further, both laminin and PA stimulated the DNA binding activity of c-Fos and c-Jun protein complex to the AP-1 site. We have also found that there is a correlation between cell growth, c-fos expression, and the ability of cell attachment to laminin or to PA in different cell types. These results suggest that the PA sequence is a potent site in laminin for both signal transduction and cell growth.
 ...
PMID:Signaling site of laminin with mitogenic activity. 153 19

We studied the role of the immediate early gene c-jun in cell proliferation and phorbol 12-myristate 13-acetate (PMA)-induced differentiation in U937 human monoblastic cells, using c-jun-specific antisense (AS) phosphorothioate oligonucleotides. In selecting the most specific and potent oligonucleotide sequence, we performed extensive analyses for the binding specificity between all candidates of c-jun AS oligonucleotides and the whole sequences in GenBank database, using a computer program. Among the 20 selected oligonucleotides, two potent 15-mer AS oligonucleotides (C-JUN AS oligonucleotides) exhibited significant inhibition of cell growth in a dose-dependent manner between 2 and 10 microM. Reverse transcription-PCR and Western blot analysis demonstrated that 10 microM of C-JUN AS oligonucleotides reduced c-jun expression at both the mRNA and protein levels. More importantly, C-JUN AS oligonucleotides showed distinct effects on two markers of PMA-induced differentiation; the C-JUN AS oligonucleotides inhibited cell adhesion, whereas they did not affect another marker of differentiation, respiratory burst (measured by nitro blue tetrazolium reduction assay). These results suggest a critical role of c-jun in both cell proliferation and PMA-induced cell adhesion but not in PMA-induced respiratory burst in U937 cells.
 ...
PMID:Suppression of c-jun by antisense oligonucleotides inhibits cell adhesion but not respiratory burst during phorbol ester-induced differentiation of U937 human monoblastic cells. 885 96

Transforming growth factor beta (TGFbeta) induces the expression of a wide variety of genes in many cell types. Our previous studies have shown that TGFbeta stimulates both clusterin mRNA and protein levels, and induces its accumulation in the nucleus of CCL64 cells. To further investigate the molecular mechanism of clusterin mRNA induction by TGFbeta, we created a 1.3-kilobase rat clusterin promoter/luciferase reporter construct. We demonstrate that TGFbeta enhances luciferase activity 2.5-6-fold in transient transfection assays of epithelial, endothelial, and fibroblast cell lines. Deletional analysis reveals that an AP-1-binding site (5'-TGAGTCA) in the minimal promoter region is necessary for initiating transactivation by TGFbeta. A single T to G base mutation in the AP-1 site (5'-TGAGGCA) abolishes TGFbeta-induced clusterin promoter transactivation. In transcription factor decoy experiments, 23-mer oligonucleotides of wild type AP-1 reduce TGFbeta induction of clusterin mRNA levels and promoter transactivation, while an oligonucleotide containing the mutated AP-1 site has no effect. Two specific protein kinase C inhibitors, GF109203X and calphostin C, block TGFbeta-induced clusterin mRNA levels and promoter transactivation. Together these results indicate that TGFbeta regulates clusterin gene expression through an AP-1 site and its cognate transcription factor AP-1, and requires the involvement of protein kinase C.
 ...
PMID:Regulation of clusterin gene expression by transforming growth factor beta. 933 43

We reported previously that the production of urokinase-type plasminogen activator receptor (uPAR) protein is greater in high-grade glioblastomas than in low-grade gliomas. Transcriptional activation of the uPAR gene or increased stability of the uPAR mRNA that encodes this protein could cause the increased production of this protein in cell lines of different grades of gliomas. We found similar half-life of uPAR mRNA of 10-12 h in glioblastoma multiforme (UWR3) and anaplastic astrocytoma (SW1783) cells. However, the human uPAR promoter was up-regulated 6-8-fold in SW1783 cells and 11-13-fold in UWR3 cells as compared with its activity in low-grade gliomas, a finding that correlates well with previous findings of increases in uPAR mRNA and protein levels in higher-grade gliomas. uPAR mRNA level was increased 11-fold over a 24-h period in low-grade glioma cell lines after treatment with phorbol myristate acetate. The region spanning -144 to -123 bp of the human uPAR promoter that contains the Sp-1 site and a PEA-3 element and an AP-1 site at -184 plays major roles in uPAR promoter activity in glioblastoma cells. Specific antibodies used in an electrophoretic mobility shift assay identified fra-1, fra-2, Jun D, and c-Jun proteins in the nuclear protein complex that bind a 51-mer containing the AP-1 consensus sequence at -184 and its flanking sequences in the uPAR promoter. We further studied the inhibition of uPAR promoter by coexpression of a transactivation domain lacking C-Jun; a dominant-negative ERK1 and ERK2 mutant and a dominant-negative C-raf in glioblastoma cell lines showed the repressed uPAR promoter activity compared with the effect of the empty expression vector. We conclude from our findings that increased transcription is the more likely mechanism underlying the increase in uPAR production in high-grade gliomas.
 ...
PMID:Regulation of the urokinase-type plasminogen activator receptor gene in different grades of human glioma cell lines. 1123 78

Reaction to certain motifs in bacterial DNA is an important function of natural immunity. For example, single stranded oligonucleotides (ODN) containing the motif "not C, unmethylated C, G, not G" are powerful mitogens and apoptosis inhibitors for mouse spleen B cells. But replacing GCGTT or ACGTT with GCGGG or ACGGG converted a stimulatory 15-mer ODN into an inhibitory ODN. All inhibitory ODN had three consecutive G, and a fourth G increased inhibitory activity, but a deazaguanosine substitution to prevent planar stacking did not affect activity. Inhibitory ODN blocked apoptosis protection and cell-cycle entry induced by stimulatory ODN, but not that induced by lipopolysaccharide, anti-CD40 or anti-IgM+IL-4. ODN-driven up-regulation of cyclin D(2), c-Myc, c-Fos, c-Jun and Bcl(XL) and down-regulation of cyclin kinase inhibitor p27(kip1) were all blocked by inhibitory ODN. The relative potency of a series of stimulatory and inhibitory ODN was the same for all readouts measured. Interference with uptake of stimulatory ODN could not account for their inhibitory effects. Even if addition of inhibitory ODN was delayed several hours, partial inhibition of stimulatory ODN effects occurred. Inhibitory ODN hold potential as antidotes for excessive ODN stimulation in the clinical setting and provide an important tool for studying ODN recognition.
 ...
PMID:Inhibitory oligonucleotides specifically block effects of stimulatory CpG oligonucleotides in B cells. 1198 8

Human ovarian cancer cell lines derived from A2780 by stepwise exposure to increasing cisplatin concentrations show progressive resistance to cisplatin. Previous studies have shown increased cellular glutathione and elevated steady-state expression of gamma-glutamylcysteine synthetase (gamma-GCS) and of the transcription factor c-Jun, all in proportion to the level of resistance in the resistant cells. We hypothesized that c-Jun was an important locus of control of the detoxicating enzymes mediating resistance, and that resistance reversal would be achieved by specific inhibition of this mechanism. A2780 (sensitive) and C30 (resistant) cells were treated with a 20-mer c-jun phosphorothioate antisense oligodeoxynucleotide (ISIS 10582, 1 microM), and a decrease in steady-state c-jun mRNA was demonstrated in the resistant cells. The expression of gamma-GCS mRNA was down-regulated and the cellular level of glutathione was decreased in C30 cells. No change in gamma-GCS expression occurred in A2780 cells. Using the microtetrazolium (MTT) cytotoxicity assay, we determined that the c-jun antisense decreased the IC50 value for cisplatin in C30 cells from 18.2 to 3.7 microM, and had a substantially smaller effect in A2780 cells. To determine if c-jun overexpression alone could confer resistance to the sensitive cell line, we transiently transfected A2780 cells with a c-jun expression vector. The transfected cells exhibited a 10.7-fold elevation of glutathione (GSH) content, a 9.2-fold increase in c-Jun protein content, and a 2-fold increase in the IC50 for cisplatin. These data suggest that altered regulation of transcription factor expression contributes to the acquired resistance phenotype in these ovarian cancer cells, and provide a novel potential target for therapeutic intervention.
 ...
PMID:Reversal of cisplatin resistance in human ovarian cancer cell lines by a c-jun antisense oligodeoxynucleotide (ISIS 10582): evidence for the role of transcription factor overexpression in determining resistant phenotype. 1200 73

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

Using a cre-loxP-mediated gene-switch approach, we achieved targeted JNK activation in adult hearts. A transgenic model is established carrying a floxed gene-switch construct that directs GFP marker gene expression in the absence of DNA recombination between two loxP sites. A tamoxifen-inducible Cre recombinase was introduced in the transgenic heart by breeding with previously established Mer-Cre-Mer transgenic mice. Upon tamoxifen administration in double transgenic adult animals, cre-loxP-mediated DNA recombination efficiently switches "off" the loxP-flanked GFP expression unit in cardiomyocytes and switches "on" the expression of the target gene, MKK7D, a constitutively activated upstream activator of c-Jun N-terminal kinases (JNK). Expression of MKK7D in adult hearts resulted in significant activation of JNK activities and causes progressive cardiomyopathy in transgenic animals. This unique animal model of cardiac-specific and temporally regulated JNK activation will provide a powerful tool to investigate the functional role of the JNK pathway in the development of heart failure. Our data also demonstrated that the inducible gene-switch approach reported here may also be applicable in other studies to achieve efficient, tissue-specific, and temporally regulated genetic manipulation in intact animals.
 ...
PMID:Temporal activation of c-Jun N-terminal kinase in adult transgenic heart via cre-loxP-mediated DNA recombination. 1259 83

Cripto, a member of the epidermal growth factor-Cripto-FRL-Criptic (EGF-CFC) family, has been described recently as a potential target for immunotherapy (Adkins et al., J Clin Invest 2003;112:575-87). We have produced rat monoclonal antibodies (mAbs) to a Cripto 17-mer peptide, corresponding to the "EGF-like" motif of Cripto. The mAbs react with most cancers of the breast, colon, lung, stomach, and pancreas but do not react or react weakly with normal tissues. The mAbs inhibit cancer cell growth in vitro, and this effect was greater with cytotoxic drugs such as 5-fluorouracil, epirubicin, and cisplatin. The anti-Cripto mAbs prevent tumor development in vivo and inhibit the growth of established tumors of LS174T colon xenografts in Scid mice. The growth inhibitory effects with these mAbs may be greater than those described elsewhere, possibly because of IgM giving more effective cross-linking or binding to a different epitope (EGF-like region versus CFC region). The mechanism of inhibitory effects of the Cripto mAbs includes both cancer cell apoptosis, activation of c-Jun-NH(2)-terminal kinase and p38 kinase signaling pathways and blocking of Akt phosphorylation. Thus, Cripto is a unique target, and mAbs to Cripto could be of therapeutic value for human cancers.
 ...
PMID:Cripto: a novel target for antibody-based cancer immunotherapy. 1517 16

We previously reported that a small peptide based on amino acids 143-153 of the c-Jun N-terminal kinase (JNK)-binding domain of JIP-1 functioned as an in vitro inhibitor of JNK activity. This peptide (TI-JIP: RP-KRPTTLNLF) resembles the kinase-interaction motif (KIM = (K/R)(2-3)X(1-6)(L/I)X(L/I)), which is common to upstream activators, downstream substrates, phosphatases, and scaffold proteins present in MAPK cascades. In this study, we characterized the mechanism of JNK inhibition by this peptide and further investigated the biochemical features of this peptide resulting in potent JNK inhibition. We also tested various KIM-based peptides for their ability to inhibit JNK activity. TI-JIP was found to be competitive with respect to the phosphoacceptor substrate c-Jun (K(I) = 0.39 +/- 0.08 microm), and exhibit mixed (non-competitive) inhibition with respect to ATP. All seven substitutions of Pro-5 we tested significantly reduced the JNK inhibition, as did altering the Pro-5 to Leu-8 spacing. When we independently tested eight substitutions of either Thr-6 or Thr-7, only one substitution in each position was well tolerated. Furthermore, peptides based on the KIMs from other proteins were significantly less potent JNK inhibitors than TI-JIP, including a peptide from the JNK interactor Sab that contained all critical inhibitory residues present in TI-JIP. Therefore, despite having previously identified Arg-4, Pro-5, Leu-8, and Leu-10 in TI-JIP as independently critical for mediating JNK inhibition, we find their presence in other 11-mer peptides is not sufficient for JNK inhibition. TI-JIP is therefore a unique KIM-based inhibitor of JNK activity.
 ...
PMID:The critical features and the mechanism of inhibition of a kinase interaction motif-based peptide inhibitor of JNK. 1520 23


1 2 Next >>