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 expression of MMP13 (collagenase-3), a member of the matrix metalloproteinase family, is increased in vivo as well as in cultured osteosarcoma cell lines by parathyroid hormone (PTH), a major regulator of calcium homeostasis. Binding sites for AP-1 and Cbfa/Runt transcription factors in close proximity have been identified as cis-acting elements in the murine and rat mmp13 promoter required for PTH-induced expression. The cooperative function of these factors in response to PTH in osteoblastic cells suggests a direct interaction between AP-1 and Cbfa/Runt transcription factors. Here, we demonstrate interaction between c-Jun and c-Fos with Cbfa/Runt proteins. This interaction depends on the leucine zipper of c-Jun or c-Fos and the Runt domain of Cbfa/Runt proteins, respectively. Moreover, c-Fos interacts with the C-terminal part of Cbfa1 and Cbfa2, sharing a conserved transcriptional repression domain. In addition to the distal osteoblast-specific element 2 (OSE2) element in the murine and rat mmp13 promoter, we identified a new proximal OSE2 site overlapping with the TRE motif. Both interaction of Cbfa/Runt proteins with AP-1 and the presence of a functional proximal OSE2 site are required for enhanced transcriptional activity of the mmp13 promoter in transient transfected fibroblasts and in PTH-treated osteosarcoma cells.
 ...
PMID:AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element. 1127 69

We previously demonstrated the presence of an enhancer that is located between nucleotides - 2264 and - 2495 in the 5' flanking region of the rat sodium/iodide symporter (NIS) gene (Ohno et al., 1999). When attached to NIS or heterologous promoters, this 232 bp fragment, which we call NUE, is able to stimulate transcription in a thyroid-specific and cAMP-dependent manner. A paired-domain transcription factor Pax8 binds to this enhancer and can stimulate the transcription in non-thyroid cells that do not normally support the NUE activities. Cotransfection of PKA, a downstream effector of cAMP, further potentiates the Pax8-mediated transactivation. However, this transcriptional machinery containing pax8 seems to require contributions from the neighboring cis-acting element that is similar to CRE/AP-1 consensus sequences. Modification of this putative CRE/AP-1 site not only represses the NUE transcriptional activities by 90% in FRTL-5 cells, but also nullifies the synergistic effect of PKA on pax8-mediated transactivation in HeLa cells. In this report, we have further characterized the putative CRE/AP-1 site within the NIS upstream enhancer using gel mobility shift assay. An oligonucleotide probe with NIS CRE/AP-1 sequence produced complex binding patterns in both FRTL-5 and HeLa cell, reflecting the presence of diverse classes of binding factors. When compared with CRE or AP-1 elements in other genes, the mobility shift pattern of NIS CRE/AP-1 was similar to those of collagenase TRE, c-Jun TRE, and somatostatin CRE, but the relative intensities of the binding complexes were quite different. This observation raises a possibility that the NIS CRE/AP-site is regulated by a novel mechanism.
 ...
PMID:Characterization of the upstream enhancer of the rat sodium/iodide symporter gene. 1157 34

Cotransfection of primary rat embryo fibroblasts (REF) with c-Jun and activated Ras leads to oncogenic transformation and this process requires the phosphorylation of the N-terminal domain of c-Jun. Ras augments this phosphorylation and, consequently activates the c-Jun transactivation property of TRE (TPA Responsive Element)-dependent promoters. To analyse the role of the c-Jun C-terminal phosphorylation site in oncogenic cooperation we tested the activities of N-terminal c-Jun Ala(63/73) (named Nt), C-terminal c-Jun Ala(234/242/246/252) (named Ct) and (Nt+Ct)-with both mutations-non-phosphorylatable c-Jun mutants. In cooperation with Ras, the Ct mutant and wt c-Jun display similar oncogenic properties whereas the Nt form was defective in transforming REF cells. Unexpectedly, the Nt+Ct mutant exhibited identical oncogenic properties to wt c-Jun, demonstrating that the Ct mutation rescues in cis the Nt mutation. The transcriptional activity and the capacity to bind the c-Jun coactivator CREB Binding Protein (CBP) were enhanced by Ras for the wt and Ct proteins but not for the Nt mutant. Interestingly, the Nt+Ct mutant presents identical transactivation and CBP binding activities to wt c-Jun. Therefore the rescue in cis of the defective Nt mutation by the Ct mutation seems to be due to the recovery of CBP binding. Our results revealed that the process of oncogenic cooperation can occur between Ras and the Nt+Ct non-phosphorylatable c-Jun protein.
 ...
PMID:The defective transforming phenotype of c-Jun Ala(63/73) is rescued by mutation of the C-terminal phosphorylation site. 1170 73

The role of activating protein-1 (AP-1) in muscle cells is currently equivocal. While some studies propose that AP-1 is inhibitory for myogenesis, others implicate a positive role in this process. We tested whether this variation may be due to different properties of the AP-1 subunit composition in differentiating cells. Using Western analysis we show that c-Jun, Fra-2, and JunD are expressed throughout the time course of differentiation. Phosphatase assays indicate that JunD and Fra-2 are phosphorylated in muscle cells and that at least two isoforms of each are expressed in muscle cells. Electrophoretic mobility shift assays combined with antibody supershifts indicate the appearance of Fra-2 as a major component of the AP-1 DNA binding complex in differentiating cells. In this context it appears that Fra-2 heterodimerizes with c-Jun and JunD. Studying the c-jun enhancer in reporter gene assays we observed that the muscle transcription factors MEF2A and MyoD can contribute to robust transcriptional activation of the c-jun enhancer. In differentiating muscle cells mutation of the MEF2 site reduces transactivation of the c-jun enhancer and MEF2A is the predominant MEF2 isoform binding to this cis element. Transcriptional activation of an AP-1 site containing reporter gene (TRE-Luc) is enhanced under differentiation conditions compared with growth conditions in C2C12 muscle cells. Further studies indicate that Fra-2 containing AP-1 complexes can transactivate the MyoD enhancer/promoter. Thus, an AP-1 complex containing Fra-2 and c-Jun or JunD is consistent with muscle differentiation, indicating that AP-1 function during myogenesis is dependent on its subunit composition.
 ...
PMID:Composition and function of AP-1 transcription complexes during muscle cell differentiation. 1187 23

Glutathione is the most abundant non-protein thiol in the cell, with roles in cell cycle regulation, detoxification of xenobiotics, and maintaining the redox tone of the cell. The glutathione content is controlled at several levels, the most important being the rate of de novo synthesis, which is mediated by two enzymes, glutamate cysteine ligase (GCL), and glutathione synthetase (GS), with GCL being rate-limiting generally. The GCL holoenzyme consists of a catalytic (GCLC) and a modulatory (GCLM) subunit, which are encoded by separate genes. In the present study, the signaling mechanisms leading to de novo synthesis of GSH in response to physiologically relevant concentrations of 4-hydroxy-2-nonenal (4HNE), an endproduct of lipid peroxidation, were investigated. We demonstrated that exposure to 4HNE resulted in increased content of both Gcl mRNAs, both GCL subunits, phosphorylated JNK1 and c-Jun proteins, as well as Gcl TRE sequence-specific AP-1 binding activity. These increases were attenuated by pretreating the cells with a novel membrane-permeable JNK pathway inhibitor, while chemical inhibitors of the p38 or ERK pathways were ineffective. These data reveal that de novo GSH biosynthesis in response to 4HNE signals through the JNK pathway and suggests a major role for AP-1 driven expression of both Gcl genes in HBE1 cells.
 ...
PMID:4-hydroxynonenal induces glutamate cysteine ligase through JNK in HBE1 cells. 1236 7

Dietary use of curcumin, the active component of tumeric, one of the most widely used spices, is linked to several beneficial health effects, although the underlying molecular mechanisms remain largely unknown. Correlations have been established between curcumin exposure and increases in enzymes for glutathione synthesis, particularly glutamate-cysteine ligase (GCL), and metabolism as well as glutathione content, suggesting the eliciting of an adaptive response to stress. In this study, using HBE1 cells, we found that the mechanism of curcumin-induced GCL elevation occurred via transcription of the two Gcl genes. Gcl transcription has been shown in several systems to be mediated through binding of transcription factor complexes to TRE and EpRE elements. Studies herein showed that curcumin caused modest but sustained increases in binding of proteins to DNA sequences for both cis elements but, more importantly, altered the compositions and nuclear content of proteins in these complexes. Curcumin exposure increased JunD and c-Jun content in AP-1 complexes and increased JunD while decreasing MafG/MafK in EpRE complexes. Thus, the beneficial effects elicited by curcumin appear to be due to changes in the pool of transcription factors that compose EpRE and AP-1 complexes, affecting gene expression of GCL and other phase II enzymes.
 ...
PMID:Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. 1251 13

The resistance of melanoma to apoptosis, as well as its growth and metastasis capabilities, can be overcome by expression of a peptide derived from amino acid (aa) 51 to 100 of ATF2. Here we show that expression of ATF2((51-100)) in human melanoma cells reduced their growth in nude mice, which was additionally inhibited upon treatment with protein kinase inhibitors UCN-01 or SB203580. Injection of a fusion protein consisting of HIV-TAT and aa 51 to 100 of ATF2 into SW1 melanomas efficiently inhibits their growth and their metastasis up to complete regression. Additionally, expression of a 10aa peptide that corresponds to aa 51 to 60 of ATF2 sensitizes melanoma cells to spontaneous apoptosis, which coincides with activation of caspase 9 and poly(ADP-ribose) polymerase cleavage, and inhibit their growth in vivo. The 10aa peptide increases the association of c-Jun NH(2)-terminal kinase with c-Jun but not with ATF2, resulting in concomitant increase in TRE-mediated transcription. Our study points to mechanisms underlying the activities of the ATF2 peptide while highlighting its possible use in drug design.
 ...
PMID:Inhibition of melanoma growth and metastasis by ATF2-derived peptides. 1554 88

FRA-1, a member of the FOS family of transcription factors, is overexpressed in a variety of human tumors, and contributes to tumor progression. In addition to mitogens, various toxicants and carcinogens persistently induce FRA-1 expression in vitro and in vivo. Although the mitogen induced expression of c-FOS is relatively well understood, it is poorly defined in the case of FRA-1. Our recent analysis of the FRA-1 promoter has shown a critical role for a TRE located at -318 in mediating the TPA-induced expression. The -379 to -283 bp promoter segment containing a critical TRE (-318), however, is insufficient for the induction of FRA-1 promoter. Here, we show that a 40-bp (-276/-237) segment, comprising a TCF binding site and the CArG box (collectively known as serum response element, SRE), and an ATF site, is also necessary for the FRA-1 induction by TPA and EGF. Interestingly, the -283 to +32 bp FRA-1 promoter fragment containing an SRE and an ATF site alone was also insufficient to confer TPA sensitivity to a reporter gene. However, in association with the -318 TRE, the SRE and ATF sites imparted a strong TPA-inducibility to the reporter. Similarly, EGF also required these motifs for the full induction of this gene. Using ChIP assays we show that, in contrast to c-Jun, SRF, Elk1, ATF1 and CREB proteins bind to SRE and ATF sites of the FRA-1 promoter, constitutively. RNAi-mediated knockdown of endogenous SRF, ELK1 and c-JUN protein expression significantly reduced TPA-stimulated FRA-1 promoter activity. Thus, a bipartite enhancer formed by an upstream TRE and the downstream SRE and ATF sites and the cognate factors is necessary and sufficient for the regulation of FRA-1 in response to mitogens.
 ...
PMID:Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements. 1580 62

c-Jun is a component of the transcription factor activator protein 1 (AP-1), which binds and activates transcription at TRE/AP-1 elements. Extra- or intracellular signals, including growth factors, transforming oncoproteins, and UV irradiation, stimulate phosphorylation of c-Jun at serine 63/73 and activate c-Jun-dependent transcription. Therefore, activated c-Jun potentially plays an important role in carcinogenesis and cancer progression. To evaluate expression patterns of activated c-Jun in breast cancer in relation to angiogenesis and proliferation, we performed immunohistochemistry on 103 cases of invasive breast cancer with an antibody recognizing phosphorylated c-Jun at serine 73. Activated c-Jun showed a predominantly nuclear expression at the invasive front in 38% of invasive breast cancer cases. Furthermore, expression of activated c-Jun was seen in mitotic cells of the invasive front in 50% of cases. Occasionally, fibroblasts, endothelial cells, and benign breast cells showed nuclear expression. Activated nuclear c-Jun expression showed positive correlations with expression of hyperphosphorylated pRb, vascular endothelial growth factor, and with microvessel density. Mitotic c-Jun expression was associated with pRb and microvessel density. Stromal c-Jun expression showed positive relations with microvessel density. In survival analysis, no significant relation was found with activated c-Jun expression and survival, although a trend with poor survival was found for mitotic cells overexpressing activated c-Jun (P = .09). Our results show that activated c-Jun is predominantly expressed at the invasive front in breast cancer and is associated with proliferation and angiogenesis. Earlier studies have established a functional, in vitro link between activated c-Jun and tumor angiogenesis. Our present results in breast cancer patients confirm this relation in vivo for the first time. Therefore, c-Jun/AP-1 targeting may provide new ways to block tumor angiogenesis.
 ...
PMID:c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer. 1673 6

The glycosylphosphatidylinositol-anchored molecule C4.4A, which shares structural features with uPAR, is frequently expressed on carcinomas with upregulated expression during tumor progression. Moreover, rare expression on nontransformed epithelial cells is strongly increased during tissue remodeling, e.g., during wound healing. This strictly regulated expression prompted us to define transcriptional activation of the C4.4A gene. C4.4A transcription was analyzed in 2 syngenic rat tumor cell lines with low or high metastatic potential, respectively. Though genomic C4.4A DNA was present in both lines, C4.4A mRNA and transcription of a reporter construct containing the C4.4A promoter was only observed in the metastasizing subline. Deletions and point mutations in the C4.4A promoter-driven reporter construct revealed that activation of the TATA-less, GC-rich core promoter (-1 to -50 bp) does not suffice to initiate transcription that requires coactivation of a proximal response element (-71 to -88 bp) and can be further increased by more distal response elements (-89 to -133 bp). Mobility-shift and cotransfection studies showed that Sp3 binding enhances C4.4A transcription, whereas potential Sp1 binding sites were ineffective. C4.4A transcription essentially requires C/EBPbeta binding to a TRE/CCAAT composite element (-71 to -88 bp) as measured by ChIP assay. C4.4A transcription is strikingly enhanced by cotransfection with JunD or c-Jun, such that C4.4A is most strongly transcribed even in the C4.4A-negative tumor cell line after cotransfection with C/EBPbeta plus JunD or c-Jun. Thus, upregulation of C/EBPbeta during tumor progression and wound repair may well provide a sufficient trigger for transcription of the C4.4A gene.
 ...
PMID:CEBPbeta, JunD and c-Jun contribute to the transcriptional activation of the metastasis-associated C4.4A gene. 1727 3


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