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 necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms.
 ...
PMID:Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. 919 36

Biosynthesis of tumor necrosis factor-alpha (TNF-alpha) is predominantly by cells of the monocytic lineage. This study examined the role of various cis-acting regulatory elements in the lipopolysaccharide (LPS) induction of the human TNF-alpha promoter in cells of monocytic lineage. Functional analysis of monocytic THP-1 cells transfected with plasmids containing various lengths of TNF-alpha promoter localized enhancer elements in a region (-182 to -37 base pairs (bp)) that were required for optimal transcription of the TNF-alpha gene in response to LPS. Two regions were identified: region I (-182 to -162 bp) contained an overlapping Sp1/Egr-1 site, and region II (-119 to -88) contained CRE and NF-kappaB (designated kappaB3) sites. In unstimulated THP-1, CRE-binding protein and, to a lesser extent, c-Jun complexes were found to bind to the CRE site. LPS stimulation increased the binding of c-Jun-containing complexes. In addition, LPS stimulation induced the binding of cognate nuclear factors to the Egr-1 and kappaB3 sites, which were identified as Egr-1 and p50/p65, respectively. The CRE and kappaB3 sites in region II together conferred strong LPS responsiveness to a heterologous promoter, whereas individually they failed to provide transcriptional activation. Furthermore, increasing the spacing between the CRE and the kappaB3 sites completely abolished LPS induction, suggesting a cooperative interaction between c-Jun complexes and p50/p65. These studies indicate that maximal LPS induction of the TNF-alpha promoter is mediated by concerted participation of at least two separate cis-acting regulatory elements.
 ...
PMID:Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors. 921 33

It is currently debated whether AP1 or Sp1 is the factor that mediates transforming growth factor beta1 (TGF-beta) stimulation of the human alpha2(I) collagen (COL1A2) gene by binding to an upstream promoter element (TbRE). The present study was designed to resolve this controversy by correlating expression of COL1A2, AP1, and Sp1 in the same cell line and under different experimental conditions. The results strongly indicate that Sp1 is required for the immediate early response of COL1A2 to TGF-beta and AP1 is not. The Sp1 inhibitor mithramycin blocked stimulation of alpha2(I) collagen mRNA accumulation by TGF-beta, whereas the AP1 inhibitor curcumin had no effect. Furthermore, antibodies against Jun-B and c-Jun failed to identify immunologically related proteins in the TbRE-bound complex, irrespective of whether they were purified from untreated or TGF-beta-treated cells. AP1 did bind to the TbRE probe in vitro, but only in the absence of the upstream Sp1 recognition sequence. Based on this finding and DNA transfection results, we conclude that the AP1 sequence of the TbRE represents a cryptic site used under experimental conditions that either eliminate the more favorable Sp1 binding site or force the balance toward the less probable. Finally, a combination of cell transfections and DNA-binding assays excluded that COL1A2 transactivation involves the retinoblastoma gene product (pRb), an activator of Sp1, the pRb-related protein p107, an inhibitor of Sp1, or the Sp1-related repressor, Sp3.
 ...
PMID:Sp1 is required for the early response of alpha2(I) collagen to transforming growth factor-beta1. 924 31

The leukocyte integrin genes CD11c and CD11b are expressed predominately in myelomonocytic cells. In previous experiments, the -70 to -65 and -121 to -103 regions of the CD11c promoter and the -66 to -59 region of the CD11b promoter were shown to be essential for Sp1-mediated activation of these genes. In vivo genomic footprinting had also revealed cell-specific binding of protein, presumably Sp1, to these regions. In this study, electrophoretic mobility shift analysis showed that the Sp1-related factor, Sp3, also binds at or near these same regions. Cotransfection of Sp3 along with CD11c promoter-luciferase constructs into Sp-deficient Drosophila Schneider 2 cells showed that Sp3 could activate the CD11c promoter. Deletion of both the -70 to -65 and -121 to -103 regions of the CD11c promoter resulted in the loss of activation by Sp3. Both sites showed activation by Sp3; however, the -70 to -65 region was more responsive to Sp3 than to Sp1. Similar transfection analysis of the -66 to -59 region of the CD11b promoter showed Sp3-dependent expression. Further, cotransfection analysis in Drosophila cells showed that Sp3, as was previously shown for Sp1, also synergizes with c-Jun to activate CD11c. Antisense experiments that knocked out endogenous Sp3 expression in the myelomocytic cell line, HL60, revealed that Sp3 participates in activation of the CD11c and CD11b promoters in vivo.
 ...
PMID:Sp3 mediates transcriptional activation of the leukocyte integrin genes CD11C and CD11B and cooperates with c-Jun to activate CD11C. 929 57

Electrical stimulation of contractions (pacing) of primary neonatal rat ventricular myocytes increases intracellular calcium and activates a hypertrophic growth program that includes expression of the cardiac-specific gene, atrial natriuretic factor (ANF). To investigate the mechanism whereby pacing increases ANF, pacing was tested for its ability to regulate mitogen-activated protein kinase family members, ANF promoter activity, and the trans-activation domain of the transcription factor, Sp1. Pacing and the calcium channel agonist BAYK 8644 activated c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated kinase. Pacing stimulated ANF-promoter activity approximately 10-fold. Furthermore, transfection with an expression vector for c-Jun, a substrate for JNK, also activated the ANF promoter, and the combination of pacing and c-Jun was synergystic, consistent with roles for JNK and c-Jun in calcium-activated ANF expression. Proximal serum response factor and Sp1 binding sites were required for the effects of pacing or c-Jun on the ANF promoter. Pacing and c-Jun activated a GAL4-Sp1 fusion protein by 3- and 12-fold, respectively, whereas the two stimuli together activated GAL4-Sp1 synergistically, similar to their effect on the ANF promoter. Transfection with an expression vector for c-Fos inhibited the effects of c-Jun, suggesting that c-Jun acts independently of AP-1. These results demonstrate an interaction between c-Jun and Sp1 and are consistent with a novel mechanism of calcium-mediated transcriptional activation involving the collaborative actions of JNK, c-Jun, serum response factor, and Sp1.
 ...
PMID:Collaborative roles for c-Jun N-terminal kinase, c-Jun, serum response factor, and Sp1 in calcium-regulated myocardial gene expression. 929 58

The small GTPase RhoB is immediate-early inducible by DNA damaging treatments and thus part of the early response of eukaryotic cells to genotoxic stress. To investigate the regulation of this cellular response, we isolated the gene for rhoB from a mouse genomic library. Sequence analysis of the rhoB gene showed that its coding region does not contain introns. The promoter region of rhoB harbors regulatory elements such as TATA, CAAT, and Sp1 boxes but not consensus sequences for AP-1, Elk-1, or c-Jun/ATF-2. The rhoB promoter was activated by UV irradiation, but not by 12-O-tetradecanoylphorbol-13-acetate treatment. rhoB promoter deletion constructs revealed a fragment of 0.17 kilobases in size which was sufficient in eliciting the UV response. This minimal promoter fragment contains TATA and CAAT boxes but no other known regulatory elements. Neither MEK inhibitor PD98059 nor p38 kinase inhibitor SB203580 blocked stimulation of rhoB by UVC (UV light, 254 nm) which indicates that ERK or p38 mitogen-activated protein (MAP) kinase are not involved in the UV induction of rhoB. Also, phosphatidylinositol 3-kinase inhibitor wortmannin, which blocks UV stimulation of both JNK and p38 MAP kinase, did not inhibit rhoB activation. Furthermore, activation of JNK by interleukin-1beta did not affect rhoB expression. These data indicate that JNK is not involved in the regulation of rhoB. Overexpression of wild-type Rac as well as the Rho guanine-dissociation inhibitor caused activation of rhoB. Wild-type RhoB inhibited both basal and UV-stimulated rhoB promoter activity, indicating a negative regulatory feedback by RhoB itself. The data provide evidence both for a signal transduction pathway independent of JNK, ERK, and p38 MAP kinase to be involved in the induction of rhoB by genotoxic stress, and furthermore, indicate autoregulation of rhoB.
 ...
PMID:rhoB encoding a UV-inducible Ras-related small GTP-binding protein is regulated by GTPases of the Rho family and independent of JNK, ERK, and p38 MAP kinase. 938 98

The response to environmental stimuli such as stress involves changes in gene transcription in both brain and pituitary, which in turn, facilitate adaptive phenotypic alterations favoring survival. In the present study we have examined the expression of the inducible immediate-early genes of the fos and jun families, and the activity of transcription factor AP-1 in the hypothalamus and anterior pituitary gland of rats, after a single restraint challenge. Restraint led to a rapid transient increase in c-fos but not c-jun expression in hypothalamus and pituitary. Changes in jun-B expression in hypothalamus were qualitatively similar to c-fos, though not statistically significant at 30 min. Furthermore, a single episode of restraint stress led to significant increases (50-100%) in nuclear AP-1 DNA binding activity in both hypothalamus and pituitary, while DNA binding of an unrelated transcription factor (Sp1) was unchanged. Associated with the stress-induced activation of pituitary AP-1 was a parallel three- to fourfold transcriptional stimulation of pituitary POMC gene expression. These data demonstrate that the rapidly inducible members of the fos and jun gene families contribute to increased activity of transcription factor AP-1 in both hypothalamus and pituitary following stress, and suggest that AP-1 may be a crucial factor involved in rapid transcriptional responses during stress.
 ...
PMID:Stress-induced stimulation of pituitary POMC gene expression is associated with activation of transcription factor AP-1 in hypothalamus and pituitary. 943 5

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is a viral oncogene whose expression is regulated by both viral and cellular factors. EBV nuclear antigen 2 (EBNA2) is a potent transactivator of LMP1 expression in human B cells, and several EBNA2 response elements have been identified in the promoter regulatory sequence (LRS). We have previously shown that an activating transcription factor/cyclic AMP response element (ATF/CRE) site in LRS is involved in EBNA2 responsiveness. We now establish the importance of the ATF/CRE element by mutational analysis and show that both EBNA2-dependent activation and EBNA2-independent activation of the promoter occur via this site but are mediated by separate sets of factors. An electrophoretic mobility shift assay (EMSA) with specific antibodies showed that the ATF-1, CREB-1, ATF-2 and c-Jun factors bind to the site as ATF-1/CREB-1 and ATF-2/c-Jun heterodimers whereas the Sp1 and Sp3 factors bind to an adjacent Sp site. Overexpression of ATF-1 and CREB-1 in the cells by expression vectors demonstrated that homodimeric as well as heterodimeric forms of the factors transactivate the LMP1 promoter in an EBNA2-independent manner. The homodimers of ATF-2 and c-Jun did not significantly stimulate promoter activity. In contrast, the ATF-2/c-Jun heterodimer had only a minor stimulatory effect in the absence of EBNA2 but induced a strong transactivation of the LMP1 promoter when coexpressed with this protein. Evidence for a direct interaction between the ATF-2/c-Jun heterodimeric complex and EBNA2 was obtained by EMSA and coimmunoprecipitation experiments. Thus, our results suggest that EBNA2-induced transactivation via the ATF/CRE site occurs through a direct contact between EBNA2 and an ATF-2/c-Jun heterodimer. EBNA2-independent promoter activation via this site, on the other hand, is mediated by a heterodimeric complex between the ATF-1 and CREB-1 factors.
 ...
PMID:An ATF/CRE element mediates both EBNA2-dependent and EBNA2-independent activation of the Epstein-Barr virus LMP1 gene promoter. 944 37

The alpha chain of the nascent polypeptide-associated complex (alpha-NAC) coactivator was shown to potentiate the activity of the homodimeric c-Jun activator, while transcription mediated by the c-Fos/c-Jun heterodimer was unaffected. The use of deletion mutants in pull-down assays revealed that alpha-NAC interacted with amino acids 1 to 89 of the c-Jun protein and that the coactivator could interact with both the unphosphorylated and the serine 73-phosphorylated form of c-Jun. N-terminal-deleted c-Jun protein failed to interact with alpha-NAC in mammalian two-hybrid assays, while mutant c-Jun proteins lacking the leucine zipper or the basic domain retained interaction with alpha-NAC in vivo. Kinetics studies with purified c-Jun homodimer and recombinant alpha-NAC proteins allowed determination of the mechanism of coactivation by alpha-NAC: the coactivator stabilized the AP-1 complex formed by the c-Jun homodimer on its DNA recognition sequence through an eightfold reduction in the dissociation constant (kd) of the complex. This effect of alpha-NAC was specific, because alpha-NAC could not stabilize the interactions of JunB or Sp1 with their cognate binding sites. Interestingly, the expression of alpha-NAC was first detected at 14.5 to 15 days postconception, concomitantly with the onset of ossification during embryogenesis. The alpha-NAC protein was specifically expressed in differentiated osteoblasts at the centers of ossification. Thus, the alpha-NAC gene product exhibits the properties of a developmentally regulated, bone-specific transcriptional coactivator.
 ...
PMID:Bone-specific expression of the alpha chain of the nascent polypeptide-associated complex, a coactivator potentiating c-Jun-mediated transcription. 948 46

Just previous to the onset of parturition, a number of genes such as the one that codes for connexin-43 (Cx43) gap junction protein are induced in the myometrium. We have shown previously that activation of protein kinase C in human myometrial cultured cells leads to an up-regulation of cx43 transcription through an activating protein-1 element in the 5'-flanking promoter. Analyses were now performed on extracts of term myometrial tissue to test for an association between the up-regulation of cx43 expression and the expression of transcription factors and steroid hormone receptors that might regulate cx43 expression at term. Immunoblot analyses were performed on extracts of term myometrial tissue from women receiving elective or indicated cesarean sections to test for an association between the up-regulation of cx43 expression and the up-regulation of expression of the transcription factors c-Jun, c-Fos, and Sp1, which have cognate binding elements in the cx43 5'-flanking promoter. Immunoblot analysis, immunohistochemistry, and receptor binding assays were also performed to analyze the levels of progesterone receptors (PR) and estrogen receptors (ER) in the same term myometrial tissue, and these were compared to the levels in nonpregnancy myometrial tissue. The levels of PR were consistently 2- to 3-fold higher in term myometrial tissue than in nonpregnancy values and did not fluctuate during the menstrual cycle as did ER levels. Surprisingly, in term myometrium, ER was barely detectable by immunoblot and had whole cell diffuse staining by immunohistochemistry. In addition, very low levels of estrogen binding were observed in the term myometrial tissue. Treatment of primary myometrial cultures containing ER with estrogen for 3 or 48 h did not result in up-regulation of c-Jun or c-Fos proteins or in trans-activation from the proximal cx43 promoter with the activating protein-1 element. In contrast, an activated form of c-Jun protein was 10- to 18-fold higher in term myometrial tissue that also had elevated cx43 expression compared to c-Jun levels in term myometrial tissue with low cx43 expression. Likewise, c-Fos and Sp1 levels were 2-4 fold higher in term myometrial tissue with elevated cx43 expression. Although c-Fos and Sp1 proteins could be detected by immunoblot in myometrial tissue from nonpregnant women, c-Jun and Cx43 proteins could not. In summary, these results suggest that up-regulation of human myometrial cx43 gene expression at term involves induction of primarily c-jun expression through a mechanism that does not directly involve myometrial ER or the loss of PR. Peptide hormones that activate protein kinase cascades, such as the protein kinase C cascade, may be important to signal the onset of labor in humans.
 ...
PMID:Elevated connexin-43 expression in term human myometrium correlates with elevated c-Jun expression and is independent of myometrial estrogen receptors. 954 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>