UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The complete structure of the human gene for 92-kDa type IV collagenase was determined. Two overlapping genomic clones spanning 26 kilobases (kb) of genomic DNA were shown to contain the entire 7.7-kb structural gene together with 15 and 3.5 kb of 5'-end and 3'-end flanking regions, respectively. The 92-kDa type IV collagenase gene contains 13 exons as does the 72-kDa type IV collagenase gene. All intron locations of the 92-kDa enzyme gene coincided with intron locations in the 72-kDa enzyme gene. Exons 5, 6, and 7 which were 174, 174, and 177 base pairs long, respectively, each encoded one complete internal repeat which resembles the collagen-binding domains of fibronectin. The sequence coding for a unique 48-residue segment in the 92-kDa type IV collagenase that has no counterpart in other metalloproteinases was not present in a separate exon, but was contained in exon 9 which also codes for sequences with homology to the other metalloproteinases. The initiation site for transcription was determined by primer extension analysis. Sequencing analysis of 599 base pairs of the 5'-end flanking region showed that the promoter does not have a TATA motif, but a TTAAA sequence at position -29 to -25. A CAAT motif was not observed but there was one GC box. Two putative 12-O-tetradecanoyl-phorbol-13-acetate (TPA) response elements, that might serve as binding sites for the transcription factor AP-1 and a consensus sequence of a transforming growth factor beta 1 (TGF-beta 1) inhibitory element were found in the promoter region. Gelatinase assay of enzyme secreted by cultured human fibrosarcoma cells (HT-1080) revealed only low levels of 92-kDa type IV collagenase activity, whereas considerable activity of the 72-kDa enzyme was present. Northern hybridization analysis confirmed these findings. Treatment of the HT-1080 cells with TPA resulted in induction of the secretion of 92-kDa type IV collagenase activity. This induction could not be significantly inhibited by concomitant incubation with TGF-beta 1. TPA and TGF-beta 1 did not markedly affect the activities of the 72-kDa enzyme. The activities of the secreted 92- and 72-kDa enzymes by HT-1080 cells correlated with the amounts of mRNA as estimated by Northern analyses.
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PMID:Complete structure of the human gene for 92-kDa type IV collagenase. Divergent regulation of expression for the 92- and 72-kilodalton enzyme genes in HT-1080 cells. 165 38

Hypoxia results in differential expression of specific genes in certain cell types. In endothelial cells, hypoxia activates several genes that are known to be inducible by transcription factor AP-1, including endothelin-1 and platelet-derived growth factor-B (PDGF-B). In this study we demonstrated that other AP-1-inducible genes are activated by hypoxia in these cells, including collagenase IV and c-jun, and sought to correlate the activation of genes by hypoxia with the activation of transcription factor AP-1. Depending upon the type of cell studied, hypoxic exposure resulted in the induction of AP-1 transcription factor DNA-binding activity with wide variations in levels of binding. The magnitude of activation of transcription factor AP-1 by hypoxia did not always strictly correlate with the level of induction of AP-1-inducible genes. This finding indicates a requirement for additional mechanisms of controlling transcription beyond the simple activation of AP-1 factor DNA-binding activity for the activation of AP-1-inducible genes during hypoxia. Hypoxia has been reported to lower the intracellular redox potential. The effect of redox state changes on AP-1 transcription factor activity and on the activation of AP-1-inducible genes was also studied. PDTC, a potent reducing agent, activated the AP-1 transcription factor in HeLa cells, and also resulted in increased accumulation of c-jun mRNA in these cells. In contrast to PDTC-mediated activation of the AP-1 transcription factor and the subsequent induction of the AP-1-regulated c-jun gene, hypoxic activation of AP-1 transcription factor binding to its cognate DNA sequence did not activate the c-jun gene in HeLa cells, thus documenting distinct differences in signals generated by the reducing intracellular microenvironments created by hypoxia and PDTC. These results demonstrate the induction of AP-1 transcription factor activity by hypoxic environments, but suggest that additional factors or cell-specific signals are involved in the regulation of hypoxia-induced genes.
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PMID:Hypoxia induces AP-1-regulated genes and AP-1 transcription factor binding in human endothelial and other cell types. 757 60

Theileria annulata infects bovine leucocytes and results in their reversible transformation such that they become immortalised and metastatic. The present study describes parasite-induced changes in host cell gene expression which have a direct bearing on this transformation process. T. annulata-infected leucocytes produce a number of novel metalloproteinase activities. One of these, previously called B1, is a 97-kDa protein which is secreted in large amounts and has been purified from protein-free, conditioned medium. An antiserum to this enzyme was used to isolate a cDNA clone. The predicted protein sequence of B1 is 81% identical to human matrix metalloproteinase 9 (MMP9), demonstrating that it is the bovine homologue of this enzyme. RNAase protection assays demonstrated that the MMP9 activity, unique to infected cells, is due to increased MMP9 mRNA levels. We also assayed the levels of transcription factor AP-1 and demonstrated that it was constitutively present in increased amounts in Theileria-infected cells. In addition we assayed the level of mRNA encoding c-Fos, a common component of AP-1 and observed that it was indeed up-regulated in infected cells. Since AP-1 is implicated in the control of the cell cycle, and MMP9 can confer metastatic properties, these results are of considerable significance with respect to the transformed phenotype induced by Theileria infection.
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PMID:Infection with Theileria annulata induces expression of matrix metalloproteinase 9 and transcription factor AP-1 in bovine leucocytes. 777 85

Moloney murine leukemia virus (Mo-MuLV) is a thymotropic and leukemogenic retrovirus which causes T lymphomas. The long terminal repeat (LTR) of Mo-MuLV affects the regulation of a number of cellular genes, including collagenase IV, monocyte chemoattractant protein-1, and c-jun genes, all of which contain 12-O-tetradecanoylphorbol-13-acetate-responsive element consensus sites within their promoters. We report here that Mo-MuLV stimulates the collagenase IV gene through transcription factor AP-1, and that the expression of a subgenomic portion of Mo-MuLV LTR alone is sufficient for this effect. Transient or stable expression of the viral LTR increases cellular AP-1 DNA binding activity. The collagenase IV 12-O-tetradecanoylphorbol-13-acetate-responsive element consensus sequence was shown to be required for this trans-activation. Deletions or mutations of this consensus site which abolished AP-1 binding also abolished trans-activation by the LTR. Transient or stable transfection of the viral LTR into cells stimulated c-jun gene expression, suggesting one mechanism whereby the viral LTR may induce cellular AP-1 activity. Thus, the Mo-MuLV LTR, through activation of the transcription factor AP-1, is capable of regulating cellular gene expression, including the induction of proto-oncogenes. This activity may be relevant to the mechanisms whereby retroviruses which do not contain oncogenes induce neoplasia.
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PMID:The Moloney leukemia retroviral long terminal repeat trans-activates AP-1-inducible genes and AP-1 transcription factor binding. 777 15

Proteolytic remodeling of the extracellular matrix occurs normally during development and pathologically in arthritis, tumor metastasis, wound healing, and angiogenesis. The major extracellular matrix-degrading proteinases belong to the matrix metalloproteinase (MMP) and plasminogen activator gene families. Intracerebral injection of 72-kDa type IV collagenase (gelatinase A) opens the blood-brain barrier. During hemorrhagic brain injury or intracerebral injection of proinflammatory cytokines, endogenous production of 92-kDa type IV collagenase (gelatinase B) occurs. The gelatinase B gene contains a phorbol ester responsive region (TRE) that binds AP-1 proteins, including c-Fos/c-Jun dimer, the early immediate response gene products. Maximum production of gelatinase B in injury occurs between 16 and 24 h, making this a late effector gene. The serine proteinase, urokinase-type plasminogen activator (uPA), is also produced at that time. Gelatinases and plasminogen activators work in concert to disrupt basement membranes proteolytically. A similar process opens the blood-brain barrier after ischemic and hemorrhagic brain injury, leading to secondary vasogenic brain edema. Delayed damage by proteolytic cascade enzymes provides opportunities for treatment much later than had been thought possible. Potential treatments possible in this second therapeutic window include interfering with the genes that produce the MMPs or inhibiting the action of the gene products.
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PMID:Matrix metalloproteinases in brain injury. 859 11

We have studied mechanisms controlling activation of the gelatinase B gene (matrix metalloproteinase-9) by fibroblast growth factor-2 (FGF-2) during angiogenesis, and the effects of the natural product curcuminoids on this process. Using a transgenic mouse (line 3445) harboring a gelatinase B promoter/lacZ fusion gene, we demonstrate FGF-2 stimulation of reporter gene expression in endothelial cells of invading neocapillaries in the corneal micropocket assay. Using cultured corneal cells, we show that FGF-2 stimulates DNA binding activity of transcription factor AP-1 but not NF-kappaB and that AP-1 stimulation is inhibited by curcuminoids. We further show that induction of gelatinase B transcriptional promoter activity in response to FGF-2 is dependent on AP-1 but not NF-kappaB response elements and that promoter activity is also inhibited by curcuminoids. In rabbit corneas, the angiogenic response induced by implantation of an FGF-2 pellet is inhibited by the co-implantation of a curcuminoid pellet, and this correlates with inhibition of endogenous gelatinase B expression induced by FGF-2. Angiostatic efficacy in the cornea is also observed when curcuminoids are provided to mice in the diet. Our findings provide evidence that curcuminoids target the FGF-2 angiogenic signaling pathway and inhibit expression of gelatinase B in the angiogenic process.
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PMID:Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B. 1074 29

Neutral matrix metalloproteinases (MMPs) play an important role in bone matrix degradation accompanied by bone remodeling. We herein show for the first time that macrophage migration inhibitory factor (MIF) up-regulates MMP-13 (collagenase-3) mRNA of rat calvaria-derived osteoblasts. The mRNA up-regulation was seen at 3 h in response to MIF (10 microg/ml), reached the maximum level at 6-12 h, and returned to the basal level at 36 h. MMP-13 mRNA up-regulation was preceded by up-regulation of c-jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1 and MMP-9 (92-kDa type IV collagenase) were also up-regulated, but to a lesser extent. The MMP-13 mRNA up-regulation was significantly suppressed by genistein, herbimycin A and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Similarly, a selective mitogen-activated protein kinase (MAPK) kinase (MEK)1/2 inhibitor (PD98059) and c-jun/activator protein (AP)-1 inhibitor (curcumin) suppressed MMP-13 mRNA up-regulation induced by MIF. The mRNA levels of c-jun and c-fos in response to MIF were also inhibited by PD98059. Consistent with these results, MIF stimulated phosphorylation of tyrosine, autophosphorylation of Src, activation of Ras, activation of extracellular signal-regulated kinases (ERK) 1/2, a MAPK, but not c-Jun N-terminal kinase or p38, and phosphorylation of c-Jun. Osteoblasts obtained from calvariae of newborn JunAA mice, defective in phosphorylation of c-Jun, or newborn c-Fos knockout (Fos -/- ) mice, showed much less induction of MMP-13 with the addition of MIF than osteoblasts obtained from wild-type or littermate control mice. Taken together, these results suggest that MIF increases the MMP-13 mRNA level of rat osteoblasts via the Src-related tyrosine kinase-, Ras-, ERK1/2-, and AP-1-dependent pathway.
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PMID:Macrophage migration inhibitory factor up-regulates matrix metalloproteinase-9 and -13 in rat osteoblasts. Relevance to intracellular signaling pathways. 1175 95

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.
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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

Epidemiologic studies have suggested an inverse correlation between dietary intake of cruciferous vegetables and cancer risk. It is thus of interest to investigate the anticancer potential of phytochemicals presented in cruciferous vegetables. In this study, methyl-3-indolylacetate (MIA), a cruciferous indole for which the bioactivity has not been previously reported, was found to significantly suppress the invasion of cancer cells stimulated by the 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Our data show that MIA pretreatments inhibited matrix metalloproteinase 9 (MMP-9) expression in a concentration-dependent manner, resulting in decreased MMP-9 activity. By using real-time reverse transcription-PCR, luciferase reporter gene assay, and electrophoretic mobility shift assay, we provided convincing evidence that MIA suppresses MMP-9 gene transcription via targeting the activator protein-1 signaling but not the nuclear factor-kappaB pathway. The TPA-induced mitogen-activated protein kinase (MAPK) activation cascade was also analyzed. Despite extensive activation of major MAPKs [c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase-1/2 (ERK1/2)] under TPA stimulation, only the ERK1/2 activation and its consequent nuclear translocation were found to be diminished by MIA. Interestingly, MIA did not affect the TPA-induced phosphorylation of either c-Raf or MAPK/ERK kinase-1/2 (MEK1/2), two upstream kinases of ERK. Moreover, using the in vitro kinase assay, MIA was shown to inhibit the kinase activity of MEK1/2, the upstream kinases of ERK, suggesting that MEK is the major molecular target of MIA. In conclusion, data from this study provided new insight into the anticancer potential of MIA, a cruciferous vegetable-derived indole compound.
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PMID:Methyl-3-indolylacetate inhibits cancer cell invasion by targeting the MEK1/2-ERK1/2 signaling pathway. 1717 32

Sporadic and familial colorectal tumours usually harbour biallelic adenomatous polyposis coli (APC)-associated mutations that result in constitutive activation of Wnt signalling. Furthermore, APC activates Asef and Asef2, which are guanine-nucleotide exchange factors specific for Rac1 and Cdc42. Here, we show that Asef and Asef2 expression is aberrantly enhanced in intestinal adenomas and tumours. We also show that deficiency of either Asef or Asef2 significantly reduces the number and size of adenomas in Apc(Min/+) mice, which are heterozygous for an APC mutation and spontaneously develop adenomas in the intestine. We observed that the APC-Asef/Asef2 complex induces c-Jun amino-terminal kinase-mediated transactivation of matrix metalloproteinase 9, and is required for the invasive activity of colorectal tumour cells. Furthermore, we show that Asef and Asef2 are required for tumour angiogenesis. These results suggest that Asef and Asef2 have a crucial role in intestinal adenoma formation and tumour progression, and might be promising molecular targets for the treatment of colorectal tumours.
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PMID:The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in Apc(Min/+)mice. 1989 77

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