Gene/Protein Disease Symptom Drug Enzyme Compound
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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

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

Although the p38 mitogen-activated protein kinase (MAPK) has been implicated in signal transduction events, its role in regulating the Mr 92,000 type IV collagenase matrix metalloprotease-9 (MMP-9) and in vitro invasiveness in cancer has not yet been determined. We made the surprising observation that, in a human squamous cell carcinoma cell line (UM-SCC-1), phorbol ester-enhanced MMP-9 secretion and in vitro invasiveness were associated with a strong activation of the p38 MAPK and its downstream target, MAPK-activated protein kinase-2. To determine the role of p38 activation in these events, we investigated the effect of SB 203580, a novel specific p38 inhibitor, on protease expression and in vitro invasion of these cells. We found that inhibition of p38 by SB 203580 resulted in the almost complete reduction of phorbol myristate acetate-induced MMP-9 secretion but not of urokinase-type plasminogen activator secretion. In contrast, the activation of a transiently transfected wild-type MMP-9 promoter by MEKK-1, a specific c-Jun NH2-terminal kinase activator, was only marginally inhibited by the compound, arguing for the specificity of SB 203580. Moreover, phorbol myristate acetate-enhanced in vitro invasion was completely blocked by SB 203580, whereas p38 inhibition had little effect on growth. These findings suggest that activation of p38 may contribute to a more invasive phenotype in vitro, possibly via the expression of MMP-9, and that targeting of p38 using SB 203580 may provide a novel means of controlling invasion of cancers in which this MAPK is activated.
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PMID:Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. 951 96

The c-jun gene is a major regulator of proliferative and stress responses of both normal and transformed cells. In general, during immortalization/transformation c-jun cooperates with oncogenic signals rather than acting as an oncogene itself. Here we report a novel example of this cooperation, the requirement for c-jun to sustain expression of the matrix metalloproteinase-2 (MMP-2) gene in cells immortalized by SV40 large T-antigen (TAg). MMP-2 encodes a type IV collagenase that is secreted by cells within normal and tumor microenvironments. We used wild-type and c-jun null primary and TAg-immortalized mouse embryonic fibroblasts (mEFs) to investigate the importance of c-jun for the regulation of this activity, and observed that c-jun is essential for MMP-2 expression in immortalized but not primary mEFs. This finding directly demonstrates a cooperative interaction of c-jun with an oncogene, and suggests that TAg dependent immortalization/transformation may require other c-Jun/AP-1-dependent genes.
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PMID:c-jun cooperates with SV40 T-antigen to sustain MMP-2 expression in immortalized cells. 1141 1

Calcium antagonists (CAs) are widely prescribed for patients with cardiovascular diseases. CAs have been reported to inhibit smooth muscle cell (SMC) proliferation in addition to their effects on vascular tone. To determine whether CAs potentially affect vascular remodeling, we measured the expression of matrix-degrading enzymes in growth factor-stimulated SMC. Human cultured SMC were stimulated with 10 ng/ml of platelet-derived growth factor (PDGF)-BB with or without a calcium antagonist, diltiazem. In the cell counting assay, diltiazem (10-5 M) alone had no effect on the proliferation of quiescent SMC, however 10-6-10-5 M of diltiazem dose-dependently inhibited PDGF-stimulated SMC proliferation. The inhibitory effects of diltiazem on SMC proliferation were further confirmed by a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and flow cytometry. In Western blotting, matrix metalloproteinase (MMP)-1 (tissue collagenase) but not MMP-2 (72-kDa gelatinase) expression was upregulated by PDGF and phorbol ester (TPA), which were reduced by diltiazem in a dose-dependent manner. The downregulation of MMP-1 expression was consistent with the reduction of collagenolytic activity measured by a FITC-conjugated type I collagen breakdown assay. PDGF-stimulated c-Jun/AP-1 expression, a major transcriptional factor for MMP-1, was not affected by diltiazem. In contrast, intracellular calcium ions measured with a fluorometric assay of Fluo-3AM-loaded cells revealed that the PDGF-stimulated increase in the intracellular calcium content was dose-dependently reduced by diltiazem. Our data suggest that diltiazem inhibits not only proliferation but also MMP-1 expression and collagenolytic activity in PDGF-stimulated SMC. The administration of CAs potentially influences the process of vascular remodeling, and this possibility should be further verified in vivo.
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PMID:Diltiazem, a calcium antagonist, inhibits matrix metalloproteinase-1 (tissue collagenase) production and collagenolytic activity in human vascular smooth muscle cells. 1160 28

The invasive phenotype of cancers critically depends on the expression of proteases such as the M(R) 92,000 type IV collagenase (MMP-9). Several growth factors and oncogenes were found to increase promoter activity and as a consequence protease expression. This frequently requires the activation of the transcription factor AP-1 by signal transduction cascades such as the ERK and JNK pathways. We have previously demonstrated that the tumor promoter TPA can induce MMP-9 expression via a third signaling cascade, the p38 pathway. Considering that TPA is a potent activator of AP-1, we hypothesized that this transcription factor might also be required for p38 pathway-dependent MMP-9 regulation. While dominant negative p38 and MKK-6 mutants reduced MMP-9 promoter activity in CAT assays, a construct encoding an activating mutation in the MKK-6 protein potently stimulated it. This was mediated via 144 bp of the 5'flanking region of the wild-type promoter, which contains an AP-1 site at -79. Both point mutations in this motif and the expression of a c-jun protein lacking its transactivation domain and therefore acting as a dominant negative AP-1 mutant abrogated MKK-6-dependent promoter stimulation. Finally SB 203580, a specific p38 pathway inhibitor, reduced MMP-9 expression/secretion and in vitro invasion of cancer cells. Thus, our results provide evidence that also the third SAPK/MAPK signaling cascade, the p38 signal transduction pathway, stimulates MMP-9 expression in an AP-1-dependent fashion.
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PMID:The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. 1171 47

Ras expression has been suggested as a marker for tumor aggressiveness of breast cancer,including the degrees of invasion and tumor recurrence.We showed previously that H-ras, but not N-ras, up-regulates matrix metalloproteinase 2 expression and induces invasive phenotype in MCF10A human breast epithelial cells (A. Moon, et al. Int. J. Cancer, 85: 176-181, 2000). In this study, we show that H-ras also promotes cell motility more effectively than N-ras in MCF10A cells. We have investigated H-ras-specific signaling pathway(s) critical for H-ras-mediated cell motility and invasive phenotype. Whereas neither H-ras nor N-ras activated c-Jun NH(2)-terminal kinase 1, both H-ras and N-ras effectively activated extracellular signal-regulated protein kinase (ERK) -1,2. Importantly, prominent activation of p38 mitogen-activated protein kinase was shown only in H-ras-activated cells but not in N-ras-activated MCF10A cells. Functional significance of H-ras-activated p38 in invasiveness and cell motility was evidenced by studies using SB203580, a chemical inhibitor of p38, and a dominant-negative construct of p38. Whereas inhibition of c-Jun NH(2)-terminal kinase 1 activity had no effect on H-ras-induced MCF10A cell invasion and motility, the inhibition of the ERK pathway using a chemical inhibitor PD98059 or dominant-negative mutant of mitogen-activated protein/ERK kinase 1, an activator of ERKs, significantly reduced H-ras-induced invasion and migration. We also provide evidence that p38 and, to a lesser degree, ERKs, are critical for H-ras-mediated up-regulation of matrix metalloproteinase 2. Taken together, the present study shows that H-ras activation of both p38 and ERKs induces cell invasion and motility, whereas N-ras activation of ERKs alone is not sufficient. This study reveals the p38 kinase as a key signaling molecule differentially regulated by H-ras and N-ras, leading to H-ras-specific cell invasive and migrative phenotypes in human breast epithelial cells.
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PMID:p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. 1450 Mar 81

In this study, we examined the expression and functions of related to testes-specific, vespid, and pathogenesis protein 1 (RTVP-1) in glioma cells. RTVP-1 was expressed in high levels in glioblastomas, whereas its expression in low-grade astrocytomas and normal brains was very low. Transfection of glioma cells with small interfering RNAs targeting RTVP-1 decreased cell proliferation in all the cell lines examined and induced cell apoptosis in some of them. Overexpression of RTVP-1 increased astrocyte and glioma cell proliferation and the anchorage-independent growth of the cells. In addition, overexpression of RTVP-1 rendered glioma cells more resistant to the apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand and serum deprivation. To delineate the molecular mechanisms involved in the survival effects of RTVP-1, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that overexpression of RTVP-1 decreased the phosphorylation of c-Jun-NH2-kinase and increased the expression of Bcl2 and that the protective effect of RTVP-1 was partially mediated by Bcl2. Finally, we found that RTVP-1 regulated the invasion of glioma cells as was evident by their enhanced migration through Matrigel and by their increased invasion in a spheroid confrontation assay. The increased invasive potential of the RTVP-1 overexpressors was also shown by the increased activity of matrix metalloproteinase 2 in these cells. Our results suggest that the expression of RTVP-1 is correlated with the degree of malignancy of astrocytic tumors and that RTVP-1 is involved in the regulation of the growth, survival, and invasion of glioma cells. Collectively, these findings suggest that RTVP-1 is a potential therapeutic target in gliomas.
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PMID:Related to testes-specific, vespid, and pathogenesis protein-1 (RTVP-1) is overexpressed in gliomas and regulates the growth, survival, and invasion of glioma cells. 1661 35


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