Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dimerization plays a pivotal role in modulating the activity of the c-Jun proto-oncogene product. Heterodimerization with activating transcription factor-2 (ATF-2) alters the DNA-binding specificity of c-Jun, allowing its targeting to several cAMP responsive element (CRE)-related sequences, which control a subset of AP-1-responsive genes. Here we show that a c-Jun/ATF-2 heterodimer binds to the AP-1 site (uPA 5'-TRE) essential for the activity of the human urokinase enhancer, conferring on this element several distinctive regulatory properties. The c-Jun/ATF-2 heterodimer was identified by binding competition assays, u.v. cross linking, and monospecific antibodies. In vitro binding studies revealed that the uPA 5'-TRE sequence is recognized by the cyclic AMP-unresponsive ATF-2 factor, but not by the cyclic AMP-inducible CREB. In addition, in vivo studies suggest that ATF-2 can mediate, at the same time, the activation of the c-Jun/ATF-2 site and the repression of the canonical collagenase AP-1 site. We report that heterodimerization with c-Fos does not increase the binding of c-Jun to the uPA 5'-TRE, in contrast to the increased binding at a consensus AP-1 site. Our data further suggest that c-Fos can act as a repressor of the c-Jun/ATF-2 binding site, revealing an important functional difference, with respect to canonical AP-1 elements.
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PMID:Heterodimerization of c-Jun with ATF-2 and c-Fos is required for positive and negative regulation of the human urokinase enhancer. 762 51

Adenovirus E1A proteins inhibit expression of the collagenase gene but activate expression of the c-jun gene. Both effects are mediated by TPA-responsive elements (TREs), the binding sites for members of the AP-1 transcription factor family. By a process that is independent of the retinoblastoma gene product, E1A distinguishes between different AP-1 factors: in vivo binding of Jun/Jun homodimers and Jun/Fos heterodimers to the collagenase TRE is totally blocked by E1A while, in contrast, there is no inhibition of Jun/ATF-2 binding to the TRE sequences in the c-jun promoter. Altered phosphorylation of the DNA binding domain of cJun is not involved in the inhibition of cJun/cJun and cJun/cFos binding. E1A does, however, cause hyperphosphorylation of the transactivation domain of cJun, which is likely to be responsible for the enhanced c-jun transcription by E1A mediated through cJun/ATF-2 heterodimers.
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PMID:Adenovirus E1A negatively and positively modulates transcription of AP-1 dependent genes by dimer-specific regulation of the DNA binding and transactivation activities of Jun. 825 81

The adenovirus E1A proteins differentially regulate AP-1-responsive genes. Collagenase and stromelysin are repressed by E1A, whereas the expression of c-jun is elevated. Inhibition of collagenase has been found to be exerted through the consensus AP-1 binding site TGAGTCA. Here we show that the distal AP-1 binding site in the c-jun promoter, the jun2TRE (TTACCTCA), is the decisive element of this promoter in mediating the positive response to the 243 amino acid E1A product. In vitro binding studies revealed that, in contrast to the consensus AP-1 site which is preferentially targeted by dimers composed of the Jun and Fos families, the jun2TRE binds heterodimers composed of cJun and ATF-2(-like) proteins. Since stimulation of c-jun transcription is a function of the transforming domain of E1A encoded by conserved region 1, cJun--ATF-2 may be one of the effector factors involved in transformation. The data further suggest that E1A can distinguish between cJun--cJun and cJun--ATF-2 in imposing opposite states of activity.
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PMID:Heterodimer formation of cJun and ATF-2 is responsible for induction of c-jun by the 243 amino acid adenovirus E1A protein. 838 9

Several promoter elements with sequence similarity to the prototype TPA-responsive element (TRE) were compared by mobility-shift analyses. Activities within whole cell extracts were identified that bind to the TRE-like elements in the collagenase, the somatostatin, and the c-jun promoters. The corresponding factors appeared to differ in their degree of selectivity for these TRE-like sequences. One protein species bound equally well to all TREs. In addition, a subset of specific activities recognised only the somatostatin and the c-jun-derived element and one DNA-protein complex had exclusive specificity for the TRE present in the c-jun promoter. By antibody 'supershift' assays some of the protein components of the specific complexes were identified as CREB- and ATF-related products. Based on these data we postulate that bZip protein dimers differ in their ability to tolerate variations from the canonical TRE sequence. We propose that TRE-like promoter elements are distinguished by this ability to bind to different subsets of a family of related transcription factors.
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PMID:Different TRE-related elements are distinguished by sets of DNA-binding proteins with overlapping sequence specificity. 847 9

Adenovirus E1A proteins modulate the expression of a large variety of genes in transformed cells by either stimulating or repressing their promoters. For example, the E1A proteins inhibit the collagenase promoter, whereas they activate the c-jun promoter. Both effects are mediated through AP-1/ATF-binding sites. Repression of transcription of the collagenase gene requires the amino-terminus and conserved region 1 (CR1) of Ad5 E1A, two regions that are also crucial for interaction of E1A with the recently isolated transcriptional adaptor protein p300. We show here that overexpressed p300 can counteract the repressive effect of E1A on the collagenase promoter. Using the CREB-binding protein (CBP), which is highly homologous to p300, the same results were obtained. The domains in E1A required for binding to p300 are also essential for E1A-mediated cell transformation. We therefore tested the effect of p300 and CBP on the transforming potential of Ad5 E1 in baby rat kidney (BRK) cells. It was found that E1A-induced focus formation was strongly inhibited by overexpression of p300 or CBP. Moreover the BRK cell colonies, obtained after cotransfection with Ad5E1 and p300, could not be established. These results indicate that one of the mechanisms by which E1A modulates transcription and transforms cells is via transcriptional adaptors like p300 and CBP.
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PMID:The adenovirus E1A-associated 300 kDa adaptor protein counteracts the inhibition of the collagenase promoter by E1A and represses transformation. 862 69

Activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases is an early response of cells upon exposure to DNA-damaging agents. JNK-mediated phosphorylation of c-Jun is currently understood to stimulate the transactivating potency of AP-1 (e.g., c-Jun/c-Fos; c-Jun/ATF-2), thereby increasing the expression of AP-1 target genes. Here we show that stimulation of JNK1 activity is not a general early response of cells exposed to genotoxic agents. Treatment of NIH 3T3 cells with UV light (UV-C) as well as with methyl methanesulfonate (MMS) caused activation of JNK1 and an increase in c-Jun protein and AP-1 binding activity, whereas antineoplastic drugs such as mafosfamide, mitomycin C, N-hydroxyethyl-N-chloroethylnitrosourea, and treosulfan did not elicit this response. The phosphatidylinositol 3-kinase inhibitor wortmannin specifically blocked the UV-stimulated activation of JNK1 but did not affect UV-driven activation of extracellular regulated kinase 2 (ERK2). To investigate the significance of JNK1 for transactivation of c-jun, we analyzed the effect of UV irradiation on c-jun expression under conditions of wortmannin-mediated inhibition of UV-induced stimulation of JNK1. Neither the UV-induced increase in c-jun mRNA, c-Jun protein, and AP-1 binding nor the activation of the collagenase and c-jun promoters was affected by wortmannin. In contrast, the mitogen-activated protein kinase/ERK kinase inhibitor PD98056, which blocked ERK2 but not JNK1 activation by UV irradiation, impaired UV-driven c-Jun protein induction and AP-1 binding. Based on the data, we suggest that JNK1 stimulation is not essential for transactivation of c-jun after UV exposure, whereas activation of ERK2 is required for UV-induced signaling leading to elevated c-jun expression.
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PMID:Activation of c-Jun N-terminal kinase 1 by UV irradiation is inhibited by wortmannin without affecting c-iun expression. 1002 64

Although the AP-1 transcription factor is known to play a role in cell proliferation and activation, it is also involved in apoptosis of cells in response to stress, DNA-damaging agents, or lack of survival signals. To understand how AP-1 might contribute to distinct biological processes, we tested a hypothesis that changes in AP-1 composition or phosphorylation state modulate its transcriptional activity during cyclosporin A-induced apoptosis of glioma cells. The induction of AP-1 DNA binding activity composed of c-Jun, JunB, JunD, and ATF-2 proteins preceded apoptosis. The compositional changes of AP-1 were associated with an elevation of c-Jun and JunB protein levels and the appearance of phosphorylated c-Jun and ATF-2 at 15-40 h posttreatment. Immunocytochemistry and staining with Hoechst 33258 revealed an accumulation of phosphorylated c-Jun protein in apoptotic cells. Because c-Jun expression and transcriptional activity are stimulated by phosphorylation at Ser63/73 by c-Jun N-terminal kinase (JNK), we measured JNK activities. We found prolonged induction of JNK activity in extracts from cyclosporin-treated cells, which suggests an involvement of persistent JNK activation in the initiation of glioma cell apoptosis. We provided evidence that variations in AP-1 composition and phosphorylation resulted in modification of trans-activating potential toward different promoters. Whereas collagenase AP-1/TRE-dependent transcription was down-regulated during apoptosis, Fas ligand promoter became activated.
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PMID:Changes of the trans-activating potential of AP-1 transcription factor during cyclosporin A-induced apoptosis of glioma cells are mediated by phosphorylation and alterations of AP-1 composition. 1061 4

Retinoic acid (RA) causes differentiation of mouse F9 embryonic carcinoma cell line into primitive and parietal (with dibutiril-cAMP) endoderm. The role of AP-1 transcription factor during RA-induced differentiation was studied in F9 cell line. It was shown that differentiated cells acquired protein complexes, which are specifically bound to well characterized AP-1 32P-labeled binding sites from collagenase (Col-AP-1) and c-jun (Jun2-AP-1) promoters. These complexes contain c-Fos/c-Jun with Col-AP-1 site and c-Jun/ATF-2 with Jun2-AP-1 site as revealed by supershift analysis. DNA-binding activity of these complexes is high in parietal endoderm but low-detectable in undifferentiated cells. DNA-binding activity of AP-1 transcription factor correlates with increased expression of c-fos and c-jun genes. RT-PCR analysis showed an increase in steady-state level of c-fos and c-jun gene transcription at the stage of parietal endoderm (terminally differentiated F9 cells). Transcription of immediate early c-fos and c-jun genes and DNA-binding activity of c-Fos/c-Jun complex are serum dependent. The rate of c-fos and c-jun gene transcription and DNA-binding activity of c-Fos/c-Jun complex decreased in serum-starved cells, but was rapidly induced upon stimulation with serum. Undifferentiated F9 cells contain a very low level of c-fos mRNA, with may be a consequence of repressive chromatin structure in promoter region. Histone deacetylase (HDAC) activity is necessary to restrict expression of specific number of genes, also HDAC inhibitors are well known inductors of differentiation and anticancer agents. Frow cytometry analysis showed a decreased rate of proliferation of F9 cells after their incubation with HDAC inhibitors, sodium butirate and trichostatin A. Also, these ihibitors induced the transcription of c-fos gene. So, we conclude that HDAC activity may be necessary to sustain a high proliferative rate of undifferentiated F9 cells.
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PMID:[Transcription of c-fos gene and DNA binding activity of transcription factor AP-1 increase upon differentiation of mouse F9 teratocarcinoma cells]. 1574 38

Matrix metalloproteinases (MMPs) are induced during inflammatory responses and are important for immune regulation, angiogenesis, wound healing, and tissue remodeling. Expression of MMPs needs to be tightly controlled to avoid excessive tissue damage. In this study, we investigated the regulation of MMP expression by inflammatory factors in primary human monocytes and macrophages. IFN-gamma, which augments inflammatory cytokine production in response to macrophage-activating factors such as TLR ligands, instead broadly suppressed TLR-induced MMP expression. Inhibition of MMP expression was dependent on STAT1 and required de novo protein synthesis. IFN-gamma strongly enhanced TLR-induced expression of the transcriptional repressor activating transcription factor (ATF-3) in a STAT1-dependent manner, which correlated with recruitment of ATF-3 to the endogenous MMP-1 promoter as detected by chromatin immunoprecipitation assays. RNA interference experiments further supported a role for ATF-3 in suppression of MMP-1 expression. In addition, IFN-gamma suppressed DNA binding by AP-1 transcription factors that are known to promote MMP expression and a combination of supershift, RNA interference and overexpression experiments implicated AP-1 family member Fra-1 in the regulation of MMP-1 expression. These results define an IFN-gamma-mediated homeostatic loop that limits the potential for tissue damage associated with inflammation, and identify transcriptional factors that regulate MMP expression in myeloid cells in inflammatory settings.
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PMID:Lipopolysaccharide-induced expression of matrix metalloproteinases in human monocytes is suppressed by IFN-gamma via superinduction of ATF-3 and suppression of AP-1. 1880 13

Elevated matrix metalloproteinase-1 (MMP-1) expression is known to correlate with poor prognosis of pancreatic cancer. We investigated the molecular mechanisms of constitutive expression of MMP-1 in pancreatic cancer cell lines. Expression of MMP-1 mRNA and protein as well as its enzymatic activity were observed in three pancreatic cancer cell lines. Transient transfection assays of two MMP-1 promoter/luciferase constructs (full-length 4.4-kb or proximal 0.6-kb region) showed high levels of transcription in pancreatic cancer cells compared with non-MMP-1 producing cells. The 0.6-kb promoter region of MMP-1 gene contained three activator protein-1 (AP-1) sites and the strong AP-1 activity was detected by electrophoretic mobility shift assays (EMSAs). In these cells, production and phosphorylation of c-Jun were commonly observed. Phosphorylated c-Jun NH2-terminal kinase (p-JNK) and activator transcription factor-2 (p-ATF-2) were also detected in two of the three cell lines. Phosphorylated extracellular signal-regulated kinase (p-ERK) was observed in one. The promoter activity, AP-1-binding activity and MMP-1 production were suppressed by a specific inhibitor of JNK or MEK. K-ras mutation, reported to be present in three cell lines used, is known to activate JNK and ERK pathways. Considering the facts together, our results revealed that activation of JNK/AP-1 or ERK/AP-1 pathway plays crucial roles in constitutive transactivation of MMP-1 in these cancer cells. This study contributes to provide new insights into strategies for inhibiting tumor cell invasion in pancreatic cancer.
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PMID:Activation of two distinct MAPK pathways governs constitutive expression of matrix metalloproteinase-1 in human pancreatic cancer cell lines. 1988 45


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