Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation or suppression of intracellular signaling via the mitogen-activated protein kinase (MAPK) family has been linked to expression of matrix metalloproteinases (MMP) in experimental models, but this association has not been demonstrated in clinical material. The objective of this study was to investigate the possible association between expression and activity of MMP, expression of the MMP inducer EMMPRIN, and the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK) and high osmolarity glycerol response kinase (p38) in effusions from patients diagnosed with serous ovarian carcinoma. MAPK level and activity were studied in 55 effusions using immunoblotting. MMP-1, MMP-2, MMP-9 and EMMPRIN expression was studied using immunocytochemistry (ICC) and mRNA in situ hybridization (ISH). The gelatinolytic activity of MMP-2 and MMP-9 was measured by zymography. ERK and phospho-ERK (p-ERK) were detected in 54/55 (98%) and 50/55 (91%) specimens, respectively. JNK and p-JNK were detected in 53/55 (96%) and 38/55 (69%) specimens, respectively. p38 was expressed in 54/55 (98%) specimens, and its phosphorylated form was found in 51/55 (92%). MMP-2 mRNA expression (P = 0.048), protein expression (P = 0.046) and gelatinolytic activity (P = 0.039) correlated with ERK phosphorylative activity. MMP-2 activity also correlated with p38 activity (P = 0.017). MMP-9 protein expression correlated with phosphorylation of p38 (P = 0.046), but enzyme activity showed inverse relationship with both p-ERK (P = 0.05) and p-p38 (P = 0.033) expression. EMMPRIN expression correlated with MMP-1 (P < 0.001), MMP-2 (P = 0.042) and MMP-9 (P = 0.029) expression, as well as with ERK activity (P = 0.001). Our results present the first evidence of a possible link between MAPK signaling and MMP expression and activity in vivo. These data may expand our understanding regarding the mechanisms by which MMP synthesis is regulated in effusions and possibly affect treatment strategies for this form of malignancy.
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PMID:Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): co-expression in metastatic serous ovarian carcinoma. 1466 93

The pro-inflammatory cytokine interleukin-1beta (IL-1) induces articular chondrocytes to produce reactive oxygen species (ROS), including hydrogen peroxide (H2O2), which mediate some IL-1-induced responses. This study aimed at elucidating the role of ROS, particularly H2O2, in mediating IL-1-induced activation of the transcription factor activator protein-1 (AP-1) in primary cultures of articular chondrocytes. AP-1 may function either as an inducer or as a repressor of the inducible nitric oxide synthase (iNOS) gene promoter. Since we observed that AP-1 is not required for iNOS expression in chondrocytes, we also investigated whether it is a repressor of this gene. The results of electrophoretic mobility shift assays showed that both IL-1 and H2O2 activated AP-1 and that inhibition of IL-1-induced ROS production abrogated AP-1 activation. The AP-1 complexes, induced by either IL-1 or H2O2, contained c-Fos/c-Jun and c-Fos/JunD heterodimers, but IL-1 activated AP-1 with a kinetics slower than that observed with H2O2. Pre-activation of AP-1, before stimulation of the cells with IL-1, did not inhibit iNOS mRNA and protein synthesis, relative to cells treated with IL-1 alone. These results indicate that H2O2 is a major mediator of IL-1-induced AP-1 activation in articular chondrocytes and that inhibition of ROS production is an effective strategy to block this IL-1-induced response. This study also identifies c-Fos/c-Jun and c-Fos/JunD heterodimers as the AP-1 transcription factors induced by IL-1, which, although not involved in the transcriptional regulation of the iNOS gene, may be important for the regulation of other genes also relevant in arthritic diseases, namely the collagenase-1 and IL-8 genes.
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PMID:Hydrogen peroxide mediates interleukin-1beta-induced AP-1 activation in articular chondrocytes: implications for the regulation of iNOS expression. 1468 13

With the advancing widespread use of photodynamic therapy, questions have arisen about the necessity to protect the adjacent healthy skin from high-dose long-wave light. The aim of the present study was to investigate the effects of high dose visible light on the skin of healthy volunteers with focus on apoptosis, DNA damage, inflammation, melanogenesis and induction of matrix metalloproteinases (MMP). Fourteen healthy volunteers were included and irradiated daily on their buttocks with 1300 kJ/m2 long wave visible light (560-780 nm) on five consecutive days with a cumulative dose of 6500 kJ/m2. In each volunteer six biopsies were taken before and 24 h after irradiation on days 1, 2, 3 and 5 and on day 8 and 12. Frozen and paraffin sections were investigated by measuring parameters for photodamage (apoptosis, p53, phosphorylated c-Jun), skin ageing (phosphorylated c-Jun, MMP-1, elastin content) melanogenesis (Melan A). Although no sunburn cells were seen, a significant increase in perinuclear vacuolization was noted (P < 0.0003) from day 5 till 7 days after the last irradiation. There was no expression of phosphorylated c-Jun, whereas the expression of p53, Melan A, MMP-1 and elastin content did not change. High-dose visible light induces a significant increase in perinuclear vacuolization, but does not result in apoptosis, photodamage or early induction of skin ageing.
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PMID:High-dose long wave visible light induces perinuclear vacuolization in vivo but does not result in early photoageing and apoptosis. 1470 1

The mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK) is a critical regulator of collagenase-1 production in rheumatoid arthritis (RA). The MAPKs are regulated by upstream kinases, including MAPK kinases (MAPKKs) and MAPK kinase kinases (MAP3Ks). The present study was designed to evaluate the expression and regulation of the JNK pathway by MAP3K in arthritis. RT-PCR studies of MAP3K gene expression in RA and osteoarthritis synovial tissue demonstrated mitogen-activated protein kinase/ERK kinase kinase (MEKK) 1, MEKK2, apoptosis-signal regulating kinase-1, TGF-beta activated kinase 1 (TAK1) gene expression while only trace amounts of MEKK3, MEKK4, and MLK3 mRNA were detected. Western blot analysis demonstrated immunoreactive MEKK2, TAK1, and trace amounts of MEKK3 but not MEKK1 or apoptosis-signal regulating kinase-1. Analysis of MAP3K mRNA in cultured fibroblast-like synoviocytes (FLS) showed that all of the MAP3Ks examined were expressed. Western blot analysis of FLS demonstrated that MEKK1, MEKK2, and TAK1 were readily detectable and were subsequently the focus of functional studies. In vitro kinase assays using MEKK2 immunoprecipitates demonstrated that IL-1 increased MEKK2-mediated phosphorylation of the key MAPKKs that activate JNK (MAPK kinase (MKK)4 and MKK7). Furthermore, MEKK2 immunoprecipitates activated c-Jun in an IL-1 dependent manner and this activity was inhibited by the selective JNK inhibitor SP600125. Of interest, MEKK1 immunoprecipitates from IL-1-stimulated FLS appeared to activate c-Jun through the JNK pathway and TAK1 activation of c-Jun was dependent on JNK, ERK, and p38. These data indicate that MEKK2 is a potent activator of the JNK pathway in FLS and that signal complexes including MEKK2, MKK4, MKK7, and/or JNK are potential therapeutic targets in RA.
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PMID:Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. 1473 42

Retinoic acid (RA) and sodium butyrate (NaB) have been implicated in the regulation of growth and differentiation in various cancer cells. To produce an agent with the properties of both RA and NaB, a butyryl aminophenyl ester of RA (4-BPRE) was synthesized. The agent was compared with an aminophenyl ester devoid of the butyryl group (4-APRE) for antitumor potential in vitro. Like RA, 4-hydroxyphenyl retinamide (4-HPR) and 4-APRE, 4-BPRE was an active ligand for all three subtypes of RAR, but not for RXR, as determined by transcription assays in COS-1 cells. In addition, regardless of the butyryl group, 4-BPRE actively suppressed c-Jun transcriptional activity, which may result in reduced expression of matrix metalloproteinases (MMP-1 and MMP-2), and effectively inhibited HCT116 cell invasion into Matrigel. In these respects, 4-BPRE is similar to 4-APRE, and even to RA and 4-HPR. However, our results showed that in HCT116 colon and A549 lung cancer cells, 4-BPRE was much more cytotoxic than RA and 4-APRE, and was also more cytotoxic than 4-HPR, which is the most cytotoxic retinoid derivative under clinical investigation. Subsequent assays using DAPI staining, DNA fragmentation, and FACS analysis suggested that the cytotoxic effect of 4-BPRE is mediated by apoptosis in HCT116 cells. Moreover, 4-BPRE inhibited histone deacetylase (HDAC) activity to some degree, although inhibition was less than that induced by the known HDAC inhibitors TSA and NaB. These results suggest that 4-BPRE could be a promising antitumor retinoid with both NaB activity and RA function.
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PMID:In vitro antitumor potential of 4-BPRE, a butyryl aminophenyl ester of retinoic acid: role of the butyryl group. 1476 28

VEGF (vascular endothelial growth factor), an important angiogenesis factor, appears also to be involved in inflammatory processes. Recent studies have shown that VEGF and its receptors (VEGFR) are expressed on osteoarthritic, but not on normal adult, chondrocytes. To elucidate possible functions of VEGF in osteoarthritic cartilage, the effects of VEGF were studied on immortalized human chondrocytes. Activated matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, interleukin (IL)-1beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) were measured in culture supernatants by enzyme-linked immunosorbent assays, nitric oxide with the Griess reagent, and cell proliferation by [3H]thymidine incorporation. VEGFR-2 mRNA was quantified by real-time reverse transcription-polymerase chain reaction and the protein was identified by immuno-gold electron microscopy. Intracellular signal transduction effects were determined by western blots and electrophoretic mobility shift assays. The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR-2. VEGF stimulation induced receptor phosphorylation, activation of the mitogen-activated protein kinases ERK 1/2, and long-lasting activation of the transcription factor AP-1 (activator protein-1). VEGF increased secreted MMP-1, MMP-3, and especially MMP-13, which could be effectively reduced by an inhibitor of VEGFR-2 kinase activity. Interestingly, VEGF diminished the expression of TIMP-1 and especially TIMP-2. Under hypoxic conditions, as occur in cartilage, the reduction in TIMP levels was even greater. Furthermore, VEGF induced IL-1beta, IL-6, TNF-alpha, and nitric oxide expression to a small extent and stimulated the proliferation of immortalized chondrocytes. These findings indicate that VEGF is an autocrine stimulator of immortalized chondrocytes that mediates mainly destructive processes in osteoarthritis.
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PMID:Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. 1499 3

Transcription factor c-Jun serves for cellular proliferation, survival, differentiation and transformation and is recognized as an important factor in cancer development, including hepatocellular carcinoma (HCC). The purpose of present study is to determine the involvement of c-Jun in matrix metalloproteinase-1 (MMP-1) expression, which is previously reported by us to be expressed only in the early stage of human HCC showing stromal invasion. Of 5 human HCC cell lines examined, only HLE cells revealed mRNA and protein expression as well as enzymatic activity of MMP-1. Transient transfection of an MMP-1 promoter/luciferase construct (including 4.4 kb full promoter region) into HLE and HCC-T cells (MMP-1 nonproducer) showed that high promoter activity was observed only in HLE cells without inducers, and that this promoter activity was still observed when a shorter 0.6 kb proximal promoter construct was transfected. The 0.6 kb promoter region contained 3 AP-1 sites, and c-jun mRNA was constitutively expressed in HLE cells without inducers. Furthermore, phosphorylated c-Jun and c-Jun NH2-terminal kinase (JNK) were detected in HLE cells. Promoter activity of the 0.6 kb construct was suppressed with SP600125, a potent inhibitor of JNK, but not with PD98059 and SB203580, potent inhibitors of MEK1/2 and p38, respectively. The inhibitory effect of SP600125 was also observed at protein expression level and in enzymatic activity of MMP-1. Taken together, this study suggests that the JNK pathway is involved in the expression of MMP-1 in HCC cells and may represent a new functional role of c-Jun for HCC development.
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PMID:c-Jun NH2-terminal kinase pathway is involved in constitutive matrix metalloproteinase-1 expression in a hepatocellular carcinoma-derived cell line. 1502 20

We have previously reported that human matrix metalloproteinase-1 (MMP1) is a p53 target gene subject to down-regulation (Sun et al. [1999]: J Biol Chem 274:11535-11540]. In the present study, we demonstrate that the down-regulation of the human -83MMP1 promoter fragment by p53 was abolished when the -72AP-1 site was eliminated and that a GAL4-cJun-mediated but not a GAL4-Elk1-mediated induction of pFR-luci was effectively inhibited by p53 suggesting an AP-1 dependent but AP-1 binding independent mechanism. Results from gel mobility shift assays were consistent with an AP-1 binding independent mechanism. We also demonstrate that both p300 and TATA box binding proteins cooperated with the transcription factor AP-1 to induce the promoter of MMP1; however, p53 only inhibited the p300-mediated induction of the MMP1 promoter and the inhibition was -72AP-1 dependent. Furthermore, the down-regulation of the MMP1 promoter and mRNA by p53 could be reversed by p300 and by a p53 binding p300 fragment that had no coactivator activity. Taken together, these results indicate that p53 down-regulates MMP1 mainly by disrupting the communications between the transactivator AP-1 and the basal transcriptional complex, which are partially mediated by p300. Finally, by using p53 truncated mutant constructs, we demonstrate that both the N-terminal activation domain and the C-terminal oligomerization domains of p53 were required for the down-regulation of MMP1 transcription.
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PMID:P53 down-regulates matrix metalloproteinase-1 by targeting the communications between AP-1 and the basal transcription complex. 1510 53

Transforming growth factor-beta (TGF-beta) signaling plays a pivotal role in extracellular matrix deposition by stimulating collagen production and other extracellular matrix proteins and by inhibiting matrix degradation. The present study was undertaken to define the role of sphingosine kinase (SphK) in TGF-beta signaling. TGF-beta markedly up-regulated SphK1 mRNA and protein amounts and caused a prolonged increase in SphK activity in dermal fibroblasts. Concomitantly, TGF-beta reduced sphingosine-1-phosphate phosphatase activity. Consistent with the changes in enzyme activity, corresponding changes in sphingolipid levels were observed such that sphingosine 1-phosphate (S1P) was increased (approximately 2-fold), whereas sphingosine and ceramide were reduced after 24 h of TGF-beta treatment. Given the relatively early induction of SphK gene expression in response to TGF-beta, we examined whether SphK1 may be involved in the regulation of TGF-beta-inducible genes that exhibit compatible kinetics, e.g. tissue inhibitor of metalloproteinase-1 (TIMP-1). We demonstrate that decreasing SphK1 expression by small interfering RNA (siRNA) blocked TGF-beta-mediated up-regulation of TIMP-1 protein suggesting that up-regulation of SphK1 contributes to the induction of TIMP-1 in response to TGF-beta. The role of SphK1 as a positive regulator of TIMP-1 gene expression was further corroborated by using ectopically expressed SphK1 in the absence of TGF-beta. Adenovirally expressed SphK1 led to a 2-fold increase of endogenous S1P and to increased TIMP-1 mRNA and protein production. In addition, ectopic SphK1 and TGF-beta cooperated in TIMP-1 up-regulation. Mechanistically, experiments utilizing TIMP-1 promoter constructs demonstrated that the action of SphK1 on the TIMP-1 promoter is through the AP1-response element, consistent with the SphK1-mediated up-regulation of phospho-c-Jun levels, a key component of AP1. Together, these experiments demonstrate that SphK/S1P are important components of the TGF-beta signaling pathway involved in up-regulation of the TIMP-1 gene.
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PMID:Sphingosine kinase 1 (SPHK1) is induced by transforming growth factor-beta and mediates TIMP-1 up-regulation. 1548 66

Antidiabetic drug thiazolidinedione (TZD) also has anti-atherogenic effects. Among these effects, inhibition of smooth muscle cell (SMC) migration is considered to be essential. However, the mechanism whereby TZD inhibits SMC migration is not well understood. Since it is known that matrix metalloproteinases (MMPs) play a permissive role for SMC migration, we determined if TZD inhibits the upregulation of MMP-1 expression in SMCs by oxidized LDL (oxLDL), a potent stimulator for atherogenesis. Results showed that oxLDL markedly stimulated MMP-1 secretion, mRNA expression, and MMP-1 promoter activity, but pioglitazone significantly inhibited the oxLDL-upregulated MMP-1 expression. In an attempt to explore the signaling mechanism by which pioglitazone inhibits the oxLDL-upregulated MMP-1 expression, we found that extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) pathways were required for the oxLDL-stimulated MMP-1 expression, but pioglitazone failed to antagonize the activation of ERK and JNK by oxLDL. Finally, our AP-1 activity assay showed that pioglitazone inhibited oxLDL-stimulated c-Jun activity. Taken together, the present study indicates that pioglitazone inhibits oxLDL-stimulated MMP-1 expression in VSMCs by inhibiting c-Jun transcriptional activity through a mitogen-activated protein kinase (MAPK)-independent mechanism.
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PMID:Pioglitazone inhibits MMP-1 expression in vascular smooth muscle cells through a mitogen-activated protein kinase-independent mechanism. 1569 31


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