Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acidic fibroblast growth factor (FGF-1), a prototype member of the heparin-binding growth factor family, influences proliferation, differentiation, and protein synthesis in different cell types. However, its possible role on lung extracellular matrix (ECM) metabolism has not been evaluated. In this study we examined the effects of FGF-1 and FGF-1 plus heparin on type I collagen, collagen-binding stress protein HSP47, interstitial collagenase (matrix metalloproteinase [MMP]-1), gelatinase A, and tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 expression by normal human lung fibroblasts. Heparin was used because it enhances the biologic activities of FGF-1. Fibroblasts were exposed either to 20 ng/ml FGF-1 plus 100 micrograms/ml heparin for 48 h or to FGF-1 or heparin alone. Messenger RNA (mRNA) expression was analyzed by Northern blot. Collagen synthesis was evaluated by digestion of [3H]collagen with bacterial collagenase, MMP-1 by Western blot, and gelatinolytic activities by zymography. Our results show that FGF-1 induced collagenase mRNA expression, which was strongly enhanced when FGF-1 was used with heparin. Likewise, both FGF-1 and FGF-1 plus heparin reduced by 70 to 80% the expression of type I collagen transcript, in part through effect on pro-alpha1(I) collagen mRNA stability. A downregulation of HSP47 gene expression was also observed. Synthesis of collagen and collagenase proteins paralleled gene expression results. FGF-1 activities were abolished with genistein, a tyrosine kinase inhibitor. Neither FGF-1 nor FGF-1 plus heparin affected the expression of TIMP-1, TIMP-2, and gelatinase A. These findings demonstrate that FGF-1, mostly in the presence of heparin, upregulates collagenase and downregulates type I collagen expression that might have a protective role in avoiding collagen accumulation during lung ECM remodeling.
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PMID:Acidic fibroblast growth factor induces an antifibrogenic phenotype in human lung fibroblasts. 1022 73

Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins, and there is evidence that they play a role in tumor cell growth, invasion and metastasis. Matrilysin (MMP-7) is over-expressed in prostate cancer cells and increases prostate cancer cell invasion. Prostate stromal fibroblasts secrete a factor(s), including fibroblast growth factor-1 (FGF-1), which induces promatrilysin expression in the prostate carcinoma cell line LNCaP but not in normal prostate epithelial cells (PrECs). Since FGF-1 is present in the prostate, an altered sensitivity to FGF-1 might explain the up-regulation of matrilysin expression in prostate cancer cells compared to normal prostate epithelium. FGF receptor-1 (FGFR-1) is not normally expressed by normal prostate epithelial cells; however, aberrant expression of this receptor has been reported in prostate cancer cells, including the LNCaP cell line. We hypothesized that aberrant expression of FGFR-1 in PrECs would render them sensitive to induction of promatrilysin expression by recombinant FGF-1. To test this hypothesis, we transiently transfected PrECs with an FGFR-1 expression vector, which resulted in over-expression of FGFR-1 protein in approximately 40% of cells. FGF-1 increased promatrilysin expression in FGFR-1-transfected PrECs 4-fold over mock-transfected cells, and this induction was inhibited by a specific FGFR-1 inhibitor, SU5402, and by co-expression of a dominant negative FGFR-1 protein. Our results demonstrate that aberrant FGFR-1 expression, an epigenetic phenomenon that has been associated with prostate cancer progression, allows induction of promatrilysin expression by FGF-1 in PrECs.
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PMID:Aberrant expression of fibroblast growth factor receptor-1 in prostate epithelial cells allows induction of promatrilysin expression by fibroblast growth factors. 1114 43

The quality of ulcer repair remains crucial for the stability of the injured tissue and for preventing recurrence. Therefore, we studied the temporo-spatial expression of the fibrillar and basement membrane collagens (types I, III, and IV), the collagenase MMP-2 as well as its inhibitor TIMP-1 before and after oral administration of basic fibroblast growth factor (b-FGF) over 30 days in acetic acid-induced rat gastric ulcers. The alterations and the exact location of the mRNA transcripts and their precipitated proteins were visualized by means of radioactive in situ hybridization and immunohistochemistry. Our data show that hybridization signals of procollagen I could first be identified 2 hours after ulcer induction. After 12 hours the ulcer was established and the mRNA was enhanced at the ulcer margin. After 24-48 hours the other procollagen transcripts were detected and all were further upregulated over the mesenchymal cells of all gastric layers up to 21 days, then declined at 30 days. In contrast, MMP-2 became prominent after 48 hours and up to 21 days. TIMP-1 was enhanced at 72 hours. After oral administration of b-FGF the transcriptional activity of the procollagens and MMP-2 was not significantly altered, while ulcer diameter was significantly reduced. We conclude that the early onset and long duration of collagens' expression points to their central structural and functional role in gastric ulcer healing. MMP-2 seems to be involved in both active ulceration and ECM remodeling. The timing of TIMP/MMP expression may be critical for proper restoration of gastric wall integrity.
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PMID:Remodeling of extracellular matrix in gastric ulceration. 1152 57

The MMP, matrilysin (MMP-7), has been shown to be overexpressed in prostate cancer cells and to increase prostate cancer cell invasion. Prostate stromal fibroblasts secrete factor(s), including fibroblast growth factor-1 (FGF-1) that induces promatrilysin expression in LNCaP cells. In the present study, we investigated the signal transduction pathway involved in the FGF-1-induced expression of promatrilysin. FGF-1 treatment significantly increased the activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). This induction was time-dependent and was sustained until 24 hours after treatment. Treating the cells with MEK1/2 inhibitor (PD98059) eliminated ERK activation completely and blocked FGF-1-mediated induction of promatrilysin expression. Transient transfection studies with human matrilysin promoter resulted in a four- to five-fold increase in reporter luciferase enzyme activity that was blocked by the MEK1/2 inhibitor (PD98059). Serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was observed after FGF-1 treatment and pretreatment with 20 microM PD98059-abolished STAT3 phosphorylation. Transient transfection with dominant negative STAT3 inhibited FGF-1-induced transactivation of the matrilysin promoter indicating that STAT3 plays an important role in FGF1-induced matrilysin expression. We propose that the FGF-1-induced signaling pathway that leads to promatrilysin expression is ERK-dependent and leads to phosphorylation of Ser-727 on STAT3, phosphorylated STAT3, then binds and transactivates the matrilysin promoter. Our results demonstrate that ERK-MAP kinase and transcription factor STAT3 are important components of FGF-1-mediated signaling, which induce promatrilysin expression in LNCaP cells.
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PMID:Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. 1192 92

Distraction osteogenesis (DO) is one of the most dramatic in vivo applications of mechanical stimulation as a means of inducing bone regeneration. A simple and reproducible murine model of tibia distraction osteogenesis was developed using a monolateral fixator. Bone formation was assessed histologically over a 35-day time course. The steady state expression of a broad family of angiogenesis-associated genes was assessed by microarray hybridization analyses over the same time course, while the immediate gene response that was induced during each cycle of distraction was assessed at 30 min and 8 h after the first and last rounds of activation of the fixator. Distraction osteogenesis promoted new bone formation primarily through an intramembranous process with maximal osteogenesis during the active distraction period. Histological analysis also showed that dense cortical bone continued to be formed, during the consolidation phase, for 2 weeks after distraction ended. The analysis of steady state mRNA expression levels over the time course of DO showed that VEGF-A and neuropilin, an alternate receptor for VEGF-A, both angiopoietin (Ang) 1 and 2 factors, and the Ang receptor Tie2 were the critical angiogenic factors during DO. A key transcriptional regulator of many of the angiogenic factors, hypoxia-induced factor1alpha (Hif-1a), the FGF binding protein pleiotropin/OSF1, and multiple MMP(s), were also induced during the active distraction period. Examination of the expression of angiogenic factors that were induced after each cycle of activation, demonstrated that Hif-1a, Nrp1, and VEGF-A were all cyclically induced after each increment of distraction. These results suggest that these factors are early mediators that are produced by distraction and contribute toward the processes that promote bone formation. These experiments represent the first step in defining the molecular mechanisms that regulate skeletal regeneration and the functional relationship between angiogenesis and osteogenesis during distraction osteogenesis.
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PMID:The role of angiogenesis in a murine tibial model of distraction osteogenesis. 1512 Oct 17

Despite novel therapies in lung cancer treatment the 5-year survival rate still remains poor. Furthermore, screening concepts for early diagnosis, based on conventional sputum cytology and chest radiography, have so far not demonstrated an impact on decreasing lung-cancer mortality. More specific molecular markers allow new insights in the process of lung carcinogenesis. Furthermore they raise the hope that they provide new tools for early diagnosis and screening of high-risk individuals, determination of prognosis, and identification of innovative treatments. In this review, these perspectives of molecular targets in lung cancer will be discussed and summarised. Angiogenesis-stimulating factors (VEGF, FGF, MMP, etc.), parameters concerning tumour cell proliferation and apoptosis (EGFR, p53, K-ras, rb, bcl-2, etc.) are well known. Several of these genetic factors have already been investigated, but no single parameter has yet gained a sufficient selectivity regarding prognostic significance or therapeutic efficacy. New aspects in the complex tumour-stroma interaction and the interactive, cross-talking signal transduction pathways and recently developed functional genomic approaches, such as DNA microarrays and proteomics might lead to further progress in biological staging models and treatment concepts.
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PMID:Molecular oncology--perspectives in lung cancer. 1555 1

Branching morphogenesis of mouse submandibular glands is regulated by multiple growth factors. Here, we report that ex vivo branching of intact submandibular glands decreases when either FGFR2 expression is downregulated or soluble recombinant FGFR2b competes out the endogenous growth factors. However, a combination of neutralizing antibodies to FGF1, FGF7 and FGF10 is required to inhibit branching in the intact gland, suggesting that multiple FGF isoforms are required for branching. Exogenous FGFs added to submandibular epithelial rudiments cultured without mesenchyme induce distinct morphologies. FGF7 induces epithelial budding, whereas FGF10 induces duct elongation, and both are inhibited by FGFR or ERK1/2 signaling inhibitors. However, a PI3-kinase inhibitor also decreases FGF7-mediated epithelial budding, suggesting that multiple signaling pathways exist. We immunolocalized FGF receptors and analyzed changes in FGFR, FGF and MMP gene expression to identify the mechanisms of FGF-mediated morphogenesis. FGFR1b and FGFR2b are present throughout the epithelium, although FGFR1b is more highly expressed around the periphery of the buds and the duct tips. FGF7 signaling increases FGFR1b and FGF1 expression, and MMP2 activity, when compared with FGF10, resulting in increased cell proliferation and expansion of the epithelial bud, whereas FGF10 stimulates localized proliferation at the tip of the duct. FGF7- and FGF10-mediated morphogenesis is inhibited by an MMP inhibitor and a neutralizing antibody to FGF1, suggesting that both FGF1 and MMPs are essential downstream mediators of epithelial morphogenesis. Taken together, our data suggests that FGFR2b signaling involves a regulatory network of FGFR1b/FGF1/MMP2 expression that mediates budding and duct elongation during branching morphogenesis.
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PMID:FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis. 1571 43

Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
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PMID:Molecular prognostic markers in pancreatic cancer: a systematic review. 1614 90

Cysteine-rich FGF receptor (CFR) was originally identified as a FGF2 receptor and found to be identical to Golgi complex-localized glycoprotein-1 (GLG1), also known as MG-160, and to a murine E-selectin ligand-1 (ESL-1). Although CFR is a 150-kDa integral membrane glycoprotein that is primarily located in the cis-medial Golgi complex, a substantial proportion of CFR is secreted but the underlying mechanism is unknown. CFR contains several possible furin-like proprotein convertase (PC) and matrix metalloproteinase cleavage sites. Cells expressing CFR were treated with the furin protease inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decCMK) or the MMP-inhibitor GM6001. In the presence of furin-like PC inhibitor, secretion of CFR was almost completely inhibited. Secretion was not affected by the GM6001 inhibitor. The secreted forms were further characterized by creating different mutant CFR proteins with N-terminal and C-terminal tags. Immunoblot analysis and immunofluorescence indicated, that successive endoproteolytical processing of CFR which takes place in the Golgi complex is essential for secretion. Secreted CFR bound to heparan sulphate proteoglycan (HSPG) could trap FGFs and thereby directly competing with tyrosine kinase receptors for FGF binding.
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PMID:Secreted cysteine-rich FGF receptor derives from posttranslational processing by furin-like prohormone convertases. 1928 38

Boundary formation is an important mechanism of development and has been studied in a number of bilaterian model organisms where it is often controlled by Notch, FGF and Wnt signalling. Tissue boundaries are also formed in simple pre-bilaterian animals. The boundary between parent and bud during asexual reproduction in the fresh water polyp Hydra vulgaris is an example. The Hydra homolog of the FGF-receptor FGFR (kringelchen) and some components of the Wnt signalling pathway are expressed at this boundary, but their precise functions are unknown. In this work we have discovered an important role for Notch signalling at this boundary. Notch signalling is needed to sharpen the kringelchen expression zone during the final budding stages from an initially broad band into a clear line demarcating the boundary between bud and parent. Expression of the Notch target gene HyHes and the putative matrix metalloprotease MMP-A3 was observed at the boundary shortly before the bud began to constrict and differentiate foot cells. When Notch signalling was inhibited with the presenilin inhibitor DAPT the expression pattern for kringelchen changed dramatically into a diffused pattern. The expression of both HyHes and MMP-A3 was abolished. Moreover, morphogenesis of the bud was not completed and buds did not constrict, failed to form a foot and never detached from the parent. This resulted in the formation of two-headed animals. We suggest that the function of Notch signalling during budding in Hydra is in promoting the formation of two stripes of differing gene expression, which are needed to differentiate the foot of the bud and a progressing narrowing of the mesoglea on the side of the parent.
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PMID:Notch signalling defines critical boundary during budding in Hydra. 2053 80


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