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)

Hepatocytes maintained in collagen gels remain differentiated for prolonged periods of time compared to cells maintained on conventional cultures. Previous studies with other culture systems in which chemical supplements or substratum modifications enhanced hepatocyte differentiation showed that in all of these systems hepatocytes do not respond to mitogens. In this study it is shown that hepatocytes maintained between two layers of collagen gels respond to mitogens HGF (also known as scatter factor (HGF/SF)) and epidermal growth factor (EGF). Cell density did not affect the responsiveness to mitogens as in conventional cultures. In addition both mitogens (HGF more pronounced) induce characteristic morphogenic changes in which hepatocytes form processes and join in formation of cords. Hepatocytes respond to mitogens for up to 6 days in culture at which point they become refractory to further mitogenic stimulation. This occurs despite electron microscopic evidence that these cells are fully viable when they become refractory to mitogenesis. The refractory state is not modified by substitution of one growth factor for the other or by addition of growth factors at different times. Hepatocytes in the refractory state become again responsive to mitogens when the collagen gels are dispersed by collagenase and the cells are replated on conventional substrates.
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PMID:Comparative analysis of mitogenic and morphogenic effects of HGF and EGF on rat and human hepatocytes maintained in collagen gels. 836 Feb 54

The leucine zipper transcription factors C/EBP alpha and C/EBP beta exhibit growth-related variations of expression and DNA binding during liver regeneration. We examined the expression of C/EBP proteins in relation to hepatocyte proliferation by studying their DNA-binding activity in primary mouse hepatocytes in vitro. Mouse hepatocytes were dissociated by collagenase perfusion and cultured in a serum-free, defined medium containing a variety of growth factors and hormones. Cell protein extracts were collected every 24 h for up to 10 d and examined for DNA-binding activity by gel retardation analysis using a C/EBP consensus sequence oligomer (bZIP). C/EBP alpha is the major bZIP-binding protein present in the dissociated cells prior to plating. With the culture conditions we employed, little or no binding of C/EBP proteins was observed in the first 24 to 48 h of cultivation. After 48 h, C/EBP beta binding activity was elevated relative to the level seen in freshly dissociated cells. In contrast, C/EBP alpha binding continued to be greatly reduced and no C/EBP delta binding was observed. C/EBP beta binding remained elevated for the duration of the experiment. Additional growth factor treatment (EGF, FGF, TGF alpha, and HGF) of the hepatocytes did not appreciably alter the pattern of C/EBP binding. However, TGF beta treatment, known to decrease hepatocyte proliferation, increased C/EBP beta binding activity earlier and more actively than in control cells. This study confirms a negative correlation between DNA binding by the C/EBP transactivator proteins and the proliferation of primary mouse hepatocytes in vitro.
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PMID:DNA binding by C/EBP proteins correlates with hepatocyte proliferation. 856 82

Matrix metalloproteinases participate in normal physiologic processes; however, their overproduction has been associated with connective tissue destruction in a variety of pathological states. Migrating basal keratinocytes transiently express collagenase-1 during normal cutaneous reepithelialization. However, the overexpression of both collagenase-1 and stromelysin-1 has been associated with the pathogenesis of chronic nonhealing ulcers. Aberrant expression of metalloproteinases in inflammation is mediated, at least in part, by soluble factors. Since hepatocyte growth factor/scatter factor (HGF/SF) has been reported to promote keratinocyte migration and proliferation, key events in wound repair, and since HGF/SF is produced by dermal fibroblasts and its c-Met receptor is expressed by basal keratinocytes in wounded skin, we have studied the effects of HGF/SF upon keratinocyte metalloproteinase expression. We have found that HGF/SF can stimulate keratinocyte collagenase-1 and stromelysin-1 production in a dose-dependent and matrix-dependent manner. Expression of 92-kDa gelatinase was not affected by HGF/SF. We determined that HGF/SF regulation of collagenase-1 expression is transcriptionally mediated and requires tyrosine kinase and protein kinase C activaties. HGF/NK1, a naturally occurring, truncated form of HGF/SF, also stimulates collagenase-1 production, but much less efficiently than does the parent molecule. However, HGF/NK2, another HGF/SF splice variant, as well as heparin, potently inhibit HGF/SF-induced collagenase-1 synthesis. These results indicate that HGF/SF and its naturally occurring splice variants have diverse biological effects on keratinocytes and suggest an additional mechanism whereby HGF/SF may regulate keratinocyte function during wound repair.
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PMID:Mechanisms of hepatocyte growth factor stimulation of keratinocyte metalloproteinase production. 879 21

Morphology and immunohistochemical features of the developmental process of the human intrahepatic biliary system (IBS) are reviewed. Human IBS arises from the ductal plate, a double-layered cylindrical structure located at the interface between portal mesenchyme and primitive hepatocytes. The ductal plate first appears from primitive hepatocytes (hepatoblasts) around 8 gestational weeks (GW), and its formation proceeds from the hepatic hilum to the periphery. The ductal plate gradually undergoes remodeling from 12 GW; some parts of the ductal plate disappear and other parts migrate into the portal mesenchyme. Around 20 GW, the migrated duct cells transform into immature bile ducts and peribiliary glands. Some immature peribiliary glands transform into pancreatic acinar cells around postnatal 3 months. The immature biliary elements express cytokeratins no. 7, 8, 18 and 19. Several growth factors (TGF-alpha, HGF) and their receptors (EGFR, MET, ERBB2) were expressed in the primitive IBS cells. Some extracellular matrix proteins including type IV collagen, laminin and tenascin are expressed in the mesenchyme around the primitive IBS. During IBS remodeling, apoptosis and cell proliferation occur with appropriate expression of apoptosis-related proteins (bcl-2, Fas, c-myc, Lewis(y)). Some pancreatic digestive enzymes (alpha-amylase, trypsinogen, lipase), cathepsin B, and matrix metalloproteinases (MMP-1, 2, 3, 9) and their inhibitors (TIMP-1, 2) are expressed in the remodeling IBS cells. Glycoconjugate residues of glycoproteins gradually appear during IBS development. The appropriate expression of these immunophenotypes may play an important role in the normal development of IBS.
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PMID:Normal and abnormal development of the human intrahepatic biliary system: a review. 914 36

In embryos and in human tumors, the expression of the ETS1 transcription factor correlates with the occurrence of invasive processes. Although this was demonstrated in cells of mesodermal origin, the expression of ETS1 was not detected in epithelial cells. In the present study, we show that during early organogenesis in the chick embryo, ETS1 mRNA expression was transiently induced in epithelial structures, during emigration of neural crest cells and dispersion of somites into the mesenchymal sclerotome. In contrast, the expression of ETS1 was not detected in situations where epithelial layers stayed cohesive while forming a new structure, such as the dermomyotome forming the myotome. The involvement of ETS1 in epithelial cell dissociation was examined in MDCK epithelial cells stimulated by scatter factor/hepatocyte growth factor (SF/HGF), a potent inducer of cell dissociation and motility. SF/HGF was found to stimulate ETS1 mRNA and protein expressions, and these increases coincided with the dispersion of cells and the expression of protease mRNAs, such as urokinase-type plasminogen activator and collagenase, but not with the protease inhibitor, plasminogen activator inhibitor type 1. Furthermore, we showed that SF/HGF was able to induce a transcriptional response involving ETS1 by using artificial as well as cellular promoters, such as the urokinase-type plasminogen activator and collagenase 1 promoters, containing RAS-responsive elements with essential ETS-binding sites. These data demonstrate expression of ETS1 during epithelial-mesenchymal transitions in the developing embryo and show that ETS1 can act as a downstream effector of SF/HGF in MDCK epithelial cells. Taken together, these data identify ETS1 as a molecular actor of epithelia cell dissociation.
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PMID:The ETS1 transcription factor is expressed during epithelial-mesenchymal transitions in the chick embryo and is activated in scatter factor-stimulated MDCK epithelial cells. 918 99

The Dunning H rat prostate tumor (R3327H) is a widely used experimental model of human prostatic adenocarcinoma (CaP). The Dunning H tumor has been characterized as androgen-sensitive, androgen-receptor (AR) positive, prostate-specific antigen and prostatic acid phosphatase (PAP) positive. To date, the tumor has been maintained by serial passage in vivo because of the lack of an in vitro cell line that retains the characteristics of the in vivo tumor. The objective of the present study was to establish a propagable cell line from R3327H adenocarcinoma that maintained androgen sensitivity and expression of AR, PSA and PAP. Tissue harvested from an in vivo R3327H tumor was dissociated with collagenase and placed into Richter's improved media (with supplements). A cytokeratin-positive epithelial cell line (HUNC-E) and a vimentin-positive stromal cell line (HUNC-S) were generated from the primary culture, subcultured continuously for >300 days, and passaged >50 times. Survival of the HUNC-E cell line in vitro depended on several media supplements, including nicotinamide, insulin, transferrin, selenium and epidermal growth factor (EGF). HUNC-E cells expressed AR and produced PSA and PAP throughout the culture period, as confirmed by immunocytochemistry and Western blot analyses. Addition of 14 nM testosterone (T) or dihydrotestosterone (DHT) to HUNC-E cells, stimulated DNA synthesis as well as anchorage-independent growth and PSA production, which demonstrated the androgen-sensitive nature of the cells in vitro. When HUNC-E and HUNC-S cells were combined in a 3:1 ratio and introduced subcutaneously into syngeneic male hosts, tumors formed in 2/3 animals with an average latency of 7 months. RT-PCR and immunocytochemical characterization of the HUNC cell lines revealed that the cells expressed several growth factors and their cognate receptors, including HGF, TGF-alpha and the TGF-betas, indicating the establishment of potential autocrine loops in the neoplastic cells. The HUNC-E and HUNC-S CaP cell lines, which retain the characteristics of the epithelial and stromal components of the in vivo R3327H tumor, will allow a more thorough and informative molecular and biological analysis of prostatic adenocarcinoma.
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PMID:Isolation and characterization of propagable cell lines (HUNC) from the androgen-sensitive Dunning R3327H rat prostatic adenocarcinoma. 960 Mar 41

During tissue-invasive events, migrating cells penetrate type I collagen-rich interstitial tissues by mobilizing undefined proteolytic enzymes. To screen for members of the matrix metalloproteinase (MMP) family that mediate collagen-invasive activity, an in vitro model system was developed wherein MDCK cells were stably transfected to overexpress each of ten different MMPs that have been linked to matrix remodeling states. MDCK cells were then stimulated with scatter factor/hepatocyte growth factor (SF/HGF) to initiate invasion and tubulogenesis atop either type I collagen or interstitial stroma to determine the ability of MMPs to accelerate, modify, or disrupt morphogenic responses. Neither secreted collagenases (MMP-1 and MMP-13), gelatinases (gelatinase A or B), stromelysins (MMP-3 and MMP-11), or matrilysin (MMP-7) affected SF/HGF-induced responses. By contrast, the membrane-anchored metalloproteinases, membrane-type 1 MMP, membrane-type 2 MMP, and membrane-type 3 MMP (MT1-, MT2-, and MT3-MMP) each modified the morphogenic program. Of the three MT-MMPs tested, only MT1-MMP and MT2-MMP were able to directly confer invasion-incompetent cells with the ability to penetrate type I collagen matrices. MT-MMP-dependent invasion proceeded independently of proMMP-2 activation, but required the enzymes to be membrane-anchored to the cell surface. These findings demonstrate that MT-MMP-expressing cells can penetrate and remodel type I collagen-rich tissues by using membrane-anchored metalloproteinases as pericellular collagenases.
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PMID:Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. 1085 Oct 27

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional factor involved both in development and tissue repair, as well as pathological processes such as cancer and metastasis. It has been identified in vivo in many types of tumours together with its tyrosine kinase receptor, Met. We show here that exogenous HGF/SF acts as a strong chemoattractant for human mesothelioma cell lines. The factor also enhanced cell adhesion to and invasion into Matrigel. The mesothelioma cell lines synthesized a panel of matrix metalloproteinases critical for tumour progression such as MMP-1, 2, 3, 9 and membrane-bound MT1-MMP. HGF/SF stimulated the expression of MMP-1, 9 and MT1-MMP and had a slight effect on expression of the MMP inhibitor TIMP-1 but not TIMP-2. However, there was no simple correlation between the levels of MMPs and TIMPs of the cell lines and their different invasion properties or between HGF/SF stimulatory effects on MMP expression and invasion. In addition, effects of protease inhibitors on invasion suggested that serine proteases were also expressed in human mesothelioma cell lines and were involved in HGF/SF-induced invasion. The results show a predominant role for HGF/SF in mesothelioma cell invasion, stimulating simultaneously adhesion, motility, invasion and regulation of MMP and TIMP levels.
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PMID:Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases. 1102 27

To understand the mechanism of invasion and metastasis of hepatocellular carcinoma (HCC), the expression of c-met and Ets-1, and the effect of HGF on these cell's motility and invasion ability were examined in four hepatoma cell lines. The analysis revealed that the overexpression of c-met and Ets-1 is closely connected with the motility and invasion ability of the HCC cell lines. Invasion activity of HepG2 and HLE cells were enhanced by the addition of HGF to medium. HGF regulated c-met transcription in HepG2 and Bel-7402 cells, HGF also induced Ets-1 transcription in Bel-7402 cell. Bel-7402 cells stably transduced with the human Ets-1 gene showed significantly increased invasion potentials compared to parental and mock-transfected cells. The expression level of c-met, MMP1, MMP9, and u-PA in Bel-7402 cells transfected with Ets-1 were markedly increased, and as a consequence of c-met expression increase. Bel-7402 cells transfected with Ets-1 were more responsive to exogenous HGF stimulation in invasiveness and motility ability. In addition, conditioned by antisense Ets-1 oligonucleotide-treat-Bel-7402 cells transfected with Ets-1 gene and HLE hepatoma cells showed markedly reduced invasion activity, and down-regulated the transcription of Ets-1, c-met, u-PA, MMP-1, and MMP-9. These results strongly suggest that Ets-1 has a crucial role in the invasive property in hepatoma cell lines, and there may exist a loop to enhance the invasive ability of hepatoma cell lines.
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PMID:Invasiveness of hepatocellular carcinoma cell lines: contribution of hepatocyte growth factor, c-met, and transcription factor Ets-1. 1152 16

Previous work has shown the importance of tumour-stroma interactions for prostate cancer development at the primary site. The aim of the present study was to find out whether evidence can be found for a tumour-stroma cross- talk also between metastatic prostate cancer cell lines and non-prostatic stromal fibroblasts which are encountered by metastatic cells at most sites. We addressed this issue in cell culture systems using 3 metastatic human prostate cancer cell lines (LnCaP, PC-3 and DU-145) on the one hand, and a human fibroblast line (HFF, human foreskin fibroblasts) on the other. We incubated fibroblasts with tumour cell- and tumour cells with fibroblast-conditioned media and evaluated several parameters important for the establishment of metastases such as cell proliferation, migration and expression of matrix degrading proteases. We also determined in the conditioned media the concentrations of several growth factors and cytokines which might be responsible for the observed effects. We found that media conditioned by all 3 metastatic prostate cancer cell lines stimulated fibroblast proliferation which corresponds to fibrous stroma induction in vivo. DU-145 cell conditioned media induced in fibroblasts expression of mmp-1 mRNA known to be important for tumour invasion. ELISA assays revealed that tumour cells secrete bFGF, PDGF and TNFalpha known to stimulate fibroblast proliferation and/or MMP-1 expression. Cultivation of DU-145 carcinoma cells in fibroblast conditioned medium resulted in an enhanced proliferation and anchorage-independent growth of this cell line in soft agar. Fibroblast conditioned medium also increased migration of PC-3 cells in the wound assay and slightly augmented mmp-1 expression. KGF (able to stimulate proliferation of normal and neoplastic prostate epithelial cells) was secreted by fibroblasts at higher concentrations than by all 3 tumour cell lines. In addition, fibroblasts secreted TNFalpha, bFGF, PDGF, HGF and also VEGF, the most important factor for tumour vascularization. Our results provide evidence that tumour-stroma interactions do not only exist at the primary site but also between metastatic prostate cancer cell lines and their fibroblastic microenvironment. These interactions, which are mediated through secreted factors, affect several steps of the metastatic cascade including proliferation, anchorage-independent growth, migration and the secretion of matrix-degrading proteases.
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PMID:Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts. 1701 25


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