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)

Rabbit antibodies raised against microtubule-associated protein 1 (MAP-1) from hog brain were found to crossreact with extracellular matrix components of mouse BALB/c 3T3 cell cultures. As shown by immunofluorescence microscopy of confluent cell cultures, the extracellular MAP-related antigen was located on dense fibrillar network arrays underlying and surrounding the cells. The immunoreactive material was sensitive to trypsin but resistant to collagenase. The microtubule-disrupting drug colcemid had no visible effect on the morphology of the anti-MAP-stained network, whereas treatment with cytochalasin B provoked its abolishment. Simian virus 40-transformed BALB/c 3T3 cells expressed considerably less extracellular antigen than did the nontransformed cells. After in vivo radiolabeling of BALB/c 3T3 cells, a secreted polypeptide of Mr 205,000 was isolated by immuno-precipitation from culture media as well as from cell-free extracellular matrices. This antigen was identified as a sulfoglycoprotein, noncollageneous in nature, that undergoes intermolecular disulfide bonding. Anti-MAP-1 antibodies affinity-purified on the extracellular Mr 205,000 protein were immunoreactive with MAP-1 and MAP-2 from brain and decorated cytoplasmic microtubules as demonstrated by immunoblotting and immunofluorescence microscopy. Thus, a structural relationship between cytoskeletal and extracellular polypeptides is demonstrated.
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PMID:Mr 205,000 sulfoglycoprotein in extracellular matrix of mouse fibroblast cells is immunologically related to high molecular weight microtubule-associated proteins. 389 71

The mitogen-activated protein kinases (MAP kinases) p42mapk and p44mapk are serine/threonine kinases rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in integrating and transmitting transmembrane signals required for growth and differentiation. Here we demonstrate that activation of these ubiquitously expressed MAP kinases is essential for growth. To specifically suppress MAP kinase activation in fibroblasts, we transiently expressed either the entire p44mapk antisense RNA or p44mapk kinase-deficient mutants (T192A or Y194F). As expected, and through independent mechanisms, both approaches strongly inhibited MAP kinase activation. The antisense reduced the expression of endogenous p42mapk and p44mapk by 90%, whereas overexpression of the T192A mutant inhibited growth factor activation of both endogenous MAP kinases by up to 70%. As a consequence, we found that the antisense as well as the T192A mutant of p44mapk inhibited growth factor-stimulated gene transcription (collagenase promoter assay with chloramphenicol acetyltransferase reporter) and cell growth. These effects were proportional to the extent of MAP kinase inhibition and reversed by coexpression of the wild-type p44mapk. Therefore we conclude that growth factor activation of p42mapk and p44mapk is an absolute requirement for triggering the proliferative response.
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PMID:Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. 839 1

Ultraviolet light (UV) and different DNA-damaging agents are known to induce AP-l-transcription-factor activity. Whereas UV induction appears to be triggered by events at the cell membrane, the mechanism of AP-l activation by alkylating or platinating agents is not known. We have here examined the effect of cisplatin on AP-l activity in RPMI-8322 melanoma cells. Cisplatin was found to induce binding of nuclear proteins to TRE elements from the c-jun and collagenase-gene promoters, and was also found to induce activation of a c-jun-promoter reporter construct. Compared with stimulation by UV, cisplatin stimulation of c-jun-promoter activity was found to be less sensitive to a dominant negative mutant of Raf-I protein kinase. Furthermore, whereas UV treatment resulted in strong MAP-kinase activation, cisplatin treatment resulted only in a weak and transient increase. These data suggest that the Raf-MAPK pathway is of minor importance for the induction of c-jun-promoter activity by cisplatin. Finally, we report that cisplatin induction of c-jun in RPMI-8322 cells was blocked by herbimycin A, an inhibitor of Src-family tyrosine kinases. In contrast, UV induction of c-jun was not blocked by herbimycin A. In conclusion, our data strongly suggest that UV and cisplatin induction of c-jun mRNA in RPMI-8322 melanoma cells occur by distinct mechanisms.
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PMID:Different mechanisms are responsible for c-jun mRNA induction by cisplatin and ultraviolet light. 863 98

The ability of rainbow trout liver cells to regulate their intracellular pH (pHi) was studied using two methods on hepatocytes isolated by collagenase digestion: (i) by monitoring pHi with the fluorescent dye BCECF-AM, and (ii) by measuring the amiloride-sensitive uptake of 22Na, which represents Na+/H+ exchange. In low-Na+ medium (¾16mmoll-1), Na+ uptake was reduced by approximately 70% in the presence of amiloride derivatives (DMA or MPA, 10(-4)moll-1). Changing separately either the extracellular pH (pHe) or the intracellular pH (pHi, clamped by treating the cells with nigericin in the presence of 140mmoll-1 K+) between 6 and 8 induced an increase in the rate of Na+ uptake when pHe was raised or when pHi was reduced. When transferred to hypertonic medium, hepatocytes shrank to nearly 72% of their initial volume, and thereafter a slow and partial regulatory volume increase phase was observed, with an increase in the amiloride-sensitive rate of Na+ uptake and an increase in intracellular pH. As DIDS-sensitive Cl- uptake was concomitantly enhanced, it is suggested that hypertonic stress activates Na+/H+ and Cl-/HCO3- exchange.
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PMID:Na+/H+ exchange and osmotic shrinkage in isolated trout hepatocytes 932 Feb 88

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.
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PMID:Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38. 987 71

During progesterone-induced decidualization of estradiol (E2)-primed human endometrial stromal cells (HESCs), the interstitial-type extracellular matrix (ECM) of the follicular phase endometrium is transformed in the luteal phase to a mixture of residual interstitial- and new basal laminar-type components. This transformation is accelerated by reduced proteolytic activity of HESCs undergoing decidualization (DZ). In cultured HESCs, progestins, but not E2, induce the expression of several DZ markers, and E2 enhances these effects despite the lack of response to E2 alone. Using this well-characterized in vitro DZ model we evaluated the expression of plasminogen activators (PAs), which degrade ECM components that undergo rapid turnover, and matrix metalloproteinases (MMPs), which degrade the bulk of ECM components. Medroxyprogesterone acetate (MPA) inhibited the catalytic activity of urokinase-type PA (uPA) and tissue-type PA (tPA) as well as the expression of such MMPs as interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3). Moreover, E2 + MPA elicited greater inhibitory effects on the expression of all of these proteases. Progestin inhibition of PA activities reflected reciprocal upregulation in the output of the PA inhibitor PAI-1, which produced large molar excesses of PAI-1 compared with the PAs in HESC-conditioned medium. By contrast, the tissue inhibitor of the MMPs, TIMP1, as well as gelatinase A (MMP-2), was constitutively expressed by the HESCs. In the absence of implantation, menstruation-associated degradation of the functional endometrial ECM is triggered by withdrawal of circulating ovarian steroids. This process was evaluated in cultured HESCs that were first decidualized during 10 days of exposure to E2 + MPA, and then withdrawn to steroid-free medium with and without the antiprogestin RU 486. As expected, steroid withdrawal reversed progestin-inhibited PA activity as well as the expression of MMP-1 and MMP-3 and progestin-enhanced PAI-1; much greater reversal was observed in medium supplemented with RU 486. Unlike the changes in PAI-1, neither TIMP1, nor MMP-2 expression was affected by withdrawal to steroid-free or to RU 486-medium. By altering the composition of the ECM of the luteal phase endometrium, progestin-elicited inhibition of the PAs, uPA and tPA, as well as that of the MMPs, MMP-1 and MMP-3, modulates trophoblast adhesion, migration and differentiation. Conversely, steroid withdrawal elicited increases in uPA, MMP-1 and MMP-3 activities would promote endometrial sloughing by degrading the mixture of decidual cell-derived basement membrane-like proteins and interstitial components that comprise the stromal ECM of the perimenstrual endometrium.
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PMID:Implications of decidualization-associated protease expression in implantation and menstruation. 1040 70

The treatment of cartilage with mediators initiates the breakdown of proteoglycan followed by collagen. This is accompanied by the modulation of different proteinases and inhibitors that include members of the MMP family and TIMPs. We have evidence that a chondrocyte membrane-associated metalloproteinase cleaves aggrecan. This activity is rapidly induced after stimulation with IL-1 and OSM and is not inhibited by TIMPs-1 and -2 but is inhibited by synthetic MMP inhibitors. This same combination of cytokines also upregulates the collagenases with the subsequent release of collagen fragments, and there is a close correlation between the amount of collagen released and collagenase activity produced. Collagen release can be prevented after treatment with specific inhibitors of MAP kinases, inhibitors of MMP transcription, synthetic metalloproteinase inhibitors, TIMPs and treatment of cartilage with agents that upregulate TIMPs. The results from bovine cartilage culture models show that collagen release occurs when TIMP levels are low, collagenases are upregulated and then subsequently activated.
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PMID:The regulation of MMPs and TIMPs in cartilage turnover. 1041 24

In this study, we show that the ETS transcription factor ER81 directly binds to and activates the promoter of the matrix metalloproteinase gene, MMP-1. Further, the oncoprotein HER2/Neu synergizes with ER81 to stimulate MMP-1 transcription. The activation of ER81 by HER2/Neu is mediated by MAP kinases, which phosphorylate ER81 in its N-terminal activation domain. Four respective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be further diminished by abolishment of phosphorylation at two non-MAP kinase sites. Altogether, our results reveal mechanisms of how phosphorylation of ER81 regulates the expression of target genes such as MMP-1, which may be important for many physiological processes from embryogenesis to adulthood as well as for tumor metastasis.
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PMID:HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1. 1159 30

The aim of the work was to analyze, on a comparative basis, the signaling pathways operating in the regulation of a panel of matrix metalloproteinases (MMP) expressed by human dermal fibroblasts submitted to mechanical stress relaxation by cytochalasin D (CD) and in a retracting collagen gel (RCG). The mRNA steady-state level of MMPs was measured by a quantitative RT-PCR procedure using a synthetic RNA as internal standard. In monolayer, most MMPs were barely detected, except MMP-2. Disruption of the actin stress fibers by CD induced a moderate increase of MMP-2 mRNA and a much larger stimulation of MMP-3, -9, -13 and -14 mRNAs. In RCG, a significant up-regulation of these MMPs was also observed although to a lower extent than in CD-treated monolayers. Among the investigated MMPs, the MMP-8 and -11 were not reproducibly detected. MMP-2 was processed to its active form both by CD and in RCG. The CD-induced up-regulation of gene expression was largely repressed by blocking protein synthesis by cycloheximide for all the MMPs, by inhibiting the tyrosine-kinases of the src family by herbimycin A for all MMPs, except MMP-2, and by inhibiting the TPA-inducible PKC isoforms by bisindoyl maleimide for all MMPs, except MMP-14. The up-regulation induced by stress relaxation in RCG was protein synthesis-dependent for MMP-2 and MMP-13, tyrosine kinases-dependent for MMP-3 and MMP-13, as previously described for MMP-1. Inhibiting TPA-inducible PKC did not affect any MMP in RCG except MMP-13, which was strongly induced. The processing of MMP-2 was tyrosine kinases-dependent but PKC-independent. Inhibitors of the ERK1,2 and p38 MAP kinases pathways diversely affected the MMPs expression. Inhibiting the Rho-kinase activity by Y-27632 was inactive. These results point to the potent regulation operated by the status of the cytoskeleton on the cell phenotype, and to distinct regulatory pathways involved in the control of different MMPs expression.
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PMID:Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension. 1169 80

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
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PMID:[New therapy developments in rheumatoid arthritis]. 1175 32


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