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)

Magnesium transport across the plasma membrane of cardiac and liver cells appears to be under hormonal control. The increase in cytosolic cAMP, following the adrenergic stimulation of both cell types, results in a major Mg2+ efflux from perfused rat hearts or livers and from collagenase-dispersed ventricular myocytes or hepatocytes. By contrast, the activation of protein kinase C by carbachol, vasopressin, phorbol-myristate acetate or diacylglycerol analogs induces Mg2+ accumulation in either of the experimental models. As for the role of intracellular compartments on Mg2+ homeostasis, the cAMP-mediated Mg2+ efflux largely depends on the mobilization of Mg2+ from mitochondria via the mitochondrial adenine nucleotide translocase. By contrast, Mg2+ influx appears to be related to the endo(sarco)plasmic reticulum and its dynamic handling of cytosolic Ca2+.
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PMID:Cell magnesium transport and homeostasis: role of intracellular compartments. 826 15

The effects of endothelin-1 (ET-1) on protein synthesis and phosphoinositide (PI) hydrolysis were investigated in ventricular myocytes isolated by collagenase digestion of adult rat hearts. The maximum stimulation of protein synthesis by ET-1 was about 35% and the EC50 value was about 0.3 nM. The stimulation was exerted at the translational stage since it was insensitive to inhibition by actinomycin D. The maximum stimulation of PI hydrolysis by ET-1 as measured by the formation of [3H]inositol phosphates was about 11-fold and the EC50 value was about 0.7 nM. The ET-1 analogue sarafotoxin-6b stimulated protein synthesis by a maximum of 27% and stimulated PI hydrolysis about 8- to 9-fold. The EC50 values were 1.6 nM and 0.6 nM, respectively. Other endothelins stimulated protein synthesis and PI hydrolysis in the following order of potency: ET-1 approximately ET-2 > ET-3. This order of potency suggests that the stimulation of both protein synthesis and PI hydrolysis is mediated through the ETA receptor. Although both angiotensin II and [Arg]vasopressin stimulated PI hydrolysis significantly, the stimulation was less than 60%, i.e., much less than the stimulation by ET-1 and its analogues. Neither insulin nor substance P stimulated PI hydrolysis. Stimulation of protein synthesis by ET-1 and its analogues correlated strongly with the stimulation of PI hydrolysis and we suggest that the stimulation of protein synthesis may be dependent on the stimulation of PI hydrolysis. We hypothesize that the mechanism may involve a protein kinase C-mediated increase in intracellular pH.
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PMID:Stimulation of adult rat ventricular myocyte protein synthesis and phosphoinositide hydrolysis by the endothelins. 838 85

Mesothelial cells play a critical role in the remodeling process that follows serosal injury. Although mesothelial cells are known to synthesize a variety of extracellular matrix components including types I, III, and IV collagens, their potential to participate in matrix degradation has not been explored. We now report that human pleural and peritoneal mesothelial cells express interstitial collagenase, 72- and 92-kD gelatinases (type IV collagenases), and the counterregulatory tissue inhibitor of metalloproteinases (TIMP). Our initial characterization of the mesothelial cell metalloenzymes and TIMP has revealed: (a) they are likely identical to corresponding molecules secreted by other human cells; (b) they are secreted rather than stored in an intracellular pool; (c) a primary site of regulation occurs at a pretranslational level; (d) phorbol myristate acetate, via activation of protein kinase C, upregulates expression of collagenase, 92-kD gelatinase, and TIMP, but has no effect on expression of 72-kD gelatinase; and (e) lipopolysaccharide fails to upregulate the biosynthesis of either metalloproteinases or TIMP. Of particular interest is the observation that the state of cellular differentiation has a striking influence on the expression of metalloenzymes and TIMP, such that epitheloid cells display a more matrix-degradative phenotype (increased 92-kD gelatinase and decreased TIMP) than their fibroblastoid counterparts. We speculate that mesothelial cells directly participate in the extracellular matrix turnover that follows serosal injury via elaboration of metalloproteinases and TIMP. Additionally, the reactive cuboidal mesothelium which is characteristic of the early response to serosal injury may manifest a matrix-degenerative phenotype favoring normal repair rather than fibrosis.
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PMID:Metalloproteinases and tissue inhibitor of metalloproteinases in mesothelial cells. Cellular differentiation influences expression. 838 95

Lysophosphatidylcholine (LPC) increases extracellularly during ischemia in vivo in both animals and man as judged by measurements from venous effluents, but more recent studies have shown little or no increase in buffer-perfused, isolated heart preparations. The appearance of LPC in blood and lymph in animals and in venous effluents in man in response to ischemia suggests a vascular site for the production of LPC. The present study was performed to assess whether thrombin could stimulate phospholipase A2 in endothelial cells and whether this would evoke an increase in and release of LPC. Endothelial cells were disassociated from canine aortas by incubating with 0.1% collagenase for 20 min. Cells were plated and allowed to grow to confluence. Measurement of LPC was performed using Bligh and Dyer extraction of lipids, high performance liquid chromatography separation, and quantification of LPC using a recently developed radiometric assay employing [3H]acetic anhydride. Incubation of endothelial cells with thrombin (0.05 unit/ml) resulted in a 2.5-fold increase in LPC to 2.3 +/- 0.1 nmol/mg of protein at 2 min (p < 0.01) and returned to control levels within 20 min. The increase in LPC induced by thrombin exhibited a concentration-dependent response with an ED50 = 0.04 unit/ml. A concentration-dependent increase in LPC was also elicited by stimulation with the peptide portion of the thrombin receptor's tethered ligand SFLLRNPNDKYEPF with an ED50 = 8 microM. The LPC produced was rapidly and completely released into the surrounding media. Hirudin completely blocked the thrombin-induced increase in LPC. Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide (0.1 microM), which rapidly inactivates thrombin's proteolytic activity in situ without impairing binding, or phenyl-prolyl-arginyl-chloromethyl ketone (PPACK, 5 nM), which inactivates thrombin due to chemical alteration of the proteolytic site, each prevented the increase in LPC in response to thrombin. Stimulation of protein kinase C with phorbol 12-myristate-13-acetate (PMA, 1 microM) enhanced the response to thrombin. In contrast, staurosporine (100 nM), H7 (15 microM), or chronic treatment with PMA for 20 h to down-regulate protein kinase C completely prevented the increase in LPC in response to thrombin. Thus, thrombin stimulation of endothelial cells in vivo during ischemia may be a primary mechanism contributing to the marked increase in LPC extracellularly during ischemia.
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PMID:Thrombin-induced release of lysophosphatidylcholine from endothelial cells. 839 49

Rat mucosal keratinocytes serially propagated under permanently serum-free conditions responded to interleukin (IL)-1 beta/IL-alpha and to transforming growth factor (TGF)-alpha/epidermal growth factor (EGF) (as well as to 12-O-tetradecanoylphorbol-13-acetate (TPA)) by upregulation of M(r) 95,000 gelatinase (MMP-9) (M(r) 95K GL) and fibroblast-type collagenase (MMP-1) (FIB-CL), whereas control cells expressed barely detectable levels of either of these enzymes. The cells secreted 8-10 micrograms/10(6) cells/day (M(r) 95K GL) and 2-3 micrograms/10(6) cells/day (FIB-CL) of enzyme protein for at least 24 h when maximally induced. This level was attained only after a 24-h lag period, and the earliest emergence of enzyme protein in the culture medium required 10-14 h. IL-1 beta was by far the most potent cytokine with maximal effect already at 10(-10) M, whereas IL-1 alpha, TGF-alpha, and EGF required 20-100-fold higher concentrations. Pretreatment of the cells with TPA (10(-7) M) abolished the subsequent response to IL-1 beta, TGF-alpha, and EGF and at the same time resulted in > 90% reduction of cytosolic protein kinase C activity. Surprisingly, staurosporine, a potent kinase inhibitor, not only failed to block growth factor/cytokine responses but itself stimulated expression of the enzymes at a magnitude comparable to TPA. The inducing effect of TGF-alpha/EGF was down-regulated by 70-85% by 10(-7) M dexamethasone. Dexamethasone was less effective in ablating the IL-1 beta response yielding 60% reduction M(r) 95K GL and little or no reduction of FIB-CL. Dexamethasone also failed to block the TPA response.
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PMID:Interleukin-1 beta and transforming growth factor-alpha/epidermal growth factor induce expression of M(r) 95,000 type IV collagenase/gelatinase and interstitial fibroblast-type collagenase by rat mucosal keratinocytes. 839 30

Burmese Russell's viper venom (RVV) caused a dose- and temperature-dependent stimulation of insulin secretion from islets of Langerhans isolated from rat pancreas by collagenase digestion. RVV stimulated both basal and glucose-induced insulin secretion at concentrations which did not compromise islet cell viability as assessed by exclusion of trypan blue dye. The effects of RVV on insulin secretion could not be attributed to the activation of protein kinase C (PKC), since down-regulation of PKC by prolonged exposure to a tumour-promoting phorbol ester did not abolish subsequent secretory responses to RVV. However, RVV-induced insulin secretion was inhibited in the absence of extracellular Ca2+, and RVV did not stimulate insulin secretion from Ca(2+)-clamped electrically permeabilized islets at either substimulatory (50 nmol/l) or stimulatory (10 mumol/l) concentrations of Ca2+, suggesting that changes in cytosolic Ca2+ are important in the stimulation of insulin secretion by RVV. The phospholipase A2 (PLA2) inhibitor quinacrine caused a dose-dependent inhibition of RVV-induced insulin secretion, suggesting that the activation of PLA2, perhaps in response to Ca2+ influx, may be partially responsible for RVV-induced insulin secretion.
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PMID:Russell's viper venom stimulates insulin secretion from rat islets of Langerhans. 842 73

We have investigated the effect of electroporation on the expression of collagen alpha 1(I), collagenase, c-fos and c-jun genes in human dermal fibroblasts (HDF), human smooth muscle cells (HSMC) and HeLa cells. Collagenase and collagen mRNA levels were respectively increased and decreased in a voltage-dependent manner in HDF harvested 2 days after a sham electroporation. These effects were still observed 10 days after electroporation. Similar effects occurred in electroporated HSMC. Neither collagen nor collagenase mRNAs were detected in control or electroporated HeLa cells. c-fos and c-jun mRNA levels were also increased in electroporated HDF, HSMC and HeLa cells harvested 1 h after plating. This suggests that factor AP1 (fos/jun) could mediate the up-regulation of collagenase expression in electroporated HDF and HSMC. When electroporation of HDF was performed in the presence of H7, an inhibitor of protein kinase C, no increase in collagenase mRNA level was observed, suggesting that protein kinase C might be involved in the transduction of the effect. All the effects reported were also suppressed when cells were electroporated in a medium containing EGTA, suggesting that Ca2+ might mediate the transduction of this effect.
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PMID:Modulation of expression of endogenous collagenase and collagen genes by electroporation: possible involvement of Ca2+ and protein kinase C. 843 82

Calcium tolerant rabbit cardiomyocytes, isolated by collagenase perfusion, were preincubated for varying periods of time followed by resuspension in fresh media and centrifugation into an ischaemic pellet with restricted extracellular fluid. Pellets were incubated for 240 min under oil at 37 degrees C to mimic severe ischaemia. Time to onset of ischaemic contracture (rod to square transformation) and trypan blue permeability following resuspension in 85 mOSM media were monitored at sequential times. The protocol of Series 1 was a 5-10 min pre-incubation, immediately followed by ischaemic pelleting. Preincubation with pinacidil (50 microM) protected cells from ischaemic insult, but pinacidil added only into the ischaemic pellet did not protect. Protection was abolished by the protein kinase (PKC) inhibitors chelerythrine (10 microM) added with pinacidil and calphostin C (200nM) added only into the ischaemic pellet. Neither PKC inhibitor had an effect on injury of untreated ischaemic myocytes (data not shown). Series 2-5 were preconditioning protocols with a 10 min intervention period, followed by a 30 min oxygenated drug-free period, prior to ischaemic pelleting. In series 2 pinacidil protected cells from ischaemic insult and this protection was abolished when glyburide (10 microM) was present during preincubation, or during post-incubation and ischaemia. Glyburide only partially inhibited the protection when glyburide was added only into the ischaemic pellet. In Series 3, 8-sulfophenyltheophyline (SPT)(100 microM) or adenosine deaminase during preincubation, or SPT only added into the ischaemic pellet abolished pinacidil's protection. In Series 4, cardiomyocytes were ischaemically preconditioned by pelleting for 10 min followed by 30 min reoxygenation. Glyburide during initial ischaemic blocked protection, but when added during post incubation and into the final pellet protection was not reduced. In Series 5 8-cyclopentyl-1,3,dipropylxanthine (DPCPX) (10 microM) added into the final pellet abolished protection by pinacidil, but not protection following ischaemic preconditioning. In contrast to pinacidil, ischaemically preconditioned cells maintain protection in the presence of glyburide, indicating that: (1) pinacidil does not exactly mimic preconditioning and (2) ischaemically preconditioned cells do not require opened K+ATP channels for protection, although they appear to be important during initiation of the preconditioned state. It is hypothesized that pinacidil opening of K+ channels may facilitate induction of preconditioning.
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PMID:Potassium channels and preconditioning of isolated rabbit cardiomyocytes: effects of glyburide and pinacidil. 852 37

The reorganization of extracellular matrix (ECM) is an important function in many biological and pathophysiological processes. Culture of fibroblasts in a three-dimensional collagenous environment represents a suitable system to study the underlying mechanisms resulting from cell-ECM interaction, which leads to reprogramming of fibroblast biosynthetic capacity. The aim of this study was to identify receptors that transduce ECM signals into cellular events, resulting in reprogramming of connective tissue metabolism. Our data demonstrate that in human skin fibroblasts alpha 1 beta 1 and alpha 2 beta 1 integrins are the major receptors responsible for regulating ECM remodeling: alpha 1 beta 1 mediates the signals inducing downregulation of collagen gene expression, whereas the alpha 2 beta 1 integrin mediates induction of collagenase (MMP-1). Applying mAb directed against different integrin subunits resulted in triggering the heterodimeric receptors and enhancing the normal biochemical response to receptor ligation. Different signal transduction inhibitors were tested for their influence on gel contraction, expression of alpha 1(I) collagen and MMP-1 in fibroblasts within collagen gels. Ortho-vanadate and herbimycin A displayed no significant effect on any of these three processes. In contrast, genistein reduced lattice contraction, and completely inhibited induction of MMP-1, whereas type I collagen down-regulation was unaltered. Calphostin C inhibited only lattice contraction. Taken together, these data indicate a role of tyrosine-specific protein kinases in mediating gel contraction and induction of MMP-1, as well as an involvement of protein kinase C in the contraction process. The data presented here indicate that different signaling pathways exist leading to the three events discussed here, and that these pathways do not per se depend upon each other.
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PMID:Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by alpha 1 beta 1 and alpha 2 beta 1 integrins. 855 56

The cellular mechanisms responsible for the connective tissue changes produced by chronic exposure to UV light are poorly understood. Collagenase, a metalloproteinase, initiates degradation of types I and III collagen and thus plays a key role in the remodeling of dermal collagen. Collagenase synthesis by fibroblasts and keratinocytes involves the protein kinase C (PKC) second messenger system, and corticosteroids have been shown to suppress its synthesis at the level of gene transcription. Long-wavelength UV light (UVA, 320-400 nm) stimulates the synthesis of interstitial collagenase, as well as increasing PKC activity, in human skin fibroblasts in vitro. This study explores the regulation of collagenase expression by UVA in cultured human skin fibroblasts. Specifically, the time course, the effect of actinomycin D, an inhibitor of RNA synthesis, as well as the effect of PKC inhibitors and dexamethasone on expression of collagenase following UVA irradiation were examined. After UVA irradiation, collagenase mRNA rose rapidly between 4 and 12 h postirradiation, peaking 18 h post-UVA. Actinomycin D completely suppressed the UVA-induced increase in collagenase mRNA. Thus, new RNA synthesis is required for the UVA-induced increase in collagenase mRNA. The PKC inhibitor, H-7, blocked the increase in collagenase mRNA in response to UVA in a dose-dependent manner. Similarly, dexamethasone also inhibited collagenase gene expression induced by UVA in a dose-dependent fashion; the majority of the inhibitory effect was seen within the first 4 h after irradiation. These studies demonstrate that the effect of UVA on collagenase gene expression is regulated at the pretranscriptional level and may involve the PKC pathway.
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PMID:Regulation and inhibition of collagenase expression by long-wavelength ultraviolet radiation in cultured human skin fibroblasts. 857 Jul 3


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