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)

The potentialities of a new non-invasive optical scanning microscopy technique were evaluated through 3D analysis of chondrocyte-matrix interactions. Five different 2D or 3D culture systems were used: (1) MonoLayer (ML) of human chondrosarcoma cell line; (2) rat or human chondrocytes encapsulated in Alginate Bead (AB); (3) human chondrocytes encapsulated in Alginate Sponge (AS); (4) Rat Femoral Head Cap (RFHC); (5) slices of knee human Osteoarthritic Cartilage (HOAC). Chondrocytes ML, AB, RFHC were incubated for 24 h in vitro in the presence of recombinant human interleukin1-beta (rhIL1-beta) and the effects on cytoskeleton organisation (F-actin filament), Focal Adhesion Kinase (FAK) expression (tyrosine kinase), collagenase B expression (metalloprotease) were studied. Furthermore, the production of intracellular IL1-beta by LPS- or rhIL1-beta-stimulated chondrocytes was shown to be partly suppressed by rhein (active metabolite of diacerhein) in all culture systems. This high resolution light microscopy gave complementary information that could be important for a better understanding of the interaction of chondrocytes with the extracellular matrix in a variety of culture devices.
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PMID:The role of 3D-microscopy in the study of chondrocyte-matrix interaction (alginate bead or sponge, rat femoral head cap, human osteoarthritic cartilage) and pharmacological application. 1091 89

Endothelins (ETs) are a family of 21-amino acid hypertensive peptides, which together with their receptors ETA and ETB are expressed in human adrenal cortex. Evidence has been provided that ETs exert a potent secretagogue effect on human adrenocortical cells, acting through both ETA and ETB receptors. Therefore, it seemed worthwhile to study the signaling cascades mediating the cortisol secretagogue effect of the two receptor subtypes. Normal adrenal glands were obtained from consenting patients undergoing unilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. Dispersed zona fasciculata-reticularis (ZF/R) cells were obtained by collagenase digestion and mechanical disaggregation. The selective activation of ETA and ETB receptors was obtained by exposing dispersed cells to ET-1 plus the ETB receptor antagonist BQ-788 and to the selective ETB receptor agonist BQ-3020, respectively. ETA and ETB receptors about equally contributed to the cortisol response of dispersed ZF/R cells to ETs. The phospholipase (PL) C inhibitor U-73122 abolished ETA-mediated secretory response, but only partially prevented the ETB-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes, while the Ca(2+)-channel blocker nifedipine was ineffective. The ETB receptor-, but not the ETA receptor-mediated cortisol response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. The inhibitors of adenylate cyclase, PKA, tyrosine kinase and lipoxygenase did not affect the secretory response to the activation of either receptor subtype. ETA-receptor activation raised inositol triphosphate (IP3) production from dispersed ZF/R cells, while ETB-receptor stimulation enhanced both IP3 and prostaglandin-E(2) production. Collectively, our findings indicate that ETs stimulate cortisol secretion from human ZF/R cells, acting through ETA receptors exclusively coupled with PLC/PKC-dependent pathway and ETB receptors coupled with both PLC/PKC- and COX-dependent cascades.
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PMID:Signaling pathways involved in the A and B receptor-mediated cortisol secretagogue effect of endothelins in the human adrenal cortex. 1117 11

Prolidase [EC 3.4.13.9] is a ubiquitously distributed imidodipeptidase that catalyzes the hydrolysis of C-terminal proline-containing dipeptides. The enzyme plays an important role in the recycling of proline for collagen synthesis and cell growth. Although, the increase in the enzyme activity is correlated with increased rate of collagen turnover, the mechanism by which prolidase is regulated remain largely unknown. In the present study we found that phosphorylation of fibroblast's prolidase may be an underlying mechanism for up regulation of the enzyme activity. Supporting evidence comes from the following observations: (1) immunoprecipitated prolidase was detected as a phosphotyrosine protein as shown by western immunoblot analysis, (2) tyrosine kinase inhibitor-erbstatin induced (in a dose dependent manner) a decrease in prolidase activity in cultured human skin fibroblasts, (3) anti-phosphotyrosine antibody reduced and phosphotyrosine phosphatase 1B antibody (anti-PTP 1B) increased (in a dose dependent manner) the prolidase activity in extract of fibroblast's homogenate, (4) decrease in prolidase activity from collagenase treated or serum starved fibroblasts can be partially prevented by incubating fibroblast's homogenate extract with anti-PTP 1B antibody. These results provide evidence that prolidase is phosphotyrosine enzyme and suggest that the activity of prolidase may be up regulated by the enzyme phosphorylation.
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PMID:Phosphorylation of prolidase increases the enzyme activity. 1145 88

Changes in cellular morphology induced as a consequence of direct perturbation of cytoskeletal structure with network-specific targeting agents (i.e. microfilament- or microtubule-disrupting drugs) results in the stimulated expression of a specific subset of genes. Transcription of c-fos, collagenase, transforming growth factor-beta, actin, urokinase plasminogen activator and its type-1 inhibitor (PAI-1) appears to be particularly responsive to shape-activated signaling pathways. Cytochalasin D (CD) or colchicine treatment of contact-inhibited and serum-deprived vascular smooth muscle (R22) cells was used, therefore, as a model system to evaluate morphology-associated controls on PAI-1 gene regulation in the absence of added growth factors. PAI-1 transcript levels in quiescent R22 cells increased rapidly and in a CD-concentration-dependent fashion, with kinetics of expression paralleling the morphological changes. Colchicine concentrations that effectively disrupted microtubule structure and reduced the cellular 'footprint' area (to approximately that of CD treatment) also stimulated PAI-1 synthesis. Shape-related increases in PAI-1 mRNA synthesis were ablated by prior exposure to actinomycin D. Unlike the mechanism of induction in growth-factor-stimulated cells, CD- and colchicine-induced PAI-1 expression required on-going protein synthesis (i.e. it was a secondary response). Although PAI-1 is a TGF-beta-regulated gene and TGF-beta expression is also shape dependent, an autocrine TGF-beta loop was not a factor in CD-initiated PAI-1 transcription. Since CD exposure resulted in actin microfilament disruption and subsequent morphological changes, with uncertain effects on interactions between signaling intermediates or 'scaffold' structures, a pharmacological approach was selected to probe the pathways involved. Signaling events leading to PAI-1 induction were compared with colchicine-treated cells. CD- as well as colchicine-stimulated PAI-1 expression was effectively and dose dependently attenuated by the MEK inhibitor PD98059 (in the 10 to 25 microM concentration range), consistent with the known MAP kinase dependency of PAI-1 synthesis in growth-factor-stimulated cells. Reduced PAI-1 mRNA levels upon exposure to genistein prior to CD addition correlated with inhibition of ERK1/2 activity, implicating a tyrosine kinase in shape-dependent MEK activation. Src-family kinases, moreover, appeared to be specific upstream elements in the CD- and colchicine-dependent pathways of PAI-1 transcription since both agents effectively activated pp60(c-src) kinase activity in quiescent R22 cells. The restrictive (src-family) kinase inhibitor PP1 completely inhibited induced, as well as basal, ERK activity in a coupled immunoprecipitation myelin-basic-protein-phosphorylation assay and ablated shape-initiated PAI-1 mRNA expression. These data suggest that PP1-sensitive tyrosine kinases are upstream intermediates in cell-shape-associated signaling pathways resulting in ERK1/2 activation and subsequent PAI-1 transcription. In contrast to the rapid and transient kinetics of ERK activity typical of serum-stimulated cells, the ERK1/2 response to CD and colchicine is both delayed and relatively sustained. Collectively, these data support a model in which MEK is a focal point for the convergence of shape-initiated signaling events leading to induced PAI-1 transcription.
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PMID:MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks. 1211 65

Periodontitis is associated with enhanced production of cytokines, prostaglandins and matrix metalloproteinases (MMPs). The aim of this study was to investigate the production and regulation of MMP-1 and MMP-3 in human gingival fibroblasts challenged with the cytokines interleukin-lbeta (IL-1beta), tumor necrosis factor alpha (TNFalpha) or epidermal growth factor (EGF). The results showed that gingival fibroblasts constitutively produce MMP-1 and MMP-3, and that the cytokines IL-1beta, TNFalpha and EGF increase both MMP-1 and MMP-3 production in gingival fibroblasts. The upregulation by the cytokines was apparent at 8 h of incubation and increased thereafter continuously during 48 h of incubation. The upregulation of MMPs, induced by IL-1beta or TNFalpha, was reduced by the cyxlooxygenase-2 (COX-2) inhibitor NS-398, the p38 MAP-kinase inhibitor SB 203580, and the tyrosine kinase inhibitor herbimycin A. In addition, MMP-1 and MMP-3 production, induced by IL-1beta, TNFalpha or EGF, was strongly reduced by the presence of the glucocorticoid dexamethasone. Our findings demonstrate that the cytokines IL-1beta, TNFalpha and EGF, respectively, enhance both MMP-1 and MMP-3 production in human gingival fibroblasts, and that the signal pathways COX-2, MAP-kinases and tyrosine kinases are partly involved in the production of MMPs.
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PMID:Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts. 1220 92

The purpose of this study was to determine the role of p42/p44 mitogen-activated protein kinase (MAPK) in alpha(1)-adrenergically and cholinergically stimulated protein secretion in rat lacrimal gland acinar cells and the pathways used by these agonists to activate MAPK. Acini were isolated by collagenase digestion and incubated with the alpha(1)-adrenergic agonist phenylephrine or the cholinergic agonist carbachol, and activation of MAPK and protein secretion were then measured. Phenylephrine and carbachol activated MAPK in a time- and concentration-dependent manner. Inhibition of MAPK significantly increased phenylephrine- and carbachol-induced protein secretion. Inhibition of EGF receptor (EGFR) with AG1478, an inhibitor of the EGFR tyrosine kinase activity, significantly increased phenylephrine- but not carbachol-induced protein secretion. Whereas phenylephrine-induced activation of MAPK was completely inhibited by AG1478, activation of MAPK by carbachol was not. Phenylephrine stimulated tyrosine phosphorylation of the EGFR, whereas carbachol stimulated p60(Src), and possibly Pyk2, to activate MAPK. We conclude that, in the lacrimal gland, activation of MAPK plays an inhibitory role in alpha(1)-adrenergically and cholinergically stimulated protein secretion and that these agonists use different signaling mechanisms to activate MAPK.
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PMID:Alpha 1-adrenergic and cholinergic agonists activate MAPK by separate mechanisms to inhibit secretion in lacrimal gland. 1238 18

Prolactin (PRL) was found to have a stimulatory effect on adrenal steroidogenesis in vivo and in vitro in several species including pigs. PRL signal transduction pathways, however, in adrenocortical cells are poorly recognized. Therefore, the goal of this paper is to ascertain the involvement of protein kinase C (PKC) and tyrosine kinases in PRL signaling in porcine adrenal cortex. Adrenals were harvested from locally slaughtered mature gilts. Cortical cells were dispersed by sequential treatment with collagenase. The cells were seeded into 24-well culture plates at a density of 3 x 10(5)/mL. Cells were incubated with or without PRL (500 ng/mL), ACTH (5 nM--a positive control), tyrosine kinase inhibitor--genistein (1; 2.5 or 5 microM), PKC inhibitor--sphingosine (20-1000 nM) and PKC activators--diacylglycerol (DiC8; 10-100 microM) and phorbol ester (PMA; 1-1000 nM). All incubations were performed for 8 h (95% air and 5% CO(2), 37 degrees C). PRL and ACTH (P < 0.05) increased cortisol and androstenedione (A(4)) secretion. DiC8 and PMA mimicked the stimulatory effect of PRL. Sphingosine (P < 0.05) suppressed basal and PRL-stimulated steroid secretion. Genistein inhibited (P < 0.05) PRL-stimulated cortisol secretion and enhanced (P < 0.05) basal and PRL-stimulated A(4) secretion. Moreover, PKC activation was assessed by measuring the specific association of [3H]phorbol dibutyrate ([3H]PDBu) with adrenocortical cells after treatment with PRL or ionomycin (a positive control). PRL (within 2-3 min) and ionomycin (within 2-5 min) increased (P < 0.05) specific binding of [3H]PDBu to the porcine adrenocortical cells. In addition, PRL did not augment the cortisol and A(4) secretion by PKC-deficient adrenocortical cells. In conclusion, presented results support the hypothesis that PKC and tyrosine kinases are involved in PRL signaling in adrenocortical cells in pigs. Moreover, activation of PKC is associated with the increased secretion of cortisol and A(4).
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PMID:Prolactin signaling in porcine adrenocortical cells: involvement of protein kinases. 1245 55

Human skin is exposed to solar ultraviolet radiation. Ultraviolet radiation damages human skin and results in an old and wrinkled appearance, called photoaging. We have previously reported that molecular mechanisms by which ultraviolet light causes photoaging involve activation of growth factor and cytokine receptors in keratinocytes and dermal cells. They lead to downstream signal transduction through activation of mitogen-activated protein kinase (extracellular signal-regulated kinase, c-jun N-terminal protein kinase, and p38) pathways. These signaling pathways converge in the nucleus of cells to form an activated complex of transcription factor activator protein 1 (cFos/cJun), which induces matrix metalloproteinases that degrade skin connective tissue. In addition to cell surface receptor activation, generation of reactive oxygen species by ultraviolet radiation is believed to be critical in triggering mitogen-activated protein kinase pathways. We investigated the ability of (i) ultraviolet irradiation to generate reactive oxygen species in human skin in vivo; and (ii) genistein, which possesses both tyrosine kinase inhibitory and antioxidant activities, and n-acetyl cysteine, which can be converted into the endogenous antioxidant glutathione, to impair responses to ultraviolet light that eventuate in photoaging in human skin in vivo. Ultraviolet irradiation caused a rapid and significant increase in hydrogen peroxide levels in human skin in vivo. Pretreatment of human skin with genistein inhibited ultraviolet-induced epidermal growth factor receptor tyrosine kinase activity, whereas n-acetyl cysteine did not. Genistein inhibited ultraviolet induction of both extracellular signal-regulated kinase and cJun N-terminal protein kinase activities. n-Acetyl cysteine inhibited extracellular signal-regulated kinase but not cJun N-terminal protein kinase activation. Both genistein and n-acetyl cysteine prevented ultraviolet induction of cJun protein. Consistent with this, genistein and n-acetyl cysteine blocked ultraviolet induction of cJun-driven enzyme, collagenase. Neither genistein nor n-acetyl cysteine acted as sunscreens as they had no effect on ultraviolet-induced erythema. These data indicate that compounds similar to genistein and n-acetyl cysteine, which possess tyrosine kinase inhibitory and/or antioxidant activities, may prevent photoaging.
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PMID:Topical N-acetyl cysteine and genistein prevent ultraviolet-light-induced signaling that leads to photoaging in human skin in vivo. 1271 90

Interleukin 10 (IL-10) stimulates rapid nuclear translocation and binding of a 22 kDa protein, termed interleukin 10 enhancer 1 (IL-10E1), to a novel enhancer element (i.e. HTE-1) of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene to upregulate TIMP-1 expression. IL-10E1 signaling involves tyrosine phosphorylation of the IL-10R JAK1 (Janus kinase) and TYK2 (tyrosine kinase) receptor kinases and tyrosine phosphorylation of two tyrosine moieties (Y57 and Y62) of a LIM domain of the IL-10E1 protein. In this paper, the studies showed that two tyrosine residues (Tyr(446) and Tyr(496)) located in the cytoplasmic domain of the IL-10R alpha chain were required for receptor function, and for phosphorylation and activation of IL-10E1. Immunoprecipitation studies revealed that 12 amino-acid peptides encompassing either of these two tyrosine residues in phosphorylated form coprecipitated IL-10E1 and blocked ligand-dependent IL-10E1 phosphorylation in a cell-free system. In contrast, peptides containing serine substitutions for Tyr(446) and Tyr(496), and tyrosine-phosphorylated peptides containing Tyr(230) or Tyr(252/259) did not prevent IL-10E1 activation or signaling. To confirm these observations in vivo, fusion protein constructs were made between a modified form of green fluorescent protein or GFP and the intact IL-10E1 protein (IL-10E1-MmGFP) and n-terminal peptides of the IL-10E1 protein (i.e. nt-nls-MmGFP and mutant sequences identified as nt-nls mC61-MmGFP and nt-nls mY57/mY62-MmGFP peptides). Confocal microscopy revealed that IL-10 triggered transport to the nucleus of IL-10E1-MmGFP, nt-nls-MmGFP, and nt-nls mC61-MmGFP by 10-30 min in HPCA-10a (human prostrate cancer cells; derived from Gleason sum 10 tumor tissue) cells. IL-10 failed to induce nuclear translocation of the mY57/mY62-MmGFP peptides with point mutations of the two tyrosine groups. Coinjection of nt-nls-MmGFP with the IL-10R Tyr(446) and Tyr(496) amino-acid residues completely blocked ligand signaling. Coinjection of peptides containing either serine substitutions for Tyr(446) and Tyr(496) or Tyr(230) and Tyr(252/259) failed to block nt-nls-MmGFP signaling. The data demonstrate that IL-10E1 is directly recruited to the ligand-activated IL-10R by binding to specific phosphotyrosine groups which control tyrosine phosphorylation of the LIM domain of the IL-10E1 protein (i.e. Y57/Y62 groups) and IL-10E1 activation.
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PMID:IL-10 signaling via IL-10E1 is dependent on tyrosine phosphorylation in the IL-10R alpha chain in human primary prostate cancer cell lines. 1280 85

The interleukin-10 (IL-10) activation of Janus kinase (JAK) family members (JAK1/TYK2) and IL-10E1 is subsequently inactivated by approximately 3-4 h in primary prostate tumor lines. We examined the effect of proteasome inhibition on IL-10 activation of the IL-10E1 pathway following stimulation of HPCA-10a cells. Treatment of HPCA-10a cells with the proteasome inhibitor, N-acetyl-L-leucinyl-L-leucinyl-norleucinal (LLnL), led to stable tyrosine phosphorylation of the IL-10 receptor and IL-10E1 following stimulation. Further investigation showed that these stable phosphorylation events were the result of prolonged activation of JAK1 and TYK2 plus IL-10E1. IL-10E1 signaling normally induced the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and LLnL treatment of the HPCA-10a and HPCA-10c cells significantly enhanced IL-10 induction of TIMP-1 levels to block tumor cell invasion in modified Boyden chamber invasion assays. These observations were confirmed using pharmacologic inhibitors by Western blot and ELISAs. In the presence of LLnL, stable phosphorylation of IL-10E1 and induction of TIMP-1 was abrogated if the tyrosine kinase inhibitor, staurosporine, was added. The effect of staurosporine on IL-10E1 phosphorylation and TIMP-1 could be overcome if the phosphatase inhibitor, vanadate, was also added, suggesting that phosphorylated IL-10E1 could be stabilized by phosphatase, but not by proteasome inhibition. These observations are consistent with the hypothesis that proteasome-mediated protein degradation can modulate the activity of the IL-10E1 pathway and TIMP-1 induction by regulating the deactivation of JAK1/TYK2.
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PMID:Interleukin-10 activation of the interleukin-10E1 pathway and tissue inhibitor of metalloproteinase-1 expression is enhanced by proteasome inhibitors in primary prostate tumor lines. 1286 Oct 49


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