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 cyclic growth activity of the hair follicle is characterized by substantial remodelling of the extracellular matrix, yet, little is known about the proteolytic activities regulating this process. In murine skin, hair cycling is highly synchronized and is associated with dramatic remodeling of all skin compartments. We therefore have assessed, in this pilot study, proteolytic activities of murine skin from various stages of the depilation-induced hair cycle. We show that the defined proteolytic activities displayed by organ cultured intact mouse skin differ between hair cycle stages. Skin with all follicles in telogen or mid anagen displayed only minimal lysis of collagen type I gels, while early anagen skin had significant collagenase activity. Skin cultured on gelatin gels at the air-liquid interphase ('histoculture') completely lysed the gel within 5 days when all follicles were in early anagen, while this was not observed with mid and very late-anagen skin. Zymography of conditioned medium from these cultures revealed the secretion of activated interstitial collagenase and of gelatinases of 72 and 92 kDa, with the maximum of interstitial collagenase activity secreted by anagen IV skin. Addition of TPA or TNF-alpha to the culture medium stimulated secreted collagenase type I activity. The C 57 BL-6 mouse offers an attractive model for dissecting and manipulating hair cycle-associated proteolysis in a physiologically relevant system.
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PMID:Correlation of proteolytic activities of organ cultured intact mouse skin with defined hair cycle stages. 791 39

The indol alkaloid staurosporine is a potent inhibitor of protein kinase C, but has also been shown to have certain effects paradoxically similar to those of protein kinase C-activating phorbol esters. We show here that collagenase mRNA expression is stimulated by 10 nM staurosporine in normal and ras-oncogene-transformed rat fibroblasts. The kinetics of collagenase mRNA induction by staurosporine were slow compared to induction by phorbol ester. Staurosporine induction of the collagenase promoter appeared to be mediated via the TPA response element (TRE). Induction did not involve any increase in jun mRNA expression and did not require expression of c-Jun. Prolonged treatment with phorbol ester to deplete protein kinase C did not inhibit stimulation of the collagenase promoter by staurosporine. Instead, involvement of cAMP-dependent protein kinase (PKA) was indicated by inhibition of staurosporine induction by the PKA inhibitor H-89. In addition, raised levels of cAMP were observed during the first hour of staurosporine treatment. Altogether, our data indicate that staurosporine induces a PKA-dependent pathway leading to c-Jun-independent activation of the collagenase TRE element.
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PMID:Induction of the collagenase phorbol ester response element by staurosporine. 796 79

Recessive dystrophic epidermolysis bullosa (RDEB) is a mutilating disease of the skin characterized by recurrent blistering and erosions that result from compromised integrity of the basement membrane zone. In this study, fibroblasts derived from the skin of RDEB patients were characterized for expression of the major metalloproteinases, particularly interstitial collagenase. Consistent with previous reports on increased collagenase protein levels in fibroblasts from some RDEB patients, we found that steady-state levels of collagenase mRNA were significantly increased in fibroblast strains derived from three of five RDEB patients compared to fibroblasts obtained from normal donors. Stromelysin mRNA was elevated in the same three fibroblast strains, whereas expression of neither the 72- nor the 92-kDa type IV collagenases was different from that of controls. Tissue inhibitor of metalloproteinases was expressed in RDEB fibroblasts at levels similar to those observed in normal fibroblasts. To investigate the mechanism behind the steady-state elevation in collagenase and stromelysin expression, AP-1 expression and activation were studied. Although levels of Jun expression were not different from those seen in normal fibroblasts, AP-1 activity, as assessed by ability to bind to a TPA response element-containing oligonucleotide, was endogenously elevated in RDEB fibroblasts compared to normal fibroblasts. Transfection studies using a plasmid construct containing the collagenase promoter linked to a CAT reporter gene demonstrated that RDEB fibroblasts were able to support active transcription of the promoter compared to normal fibroblasts. These studies support the hypothesis that RDEB fibroblasts contain chronically activated AP-1, and perhaps other transactivating factors, that contribute to the cellular phenotype of collagenase and stromelysin overexpression.
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PMID:Constitutive activation of the collagenase promoter in recessive dystrophic epidermolysis bullosa fibroblasts: role of endogenously activated AP-1. 814 67

Adenovirus E1A proteins inhibit expression of the collagenase gene but activate expression of the c-jun gene. Both effects are mediated by TPA-responsive elements (TREs), the binding sites for members of the AP-1 transcription factor family. By a process that is independent of the retinoblastoma gene product, E1A distinguishes between different AP-1 factors: in vivo binding of Jun/Jun homodimers and Jun/Fos heterodimers to the collagenase TRE is totally blocked by E1A while, in contrast, there is no inhibition of Jun/ATF-2 binding to the TRE sequences in the c-jun promoter. Altered phosphorylation of the DNA binding domain of cJun is not involved in the inhibition of cJun/cJun and cJun/cFos binding. E1A does, however, cause hyperphosphorylation of the transactivation domain of cJun, which is likely to be responsible for the enhanced c-jun transcription by E1A mediated through cJun/ATF-2 heterodimers.
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PMID:Adenovirus E1A negatively and positively modulates transcription of AP-1 dependent genes by dimer-specific regulation of the DNA binding and transactivation activities of Jun. 825 81

Several promoter elements with sequence similarity to the prototype TPA-responsive element (TRE) were compared by mobility-shift analyses. Activities within whole cell extracts were identified that bind to the TRE-like elements in the collagenase, the somatostatin, and the c-jun promoters. The corresponding factors appeared to differ in their degree of selectivity for these TRE-like sequences. One protein species bound equally well to all TREs. In addition, a subset of specific activities recognised only the somatostatin and the c-jun-derived element and one DNA-protein complex had exclusive specificity for the TRE present in the c-jun promoter. By antibody 'supershift' assays some of the protein components of the specific complexes were identified as CREB- and ATF-related products. Based on these data we postulate that bZip protein dimers differ in their ability to tolerate variations from the canonical TRE sequence. We propose that TRE-like promoter elements are distinguished by this ability to bind to different subsets of a family of related transcription factors.
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PMID:Different TRE-related elements are distinguished by sets of DNA-binding proteins with overlapping sequence specificity. 847 9

Our previous work demonstrated that collagenase mRNA levels are increased in fibroblasts derived from patients with cutis laxa (CL). To pursue the mechanism of the upregulation of collagenase expression, we investigated transcriptional levels of the collagenase gene in CL fibroblasts. Fibroblasts cultured from the skin of three congenital CL patients were studied. Northern blot hybridization revealed 2.8- to 7.3-fold increases in collagenase mRNA levels in CL fibroblasts compared with normal cells. Nuclear run-off experiments demonstrated that the transcription rate of the collagenase gene in nuclei isolated from the same cells was 5.1- to 10.2-fold higher in the CL fibroblasts than in the controls. Transient transfection of a normal collagenase promoter-CAT construct into the cells further showed significantly enhanced transcriptional activity in CL but not in normal fibroblasts. Experiments of transient transfection of deleted or small substituted collagenase promoter-CAT constructs indicated that collagenase transcription in CL fibroblasts was activated the TPA-responsive element site of the collagenase promoter gene. Although the levels of Jun and Fos gene expression did not differ from those observed in normal fibroblasts, AP-1-binding activity, as measured by the ability to bind to an oligonucleotide containing a TPA-responsive element, was significantly elevated in CL fibroblasts as compared with normal fibroblasts. These data suggest that collagenase expression is upregulated at the transcriptional level by endogenous activation of DNA binding of AP-1 in CL fibroblasts [corrected].
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PMID:Collagenase gene expression in cutis laxa fibroblasts is upregulated by transcriptional activation of the promoter gene through a 12-0-tetradecanoyl-phorbol-13-acetate (TPA)-responsive element. 861 96

Cellular interactions mediated by both contact-dependent and contact-independent mechanisms are probably important to maintain luteal function. The present studies were performed to evaluate the effects of luteotropic and luteolytic hormones, and also intracellular regulators, on contact-dependent gap junctional intercellular communication (GJIC) of bovine luteal cells from several stages of luteal development. Bovine corpora lutea (CL) from the early, mid and late luteal phases of the estrous cycle were dispersed with collagenase and incubated with no treatment, LH, PGF or LH + PGF (Experiment 1), or with no treatment, or agonists or antagonists of protein kinase C (TPA or H-7) or calcium (A23187 or EGTA; Experiment 2). After incubation, media were collected for determination of progester-one concentrations. Then the rate of GJIC was evaluated for small luteal cells in contact with small luteal cells, and large luteal cells in contact with small luteal cells by using the fluorescence recovery after photobleaching technique and laser cytometry. Luteal cells from each stage of the estrous cycle exhibited GJIC, but the rate of GJIC was least (P < 0.05) for luteal cells from the late luteal phase. LH increased (P < 0.05) GJIC between small luteal cells from the mid and late but not the early luteal phase. PGF increased (P < 0.05) GJIC between small luteal cells from the mid luteal phase and diminished (P < 0.05) LH-stimulatory effects on GJIC between small luteal cells from the late luteal phase. Throughout the estrous cycle, TPA decreased (P < 0.05) the rate of GJIC between large and small, and between small luteal cells, and A23187 decreased (P < 0.05) the rate of GJIC between large and small luteal cells. LH and LH + PGF, but not PGF alone increased (P < 0.05) progesterone secretion by luteal cells from the mid and late luteal phases. Agonists or antagonists of PKC or calcium did not affect progesterone secretion by luteal cells. These data demonstrate that both luteal cell types communicate with small luteal cells, and the rate of communication depends on the stage of luteal development. LH and PGF affect GJIC between small luteal cells during the fully differentiated (mid-luteal) and regressing (late luteal) stages of the estrous cycle. In contrast, at all stages of luteal development, activation of PKC decreases GJIC between small and between large and small luteal cells, whereas calcium ionophore decreases GJIC only between large and small luteal cells. Luteotropic and luteolytic hormones, and intracellular regulators, may be involved in regulation of cellular interactions within bovine CL which likely is an important mechanism for coordination of luteal function.
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PMID:Gap junctional intercellular communication of bovine luteal cells from several stages of the estrous cycle: effects of prostaglandin F2 alpha, protein kinase C and calcium. 893 84

Gene expression of the matrix-degrading enzyme collagenase-1 in rabbit synoviocytes and human fibroblasts is down-regulated by prostaglandin E1 (PGE1) through a cyclic adenosine monophosphate (cAMP)-dependent pathway. In the current study, we examined the role of protein kinase A (PKA) in the PGE1-mediated effect on collagenase-1 gene expression. Collagenase-1 gene expression was rapidly induced several-fold above control both by a phorbol ester, 12-o-tetradecanoyl phorbol 13 acetate, and interleukin-1 beta (IL-1 beta) in HIG-82 synoviocytes. Treatment with PGE1 and forskolin increased PKA activity in the HIG-82 cells within 15 minutes of adding the stimulating agents. Two inhibitors of PKA, the isoquinoline-sulfonamide derivative, H-89 and a cAMP analog, RpcAMP, blocked the ability of PGE1 to down-regulate collagenase-1 gene expression. However, if PGE1 was added from 6 h to 30 minutes before the PKA inhibitor H-89, collagenase-1 gene expression was inhibited. Constitutive PKA activity was increased in HIG-82 synoviocytes stably transfected with an expression vector pCMV.C alpha that caused the HIG-82 cells to overexpress an active catalytic subunit of PKA. Cells stably transfected with an inactive, mutated C-alpha-variant showed no change in PKA activity. Collagenase-1 mRNA levels in TPA-stimulated cells were reduced to baseline levels in the pCMV.C alpha but not in the mutated C-alpha-transfected cells. These data show the importance of PKA in regulating collagenase-1 gene expression in a synoviocyte cell line.
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PMID:Role of protein kinase A in collagenase-1 gene regulation by prostaglandin E1: studies in a rabbit synoviocyte cell line, HIG-82. 910 67

Human umbilical cord vein endothelial cells can be induced to undergo morphogenesis (tube formation) by phorbol ester (TPA) when cultured on or in three-dimensional collagen gels. Induction of morphogenesis by TPA is accompanied by increased activity of the collagenase gene transcription factors, ETS1 and API, and the elaboration of collagenase by the endothelial cells. In the present study, we used endothelial cell elongation as a measure of morphogenesis and showed that oxidized low density lipoprotein (oxLDL) inhibited endothelial cell migration in monolayer cultures and TPA-induced morphogenesis in collagen gels in a dose-dependent manner. Moreover, the inhibition was positively correlated with the extent of LDL oxidation. In contrast, native LDL stimulated cell migration and TPA-induced morphogenesis under the same culture conditions. However, in the absence of TPA, LDL showed no effect on EC morphogenesis. Further studies showed that inhibition of TPA-induced endothelial cell morphogenesis by oxLDL is correlated with suppression of the protein kinase C (PKC) and ETS1/AP1 activities. The results indicated that the inhibition of endothelial cell morphogenesis by oxLDL is probably mediated through inhibition of the TPA-activated PKC pathway and its subsequent suppression of the ETS1/AP1 activity. The results also indicated that EC migration can be mediated through PKC-dependent and independent pathways and only the former pathway can induce EC morphogenesis as well.
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PMID:Oxidized LDL inhibits vascular endothelial cell morphogenesis in culture. 915 39

Hormone-independent growth and invasiveness represent phenotypic properties acquired during early progression of breast cancer. We compared human mammary adenocarcinoma cells, MCF-7, which are estrogen-dependent and poorly metastatic, with the estrogen-independent and highly metastatic subline, MCF7/LCC1, with regard to expression of tissue-degrading factors of the matrix metalloproteinase (MMP)-and urokinase (uPA)-dependent degradative pathways, as well as for their in vitro invasive properties. Both cell lines showed low constitutive mRNA expression of the MMP inhibitor TIMP-1. Baseline expression of TIMP-2 mRNA was also very low in MCF-7 cells, whereas the MCF7/LCC1 level was much higher (approximately 10-fold). Furthermore, both cell lines revealed low constitutive capacity to migrate in an in vitro invasion assay. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM) induced the mRNAs for TIMP-1 as well as for MMP-1, MMP-9, the uPA receptor, and the uPA inhibitor PAI-1, amongst which only the responses of MMP-9 and PAI-1 were cell-specific. The mRNA levels of MMP-9 and PAI-1 were approximately 10-fold and approximately 15-fold higher in MCF7/LCC1 cells compared to MCF-7 cells. The secretion of immunoreactive PAI-1 was considerably elevated (> 20-fold) in TPA-treated MCF7/LCC1 cells, whereas the TPA-dependent level of 92-kDa MMP-9 was only approximately 2-fold higher in MCF7/LCC1 cells than in MCF-7 cells. In both cell lines treatment with TPA was associated with an increase (approximately 10-fold) in in vitro migration, which in the MCF7/LCC1 cells was significantly attenuated by a reconstituted basement membrane extract (Matrigel). These data suggest that TPA-responsive in vitro invasive properties that are probably associated with PAI-1 expression may co-vary with progression from hormone-dependent to -independent breast cancer.
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PMID:Regulation of tissue-degrading factors and in vitro invasiveness in progression of breast cancer cells. 956 38


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