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At least 721 records · Page 40Linked to original sources
PubMed1999

Structural organization and expression patterns of the human and mouse genes for the type I procollagen COOH-terminal proteinase enhancer protein.

The procollagen C-proteinase enhancer (PCPE) is a glycoprotein that potentiates enzymatic cleavage of the type I procollagen C-propeptide by bone morphogenetic protein-1 (BMP-1). The human PCPE gene (PCOLCE) was previously mapped to 7q22, an area frequently disrupted in uterine leiomyomata, while disruption of the rat PCPE gene leads to anchorage-independent growth and loss of contact inhibition in rat fibroblasts. Here we describe the entire intron/exon organizations of PCOLCE and the mouse PCPE gene (Pcolce) and analyze expression of PCOLCE RNA in various human adult and fetal tissues and of Pcolce RNA at various stages of mouse development. PCOLCE and Pcolce are shown to be small genes 6.0 and 6.5 kb, respectively, with a conserved intron/exon structure comprising 9 exons. A notable difference between the two genes derives from insertion of multiple Alu sequences immediately upstream and downstream and within PCOLCE. Temporal expression of PCPE mRNA is shown to differ from that of BMP-1 and type I procollagen during mouse development, consistent with possible additional functions for PCPE beyond enhancement of C-proteinase activity. Consistent with a possible role in leiomyomata, PCOLCE is shown to be expressed at relatively high levels in uterus.

Adult↗
PubMed2004

Triterpenoid from Tiarella polyphylla, regulation of type 1 procollagen and MMP-1 in ultraviolet irradiation of cultured old age human dermal fibroblasts.

Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of natural products. Ultraviolet irradiation is widely considered to be an environmental stress. Here we investigated the effect of 3,23-dihydroxy-20(29)-lupen-27-oic acid on the regulation of MMP-1 and type 1 procollagen in Ultraviolet irradiation of cultured old age human dermal fibroblasts. 3, 23-dihydroxy-20(29)-lupen-27-oic acid was isolated from Tiarella polyphylla D. Don (Saxifragaceae). Among them, 3, 23-dihydroxy-20(29)-lupen-27-oic acid induced the regulation of Type 1- procollagen and reduced the regulation of MMP-1 at the protein levels in a dose-dependent manner by ultraviolet irradiation. Taken together, our results suggest that 3, 23-dihydroxy-20(29)-lupen-27-oic acid plays an important role in the induction of Type 1-procollagen and reduction of MMP-1 by ultraviolet irradiation in old age human dermal fibroblasts.

Aged↗
PubMed2006

Up-regulation of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase were coupled with that of type I procollagen in granulation tissue response after the onset of aortic dissection.

The pathophysiological significance of matrix metalloproteinases (MMPs) in aortic dissection remains poorly understood. The purpose of the present study is to clarify the significance of MMPs in aortic dissection. The activities and distributions of MMP-2, membrane-type 1-MMP (MT1-MMP), and MMP-9 were evaluated by gelatin zymography, immunohistochemistry, and in situ hybridization in 29 patients and seven autopsy cases. To assess if these MMPs are related to a tissue remodeling process, we compared the expression of these MMPs with that of type I procollagen and platelet-derived growth factor receptor beta chain (PDGF Rbeta). Patients were divided into three groups based on histological findings: acute, intermediate, and healed groups. The most remarkable changes were observed in the intermediate group, in which MMP-2 activity peaked and tissue expression of mRNAs for MMP-2 and MT1-MMP were observed in spindle-shaped cells in the neointima, organizing thrombus, and the adventitia. These expression patterns were essentially coupled with those of type I procollagen mRNA and PDGF-Rbeta protein. The association of MMP-2, MT1-MMP, type I procollagen, and PDGF-Rbeta suggests that MMP-2 and MT1-MMP could be involved not only in the degradation of aortic tissue but also in tissue remodeling, which may be associated with the healing process.

Aged↗
PubMed2005

Expression of procollagen C-proteinase enhancer-1 in the remodeling rat heart is stimulated by aldosterone.

Excessive collagen deposition is a common complication of myocardial infarction that causes progressive heart disease. Several pro-fibrotic cytokines and hormones, including aldosterone, control this process. Procollagen processing by procollagen C-proteinase(s) is critical for collagen deposition and is potentiated by procollagen C-proteinase enhancer proteins (PCPEs). We have shown previously that, in addition to stimulation of collagen I expression, aldosterone increases PCPE-1 expression in cultured heart fibroblasts. The present study was designed to examine whether aldosterone acts similarly in vivo. Rats underwent coronary artery ligation to induce myocardial infarction. They were then left either untreated (control) or treated with spironolactone (an aldosterone receptor antagonist) for 5 weeks when they were sacrificed and their hearts removed for analysis. In situ hybridization co-localized PCPE-1 and collagen I mRNAs to fibroblasts surrounding the scar region and adjacent blood vessels. The levels of both transcripts in the remodeling myocardium of untreated rats increased twofold as compared to sham-operated controls, an increase greatly reduced by spironolactone. Correspondingly, a 2-5 fold increase in PCPE-1 and collagen I was observed in the hearts of untreated rats as compared to both the spironolactone-treated and sham-operated controls. The results establish aldosterone as a physiological stimulator of PCPE-1 expression in the remodeling myocardium after infarction. Since PCPE-1 itself is a positive regulator of collagen deposition, this finding suggests PCPE-1 as a new potential target for intervention with cardiac fibrosis.

Aldosterone↗
PubMed2004

The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen alpha1(I), TIMP-1 and MMP-2.

BACKGROUND: Pirfenidone (5 methyl-1-phenyl-2(1H)-pyridone) is a novel anti-fibrotic agent, which has been shown to decrease collagen deposition in a variety of animal models in vivo, and recently in hepatic fibrosis also. At cellular level, we have recently demonstrated that pirfenidone is able to inhibit proliferation of hepatic stellate cells induced by platelet-derived growth factor, as well as collagen type I accumulation and alpha1(I) procollagen mRNA expression. AIMS: To evaluate if pirfenidone maintains its anti-fibrotic properties also when administered after the induction of hepatic damage and to further investigate the molecular mechanisms leading to the anti-fibrotic effect of pirfenidone. METHODS AND RESULTS: Rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks received a liquid diet containing 0.5% pirfenidone starting from the third week. Pirfenidone treatment reduced the degree of liver injury, as determined by alanine aminotransferase values and necro-inflammatory score, which was associated with reduced hepatic stellate cells proliferation and collagen deposition. Treatment with dimethylnitrosamine increased transcripts levels for transforming growth factorbeta1, procollagen alpha1(I), tissue inhibitors of metalloproteinase-1 and matrix metalloproteinase-2 by 7-, 7-, 4- and 15-fold, respectively. Pirfenidone administration downregulated elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition. CONCLUSIONS: (1) Pirfenidone is effective also if administered after the induction of the hepatic damage; (2) the anti-fibrotic effect of pirfenidone is mainly due to the reduced expression of profibrogenic procollagen alpha1(I) and TIMP-1, most likely through the downregulation of transforming growth factorbeta1 mRNA, and of matrix metalloproteinase-2, which is mainly implicated in the degradation of the normal extracellular matrix.

Animals↗
PubMed2005

The effect of tiarellic acid on the expressions of matrix metalloproteinase-1 and type 1 procollagen in ultraviolet irradiated cultured human skin fibroblasts.

Long term and repeated exposure of ultraviolet (UV) light, a harmful environmental stress, on the skin often induces chronic skin diseases such as skin cancer as well as photoaging (premature skin aging), and the mechanisms of these skin damages are closely associated with up-regulation of matrix metalloproteinases (MMPs) activities. Here we investigated the effect of tiarellic acid on the expressions of MMP-1 and type 1 procollagen in ultraviolet irradiation of cultured human skin fibroblasts. Tiarellic acid reduced the expression of MMP-1 and induced the expression of type 1- procollagen at the protein levels in a dose-dependent manner by ultraviolet irradiation. Taken together, our results suggest that tiarellic acid plays an important role in the reduction of MMP-1 and induction of type 1- procollagen by ultraviolet irradiation.

Catechin↗
PubMed1990

Procollagen type I C-proteinase enhancer is a naturally occurring connective tissue glycoprotein.

Using antibodies to the procollagen C-proteinase enhancer of mouse fibroblast culture medium, we have screened by immunoblotting extracts of several post natal mouse and rat tissues for the presence of the enhancer antigen. All rodent connective tissues were relatively rich in enhancer; lower amounts were found in skeletal muscle and heart and essentially no enhancer was detected in kidney, liver or brain. The amounts of enhancer in mouse tendon and calvaria extracts were age related, with highest amounts in 11 and 19 d tendons and in 1 d calvaria-the times of rapid growth of these organs. The results suggest that procollagen C-proteinase enhancer is a specific connective tissue glycoprotein that is likely to regulate procollagen processing in vivo.

Animals↗
PubMed1986

Evidence for a protein that enhances the activity of type I procollagen C-proteinase.

Gel-filtration separated type I procollagen C-proteinase from a glycoprotein that enhanced the enzyme activity by approximately 4-fold. The enhancer was purified by affinity chromatography on a column of Sepharose coupled to the carboxyl propeptide of type I procollagen. Sodium-dodecyl-sulfate- polyacrylamide gel electrophoresis of the affinity-purified enhancer revealed two active major protein bands with molecular weights of 36 and 34 kdal. Both proteins were glycosylated, as shown by binding to concanavalin-A. The enhancer is extremely heat stable (100 degrees C, 15 min) but its activity is totally abolished by treatment with trypsin or bacterial elastase. The enhancer does not alter the digestion intermediates or final products of the enzymatic reaction but it changes the kinetic properties of the reaction, increasing the apparent Km and Vmax values 16- and 20-fold, respectively. It is suggested that the enhancer might play a regulatory role in procollagen processing.

Animals↗
PubMed1976

NH2-terminal extensions on skin collagen from sheep with a genetic defect in conversion of procollagen into collagen.

A modified form of procollagen was extracted with 10 M urea from the skin of lambs with dermatosparaxis, a disease which is produced by a genetic defect in the conversion of procollagen to collagen. The extracts contained little if any alpha1 and alpha2 chains of normal type I collagen, and instead they contained the larger polypeptides palpha1 and palpha2 together with high polymers. palpha1 was purified by ion-exchange chromatography and gel filtration. The polypeptide was shown to be related to alpha1 by its chromatographic behavior, its amino acid composition, and the peptides obtained after cleavage with cyanogen bromide. The molecular weight of palpha1 by gel filtration was 112 300 +/- 6300. After digestion of palpha1 with bacterial collagenase, a fragment of about 100 amino acid residues was obtained which was similar in amino acid composition and antigenic activity to a comparable fragment previously obtained from the NH2-terminal region of palpha1 chains from dermatosparaxic cattle. However, after cleavage of palpha1 with cyanogen bromide, a larger NH2-terminal fragment of about 160 amino acid residues was obtained. The larger cyanogen bromide fragment contained 8 residues of hydroxyproline, 12 residues of proline, and 19 residues of glycine not found in the NH2-terminal fragment isolated after digestion with bacterial collagenase. The results indicated that, in addition to containing amino acid sequences similar to those found in globular proteins, the peptide extensions on the NH2-terminal end of the palpha1 chain of procollagen also contain amino acid sequences similar to those found in the triple-helical region of the collagen molecule. The molecular weight of palpha2 by gel filtration was 102 400 +/- 6800. No additional peptide fragment was recovered after digestion of palpha2 with bacterial collagenase.

Amino Acids↗
PubMed2001

Folding and activity of recombinant human procollagen C-proteinase enhancer.

Recombinant human procollagen C-proteinase enhancer (rPCPE) was expressed using a baculovirus system and purified to homogeneity using a three-step procedure including heparin affinity chromatography. Heparin binding was dependent on the C-terminal netrin-like domain. The recombinant protein was found to be active, increasing the activity of procollagen C-proteinase/bone morphogenetic protein-1 on type I procollagen in a manner comparable to the native protein. Enhancing activity was dependent on intact disulfide bonding within the protein. By circular dichroism, the observed secondary structure of rPCPE was consistent with the known three-dimensional structures of proteins containing homologous domains.

Animals↗
PubMed1971

Collagen biosynthesis: synthesis and secretion of a high molecular weight collagen precursor (procollagen).

Sodium dodecyl sulfate-acrylamide gel electrophoresis and molecular-sieve chromatography on 8% agarose demonstrate the existence of a very high molecular weight (500,000-600,000), proline-rich protein in cultured 3T6 fibroblasts that appears to be the precursor molecule (procollagen) of collagen. The kinetics of [(3)H]-proline uptake indicate that this precursor is synthesized at a different rate than are other cell proteins and is secreted apparently unchanged into the medium, where it undergoes modification; it then precipitates around the cells as collagen fibrils that contain the characteristic tropocollagen polypeptide chains. The solubility of this precursor in hot 5% Cl(3)CCOOH, its hydroxyproline to proline ratio, and its sensitivity to highly-purified bacterial collagenase all indicate that this molecule is of collagenous nature, but that it has considerable regions of noncollagen peptide (about half of the molecule is collagenase sensitive, and it has half of the normal amount of hydroxylated proline residues). These results support the concept of a procollagen molecule, of molecular weight about 500,000-600,000, that contains large regions of noncollagen peptides, which might allow the collagen alpha-chain regions to associate in register and that also can provide the correct chain composition for tropocollagen. Upon secretion of the procollagen molecule, the intercollagen-peptide regions are cleaved and the finished tropocollagen molecule then polymerizes into typical intercellular fibrils.

Acrylamides↗
PubMed1973

Collagen and procollagen production by a clonal line of Schwann cells.

A well-characterized line of rat Schwann cells has been examined for its ability to produce collagen. About 14% of the [(3)H]proline in the proteins that were secreted into the culture medium by the cells was hydroxylated, while only 1% of the labeled proteins in the cell layer contained [(3)H]hydroxyproline. Three sizes of procollagen polypeptides, of molecular weights about 105,000, 120,000, and 155,000, were present in the medium, as well as tropocollagen molecules that contained the usual alpha1 and alpha2 chains. Subsequently, the Schwann cells ceased producing the smaller collagenous polypeptides, although the total [(3)H]hydroxyproline content of the medium was unchanged. The [(3)H]hydroxyproline was almost entirely accounted for by the polypeptide of 155,000 daltons; this peptide was rapidly digested by collagenase or pepsin or chymotrypsin. The destruction by pepsin and chymotrypsin indicates that the large polypeptide, in contrast to procollagen and tropocollagen, is not in the collagenous (helical) conformation. Possibly, this substance is a very early form of procollagen that does not fold into the collagen conformation. The data show that cells of neuroectodermal origin can synthesize collagen, and also suggest that Schwann cells may be responsible for a large proportion of the collagen seen in peripheral neurinomas in vivo.

Animals↗
PubMed1974

Calf tendon procollagen peptidase: its purification and endopeptidase mode of action.

The procollagen peptidase activity of calf tendon has been purified. The enzyme has a high degree of specificity for native procollagen and converts both pro alpha1 and alpha2, to alpha1 and alpha2, respectively. The purified enzyme is an endopeptidase which excises the amino terminal peptide extensions of the precursor chains in block; the molecular size and amino-acid composition of the excised peptides compare favorably with those predicted in previous reports. Antisera to the enzyme and to procollagen have been prepared and have been used to characterize the enzyme, the enzymatically excised peptides, and the enzyme-peptide complex in reaction mixtures.

Amino Acids↗
PubMed1986

Exon/intron organization of the chicken type II procollagen gene: intron size distribution suggests a minimal intron size.

Overlapping genomic clones have been isolated that contain the alpha chain and COOH-terminal propeptide coding regions of the chicken type II procollagen gene. All type II procollagen exon sequences present in these clones have been identified and mapped by DNA sequencing. These include 43 exons coding for the alpha-chain triple helix, 1 exon coding for the junction between the COOH-terminal propeptide and the alpha-chain region, and 3 exons coding for the COOH-terminal propeptide and 3' noncoding sequences. With the exception of one additional intron between 2 exons coding for amino acids 568-585 and 586-603, exon-intron boundaries have been conserved when compared with genes for all other characterized genes for fibrillar collagens. The chicken type II procollagen gene differs from most other collagen genes in having introns of considerably smaller average size. The size distribution of the introns suggests that approximately equal to 80 base pairs may be a minimal functional size for introns in this gene. This size of intron may be necessary in a gene with a very large number of small exons to prevent aberrant splicing from removing exon sequence together with intron sequence.

Animals↗
PubMed2002

Low resolution structure determination shows procollagen C-proteinase enhancer to be an elongated multidomain glycoprotein.

Procollagen C-proteinase enhancer (PCPE) is an extracellular matrix glycoprotein that can stimulate the action of tolloid metalloproteinases, such as bone morphogenetic protein-1, on a procollagen substrate, by up to 20-fold. The PCPE molecule consists of two CUB domains followed by a C-terminal NTR (netrin-like) domain. In order to obtain structural insights into the function of PCPE, the recombinant protein was characterized by a range of biophysical techniques, including analytical ultracentrifugation, transmission electron microscopy, and small angle x-ray scattering. All three approaches showed PCPE to be a rod-like molecule, with a length of approximately 150 A. Homology modeling of both CUB domains and the NTR domain was consistent with the low-resolution structure of PCPE deduced from the small angle x-ray scattering data. Comparison with the low-resolution structure of the procollagen C-terminal region supports a recently proposed model (Ricard-Blum, S., Bernocco, S., Font, B., Moali, C., Eichenberger, D., Farjanel, J., Burchardt, E. R., van der Rest, M., Kessler, E., and Hulmes, D. J. S. (2002) J. Biol. Chem. 277, 33864-33869) for the mechanism of action of PCPE.

Amino Acid Sequence↗
PubMed2003

NMR structure of the netrin-like domain (NTR) of human type I procollagen C-proteinase enhancer defines structural consensus of NTR domains and assesses potential proteinase inhibitory activity and ligand binding.

Procollagen C-proteinase enhancer (PCOLCE) proteins are extracellular matrix proteins that enhance the activities of procollagen C-proteinases by binding to the C-propeptide of procollagen I. PCOLCE proteins are built of three structural modules, consisting of two CUB domains followed by a C-terminal netrin-like (NTR) domain. While the enhancement of proteinase activity can be ascribed solely to the CUB domains, sequence homology of the NTR domain with tissue inhibitors of metalloproteinases suggest proteinase inhibitory activity for the NTR domain. Here we present the three-dimensional structure of the NTR domain of human PCOLCE1 as the first example of a structural domain with the canonical features of an NTR module. The structure rules out a binding mode to metalloproteinases similar to that of tissue inhibitors of metalloproteinases but suggests possible inhibitory function toward specific serine proteinases. Sequence conservation between 13 PCOLCE proteins from different organisms suggests a conserved binding surface for other protein partners.

Agrin↗
PubMed2006

The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function.

The function of the NH(2)-terminal propeptide of type I procollagen (N-propeptide) is poorly understood. We now show that a recombinant trimeric N-propeptide interacts with transforming growth factor-beta1 and BMP2 and exhibits functional effects in stably transfected cells. The synthesis of N-propeptide by COS-7 cells results in an increase in phosphorylation of Akt and Smad3 and is associated with a marked reduction in type I procollagen synthesis and impairment in adhesion. In C2C12 cells, N-propeptide inhibits the osteoblastic differentiation induced by BMP2. Our data suggest that these effects are mediated by the interaction of N-propeptide with an intracellular receptor in the secretory pathway, because they are not observed when recombinant N-propeptide is added to the culture medium of either COS-7 or C2C12 cells. Both the binding of N-propeptide to cytokines and its functional properties are entirely dependent on the exon 2-encoded globular domain, and a mutation that substitutes a serine for a highly conserved cysteine in exon 2 abolishes its function. Our findings suggest that N-propeptide performs an important feedback regulatory function and provides a rationale for the prominence of a homotrimeric form of type I procollagen (alpha1 trimer) during vertebrate development.

Animals↗
PubMed1975

Location of procollagen in chick corneal and tendon fibroblasts with ferritin-conjugated antibodies.

Three distinct antiprocollagen preparations were characterized and used in immunocytochemical staining of chick embryo corneal and tendon cells. The several ferritin-conjugated antibody preparations permitted similar location of procollagen in the cisternae of the rough endoplasmic reticulum and in Golgi elements in both cell types. The ability to demonstrate and interpret specific ferritin staining was dependent on the extent of membrane breakage in each of those organelles, coupled with adequate retention of cell morphology. Corneal fibroblasts appeared to suffer more extensive intracellular membrane damage under controlled conditions of homogenization than tendon fibroblasts, facilitating the identification of procollagen in Golgi vacuoles of these cells. None of the labeled material appeared to by cytoplasmic in origin since ferritin was observed in the cytoplasm only in the vicinity of Golgi elements that were extensively broken. This study extends previous immunological evidence for the presence of procollagen in the Golgi complex and calls attention to the problems to be encountered in locating the antigen in small Golgi vesicles and lamellae.

Animals↗