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PubMed1990

The human type II procollagen gene: identification of an additional protein-coding domain and location of potential regulatory sequences in the promoter and first intron.

The complete DNA sequence (6 kb) of the 5' portion of the human type II procollagen gene (COL2A1) was determined from the promoter through the third exon including intron sequences and 690 bp of 5' flanking sequence. Three regions between -501 and -649 in the human promoter share high sequence homology to the rat type II procollagen gene and suggest that the functional sequences within the promoter may extend to at least 649 bp upstream from the start site of transcription. The first intron of the human gene contains elements known to play a role in transcription of other genes: three GC boxes, an inverted repeat with homology to a serum responsive element, a viral core enhancer motif, a high-affinity recognition sequence for nuclear factor-1, and an alternating purine/pyrimidine stretch composed of GT repeats. Both the promoter and a portion of the first intron have a high percentage of G + C residues and a high frequency of CpG dinucleotides. In addition, a protein domain that has been identified in the human COL2A1 gene is present in pro-alpha 1(I) and pro-alpha 1(III) collagen but was not previously described for pro-alpha 1(II) collagen. On the basis of this new information we present a modified gene structure for the exons encoding the pro-alpha 1(II) collagen NH2-propeptide.

Amino Acid Sequence↗
PubMed2006

The relation of amino-terminal propeptide of type III procollagen and severity of coronary artery disease in patients without myocardial infarction or hibernation.

OBJECTIVES: The association of cardiac fibrosis and coronary artery disease (CAD) in patients without infarction or hibernation is unclear. We investigated the relationship between serum concentrations of procollagen propeptides and severity of CAD in such patients. DESIGN AND METHODS: Forty-six patients (32 men; mean age 64 years) with chest pain were enrolled. All patients received stress thallium-201 single photon emission computed tomography (SPECT) and analysis of the serum levels of the amino-terminal propeptide of type I and III procollagen (PINP and PIIINP). RESULTS: In patients with thallium-201 perfusion defects, the number of diseased vessels was associated significantly with PIIINP (p=0.024) rather than PINP (p=0.613). Follow-up serum PINP and PIIINP levels after coronary intervention (mean 84 days) revealed no significant decrease. CONCLUSIONS: Serum PIIINP level is significantly associated with the severity of CAD in patients without myocardial infarction or hibernation.

Aged↗
PubMed1986

Demonstration of elevated type I and type III procollagen mRNA levels in cutaneous wounds treated with helium-neon laser. Proposed mechanism for enhanced wound healing.

To assess laser modulation of wound healing, full-thickness cutaneous wounds were produced in the backs of pigs, and subjected to treatment with helium-neon laser. For comparison, some wounds were treated with non-laser energy source (a tungsten light) or left untreated as controls. Type I and type III procollagen mRNA levels were determined in the wounds by molecular hybridization with cDNA probes. The results indicated that type I and type III mRNA levels were markedly increased at days 17 and 28 of the healing in wounds treated with He-Ne laser, when compared to control or tungsten light-treated wounds. The results suggest that helium-neon laser stimulates wound healing by enhancing procollagen gene expression. These observations may have relevance to previous clinical studies suggesting that helium-neon laser stimulates wound healing.

Animals↗
PubMed1986

Identification of a disulfide-bonded 70 Kd type X procollagen in embryonic chick sternum cartilage.

Chondrocytes from the presumptive calcification region of 20 day old embryonic chick sternum were found to synthesize a 70 Kd Type X procollagen precursor in addition to the previously described 59 Kd Type X collagen molecules. The 70 Kd molecules exhibited an additional cyanogen bromide peptide, contained a disulfide-bonded domain, and were converted into the 59 Kd moieties during pulse-chase experiments. The conversion of the 70 Kd to the 59 Kd Type X collagen was prevented upon microtubular transport inhibition with colchicine and resulted in tissue accumulation of the 70 Kd Type X procollagen.

Animals↗
PubMed1987

von Willebrand factor shares a distinctive cysteine-rich domain with thrombospondin and procollagen.

The identification of common domains among different proteins is of great interest at present. We have found that a cysteine-rich domain in thrombospondin, also present in types I and III procollagen alpha 1 chains, is related to two internally homologous domains in von Willebrand factor. In the four proteins these domains are similar in length (64-74 residues) and have nine invariant cysteines, some of which form intramolecular disulfide bonds. The structural and functional similarities of this domain in the four kinds of proteins, and its correspondence in procollagen to an exon, support our hypothesis of a common origin for the domain.

Amino Acid Sequence↗
PubMed2001

Pravastatin therapy increases procollagen I N-terminal propeptide (PINP), a marker of bone formation in post-menopausal women.

BACKGROUND: The aim of our study was to evaluate whether pravastatin treatment affected biochemical markers of bone turnover. METHODS: Thirty-six hypercholesterolemic post-menopausal women, not on hormonal replacement therapy, were selected from a population study evaluating factors affecting cholesterol response to pravastatin. After a 6-week period on a 30% fat diet, participants received treatment with 20 mg/day of pravastatin during a 16-week follow-up period. Pre- and post-treatment samples were analyzed for procollagen I aminoterminal peptide (PINP) and bone alkaline phosphatase (bAP) as markers of bone formation, carboxyterminal telopeptide of collagen I (CTX) as a marker of bone resorption, and procollagen III aminoterminal propeptide (PIIINP) as a marker of fibrogenesis. RESULTS: Total cholesterol decreased from 7.26+/-0.83 to 6.1+/-0.77 mmol/l with pravastatin treatment. PINP levels significantly increased (from 33.6+/-13 to 37.4+/-16, p=0.03) without changes in bAP or CTX. Individual changes in PINP correlated with individual reduction in cholesterol levels (r=0.337, p=0.04). There was no significant change in PIIINP concentration. CONCLUSIONS: Pravastatin treatment increased PINP levels, a marker of bone formation, in hypercholesterolemic, post-menopausal women, without affecting bone resorption. PIIINP concentration, a marker of liver fibrogenesis, was not affected by the treatment.

Adult↗
PubMed1997

The aminoterminal propeptide of type I procollagen: evaluation of a commercial radioimmunoassay kit and values in healthy subjects.

OBJECTIVES: Evaluation of the performance of a radioimmunoassay kit for measuring serum concentrations of the aminoterminal extension peptide of human type I procollagen, S-PINP. DESIGN AND METHODS: S-PINP concentrations in 229 healthy subjects, 140 females, aged 3.8-81 years, and 89 males, aged 0.9-71 years, were measured with the kit. Because PINP and PICP (the carboxy-terminal propeptide of type I procollagen) are formed in equimolar concentrations, we also calculated the PICP/PINP ratio and compared the S-PINP values to those of S-PICP, which have been shown to correlate with bone formulation rate. RESULTS: The sensitivity of the assay was 2.3 micrograms/L, the spiking recovery ranged from 95.5 to 100.3%, the dilution recovery from 79.3 to 103.1%. The intra-assay imprecision was 2.3 to 3.5% (CV), the interassay imprecision within one reagent lot 2.5-5.2% and, between several reagent lots, 2.7 to 6.1% (CV). S-PINP in females over 20 years old ranged from 12 to 90 micrograms/L (x = 39.7, SD = 14.7), in males over 25 years old, from 22 to 89 micrograms/L (x = 49.9, SD = 15.8); the PICP/PINP ratio ranged from 1.5 to 5.2 and from 1.8 to 4.9, respectively. In females under 20 years old, S-PINP ranged from 52 to 820 micrograms/L, in males aged 25 years or younger from 35 to 1404 micrograms/L; the PICP/PINP ratio was 0.44-2.3 and 0.38-2.8. In females under 20 years and males under 25 years, there was a significant negative correlation between S-PINP and age: r = -0.70, p < 0.001 for females, r = -0.52, p = 0.004 for males. In different groups of healthy subjects, the correlation of S-PINP and S-PICP was significant (r = 0.67-0.86, p < 0.001). CONCLUSION: The assay performance is good. The significant positive relationship between S-PINP and S-PICP suggests that S-PINP also reflects bone formation rate. Because the clearance of PINP is probably less sensitive to hormonal changes, PINP may prove to be superior to PICP as a marker of bone formation.

Adolescent↗
PubMed1991

Type IV procollagen mRNA regulation: evidence for extracellular matrix/cytoskeleton/nuclear matrix interactions in human urothelium.

The absence of basement membrane components correlates with tumor stage and progression in human bladder cancers. We have previously shown that invasive tumors possess the ability to degrade basement membrane. However, the presence of basement membrane may be affected not only by its degradation, but by its synthesis and deposition as well. Our results in the present study suggest that while the invasive human transitional carcinoma cell line EJ has an increased amount of type IV procollagen mRNA when compared to the non-invasive RT4 cell line, type IV collagen staining is absent in the invasive EJ cells and intensely present in the non-invasive RT4 cells. Moreover, when EJ cells were grown on an artificial basement membrane (Matrigel), type IV procollagen mRNA expression was down-regulated to the levels seen with the non-invasive RT4 cells. We also discovered that the invasive cells, when grown on Matrigel, appeared morphologically different from the same cells grown on plastic tissue cultures. We conclude that a deficient basement membrane in invasive cancer cells may be due not only to active proteolytic activity but also to an abnormal production and deposition of extracellular matrix components. In addition, we also demonstrated that basement membrane components may have a significant effect on epithelial cell morphology and gene regulation, and that any alterations of the extracellular matrix-cytoskeleton-nuclear matrix interactions can lead to altered gene regulations and cell function.

Basement Membrane↗
PubMed1987

Procollagen type I production by hepatocytes: a marker of progressive liver disease?

The presence of collagen-producing cells and its relation to disease activity were determined in cryostat liver tissue sections from subjects with active cirrhosis (n = 15), inactive cirrhosis (n = 5), chronic persistent hepatitis (n = 8), or normal histology (n = 3) by means of an immunofluorescence technique using a monoclonal antibody to the carboxy-terminal domain of procollagen type I (anti-Pc). In all patients with active cirrhosis hepatocytes showed a strong intracellular staining with anti-Pc; in 4 of them bileducts also showed a membrane-like reaction. By contrast, tissue sections from chronic inactive liver disease and normal liver were essentially negative. These findings suggest that in chronic liver disease hepatocytes and sometimes biliary epithelium produce collagen and that production is related to disease activity. The detection of active production of procollagen type I by hepatocytes could become a useful marker of progressive liver disease.

Adult↗
PubMed1998

Inhibitory effects of the herbal medicine Sho-saiko-to (TJ-9) on cell proliferation and procollagen gene expressions in cultured rat hepatic stellate cells.

BACKGROUND/AIMS: It is of extreme importance to prevent liver fibrosis and subsequent progression to liver cirrhosis. The aim of our study was to elucidate in vitro whether Sho-saiko-to exerted inhibitory effects on hepatic stellate cells. METHODS: Hepatic stellate cells were isolated from male Wistar rats. Water-soluble ingredients of Sho-saiko-to were obtained at concentrations of 10, 100, 250, 500 and 1000 microg/ml. Morphological transformation was observed under a phase-contrast microscope. Flow cytometric analysis was performed on day 4 after culture to evaluate the potential to proliferate of the stellate cells by analyzing cell cycles. Northern blot analysis was carried out on day 3 after culture to determine the expressions of type I and type III procollagen mRNAs. RESULTS: (i) Sho-saiko-to 500 and 1000 microg/ml inhibited morphological transformation of the stellate cells to myofibroblast-like cells. (ii) Sho-saiko-to 500 and 1000 microg/ml significantly (p<0.0001) accumulated the cells in the G0/G1 phase (118.8+/-0.7%, 119.2+/-0.5%, respectively as compared with control) and significantly (p<0.0001) decreased cell numbers subsequently in G2/M phase (47.5+/-8.1%, 48.9+/-2.0%, respectively). (iii) Sho-saiko-to 500 and 1000 microg/ml also significantly (p<0.05 or p<0.0001) suppressed procollagen mRNA expression of type I to 51.5+/-6.4%, 34.9+/-3.7%, respectively, and type III to 51.3+/-12.3%, 46.7+/-11.4%, respectively. CONCLUSIONS: We have clarified the inhibitory effects of Sho-saiko-to on hepatic stellate cells in vitro. Sho-saiko-to could be a potent inhibitor in the pathogenesis of liver fibrosis.

Adipocytes↗
PubMed1998

Interferon gamma treatment prevents procollagen gene expression without affecting transforming growth factor-beta1 expression in pig serum-induced rat liver fibrosis in vivo.

BACKGROUND/AIM: The aim of this study was to investigate the effect of interferon gamma on the synthesis of matrix proteins such as collagens with the relation to transforming growth factor-beta1 expression in vivo. METHODS: We investigated the effects of interferon gamma in a model of liver fibrosis induced by pig serum in male Wistar rats, which develops fibrosis without an increase in serum alanine aminotransferase (i.e., without hepatocyte injury). Rats were injected with 0.5 ml of pig serum twice a week for 8 weeks with or without 20,000 or 50,000 U of interferon gamma. RESULTS: Interferon gamma at doses up to 50,000 U/day prevented fibrosis, as indicated by reduced hydroxyproline content in the liver. Interferon gamma at 50,000 U/day also reduced expression of type I and III procollagen in the liver. However, the expression of transforming growth factor-beta1 mRNA and protein in the liver was not reduced by interferon gamma. Histologically, interferon gamma at 50,000 U/day also reduced the number of myofibroblast-like cells (activated stellate cells). CONCLUSIONS: These results indicate that interferon gamma can prevent fibrosis by inhibiting the activation and proliferation of stellate cells, resulting in reduced expression of procollagen without affecting transforming growth factor-beta1 expression in pig serum-induced rat liver fibrosis in vivo.

Animals↗
PubMed1981

Cell-free synthesis of putative type V procollagen chains programmed by Chinese hamster lung cell mRNA.

A messenger RNA fraction isolated from cultured Chinese hamster lung (CHL) cells programs in a cell-free system prepared from wheat germ the efficient incorporation of [14C] proline into newly synthesized protein with a significant fraction of the incorporated substrate being digestible with bacterial collagenase. This reaction requires both subcellular fractions, an energy source, and is inhibited by the antibiotic puromycin. The relative amount of collagenase-digestible to non-digestible cell-free product depends upon the ratio of CHL mRNA to wheat germ lysate, is not affected by either the Mg2+ or K+ concentrations employed, and under optimal condition, approximately 38% of the total incorporated substrate is collagenase-sensitive. Electrophoresis on SDS-polyacrylamide gels of the products programmed by CHL mRNA indicates that the collagenase-digestible material corresponds in size to a procollagen chain with an apparent molecular mass of approximately 170,000 daltons. These studies suggest that the collagen alpha 1 (V) chain is initially synthesized as a precursor procollagen chain and demonstrate that a significant amount of the mRNA in Chinese hamster lung cells codes for this protein.

Animals↗
PubMed1982

Separation of human pro alpha 1 (I) and pro alpha 2 (I) procollagen chains by reverse phase high performance liquid chromatography.

Human pro alpha 1 (I) and pro alpha 2 (I) procollagen chains have been separated on a large por (33 nm) reverse phase high performance liquid chromatography C18 column using an acetonitrile aqueous gradient containing 9 mM trifluoroacetic acid. The separation of the chains was evaluated by gel electrophoresis. The yield of the chromatography, based on radiolabel recovery, is equal to or better than 80%. Absorbance monitoring at 210 nm permits detection of less than 5 micrograms procollagen.

Chromatography, High Pressure Liquid↗
PubMed1984

Skin collagen metabolism in the streptozotocin-induced diabetic rat: free hydroxyproline, the principal in vivo degradation product of newly synthesized collagen--probably procollagen.

We characterized the degradation products of recently synthesized collagen present in skins of control and diabetic rats. Specifically, the TCA-soluble fractions of homogenized skins from control and diabetic rats (killed 1 and 4 hours after [3H]-proline injection) were fractionated by molecular sieve chromatography, and eluted fractions were analyzed for hydroxyproline and [3H]-hydroxyproline. Free [3H]-hydroxyproline was the principal (greater than 95%), low molecular weight (greater than 2000 daltons), [3H]-hydroxyproline-containing material eluted from the molecular sieve column, this amount representing approximately 80% (controls) and approximately 87% (diabetics) of [3H]-hydroxyproline-containing material in TCA-soluble fractions of skin homogenates. These observations are similar to those from the intracellular degradation of cellular and secretory proteins in that the principal--almost exclusive--degradation product was the free amino acid. The free hydroxyproline had a greater specific radioactivity than that in any other [3H]-hydroxyproline-containing fraction (soluble and insoluble, see below); furthermore, the total radioactivity of free [3H]-hydroxyproline was greater at 1 hour than 3 hours later. These two properties (identity with free amino acid; time-dependent decrease in amounts) are consistent with [3H]-hydroxyproline arising from the intracellular degradation of procollagen. The [3H]-hydroxyproline-containing material eluting before free hydroxyproline (designated peptidyl [3H]-hydroxyproline) was similar to free [3H]-hydroxyproline in terms of specific radioactivity and the time-dependent decreases of specific and total radioactivities, these similarities indicating that the peptidyl [3H]-hydroxyproline are intermediates in the degradative pathway of procollagen to free amino acids. Results for control and diabetic rats were qualitatively similar, with regard to the inter-fraction ratios of specific radioactivities and their time-dependent changes. However, the degradative process, as assessed by the release of free and peptidyl [3H]-hydroxyproline, was dramatically enhanced by the diabetic state, extending our previous results based on analyses of uncharacterized degradation products.

Animals↗
PubMed1985

Ultrastructural immunocytochemical localization of type I procollagen in cultured human fibroblasts.

An immunoelectron microscopic study of cultured human fibroblasts was performed with antibody specific for the carboxyl propeptides of human type I procollagen (Goldberg et al., 1985). In cells permeabilized with detergent, the unlabeled antibody peroxidase-antiperoxidase method localized the antigen in the rough endoplasmic reticulum, in the Golgi complex, and upon the plasma membrane. Immunostained thread-like periodic fibrillar aggregates within cytoplasmic vacuoles were not apparent. Extracellular fibrils 20-80 nm in thickness were diffusely and heavily stained. Immunostaining also defined a thin extracellular periodic fibril (diameter 10-20 nm; axial period 53.7 nm +/- 6.5 S.D.). These data are discussed in terms of current views of procollagen secretion and collagen fibrillogenesis.

Cell Line↗
PubMed2001

Quality control in the endoplasmic reticulum: PDI mediates the ER retention of unassembled procollagen C-propeptides.

Quality control within the endoplasmic reticulum (ER) is thought to be mediated by the interaction of a folding protein with one or several resident ER proteins [1]. Protein disulphide isomerase (PDI) is one such ER resident protein that has been previously shown to interact with proteins during their folding and assembly pathways [2, 3]. It has been assumed that, as a consequence of this interaction, unassembled proteins are retained within the ER. Here, we experimentally show that this is indeed the case. We have taken advantage of our previous finding that PDI interacts with procollagen chains early on in their assembly pathway [2] to address the role of this protein in directly retaining unassembled chains within the ER. Our experimental approach involved expressing individual C-propeptide domains from different procollagen chains in mammalian cells and determining the ability of these domains to interact with PDI and to be secreted. The C-propeptide from the proalpha2(I) chain was retained within the cell, where it formed a complex with PDI. Conversely, the C-propeptide from the proalpha1(III) chain did not form a complex with PDI and was secreted. Both domains were secreted, however, from a stable cell line expressing a secreted form of PDI lacking its ER retrieval signal. Hence, we have demonstrated directly that the intracellular retention of one substrate for ER quality control is due to an interaction with PDI.

Cell Line↗
PubMed1982

Isolation and characterization of type IV procollagen, laminin, and heparan sulfate proteoglycan from the EHS sarcoma.

We have studied the extractability of type IV collagen, laminin, and heparan sulfate proteoglycan from EHS tumor tissue growth in normal and lathyritic animals. Laminin and heparan sulfate proteoglycan were readily extracted with chaotropic solvents from both normal and lathyritic tissue. The collagenous component was only solubilized from lathyritic tissue in the presence of a reducing agent. These results indicate that lysine-derived cross-links and disulfide bonds stabilize the collagenous component in the matrix but not the laminin or the heparan sulfate proteoglycan. The majority of the collagen present in the extracts had a native triple helix based upon the pattern of peptides resistant to pepsin digestion and visualization in the electron microscope by the rotary shadow technique. This protein was composed of chains (Mr 185000 and 170000) identical in migration to the chains of newly synthesized type IV procollagen. This finding confirms earlier work that indicates that the biosynthetic form, type IV procollagen, is incorporated as such in the basement membrane matrix. Material with smaller chains (Mr 160000 and 140000) appeared on storage in acetic acid solutions. These results indicate that the lower molecular weight collagen in acid extracts of basement membrane arises artifactually due to an endogenous acid-active protease.

Animals↗
PubMed1983

Structure of a cDNA for the pro alpha 2 chain of human type I procollagen. Comparison with chick cDNA for pro alpha 2(I) identifies structurally conserved features of the protein and the gene.

Nucleotide sequences were determined for cloned cDNAs encoding for more than half of the pro alpha 2 chain of type I procollagen from man. Comparisons with previously published data on homologous cDNAs from chick embryos made it possible to examine evolution of the gene in two species which have diverged for 250-300 million years. The amino acid sequence of the alpha-chain domain supported previous indications that there is a strong selective pressure to maintain glycine as every third amino acid and to maintain a prescribed distribution of charged amino acids. However, there is little apparent selective pressure on other amino acids. The amino acid sequence of the C-propeptide domain showed less divergence than the alpha-chain domain. The 5' end or N terminus of the human C-propeptide, however, contained an insert of 12 bases coding for 4 amino acids not found in the chick C-propeptide. About 100 amino acid residues from the N terminus, two residues found in the chick sequence were missing from the human. In the second half of the C-propeptide, there was complete conservation of a 37 amino acid sequence and conservation of 50 out of 51 amino acids in the same region, an observation which suggested that the region serves some special purpose such as directing the association of one pro alpha 2(I) C-propeptide with two pro alpha 1(I) C-propeptides so as to produce the heteropolymeric structure of type I procollagen. In addition, comparison of human and chick DNAs for pro alpha 2(I) revealed three different classes of conservation of nucleotide sequence which have no apparent effect on the structure of the protein: a preference for U on the third base position of codons for glycine, proline, and alanine; a high degree of nucleotide conservation in the 51 amino acid highly conserved region of the C-propeptide; a high degree of nucleotide conservation in the 3'-noncoding region. These three classes of nucleotide conservation may reflect unusual features of collagen genes, such as their high GC content or their highly repetitive coding sequences.

Amino Acid Sequence↗