Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.11.2 (prolyl hydroxylase)
 1,814 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tight-skin (Tsk) mouse is a genetic model of pulmonary emphysema linked to a deficiency of serum antielastase. In this mouse occurrence of connective tissue abnormalities in various organs (systemic scleroderma) has been reported. The aim of the present work was to study lung collagen synthesis and deposition in Tsk mice. No differences in the collagen synthesis rate and morphology at the ultrastructural level were found in Tsk mice at birth. At 2 months of age, a marked increase in collagen was observed within the alveolar septa. At this time, an increased lung collagen synthesis, assessed by determining prolyl hydroxylase activity and incorporation of radiolabeled proline, was found in Tsk mice with respect to control mice. However, due to the ongoing parenchymal destruction, the values of total lung collagen at 6 and 12 months of age were only moderately but significantly increased with respect to those observed at 2 months. As a consequence, a progressive accumulation of lung collagen fibers was observed in the residual septa. The increase in collagen deposition was accompanied by a relative increase in type I collagen. Although the data in the literature would suggest a genetic cause for the lung collagen change in Tsk mice, the data presented here indicate that the change in lung collagen metabolism may be a part of a remodeling process taking place after lung destruction.
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PMID:Lung collagen synthesis and deposition in tight-skin mice with genetic emphysema. 158 42

The relative steady-state levels of RNAs encoding type I collagen and prolyl 4-hydroxylase were examined in exponentially growing primary cultures of chicken embryo tendon fibroblasts. The RNA levels of the alpha 1 and alpha 2 chains of type I collagen were maximal when the fibroblasts reached the confluent state. The RNA levels of the alpha-subunit of prolyl 4-hydroxylase were also maximal at confluency and rose and fell with the RNA levels of the two collagen chains. The RNA levels of the beta-subunit of prolyl 4-hydroxylase did not correlate with the changes observed for the alpha-subunit or for either chain of type I collagen. The RNA levels of the beta-subunit were slightly higher than the RNA levels of the alpha-subunit. These results support our hypothesis that the synthesis of the alpha-subunit and thus the association of newly synthesized alpha-subunits with pre-existing beta-subunits is the rate-limiting factor in determining prolyl 4-hydroxylase activity in cultured cells.
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PMID:Correlation of the steady-state RNA levels among the alpha-subunit of prolyl 4-hydroxylase and the alpha 1 and alpha 2 chains of type I collagen during growth of chicken embryo tendon fibroblasts. 184 36

The biochemical and morphological consequences of procollagen prolyl 4-hydroxylase inhibition by pyridine-2,4-dicarboxylic acid (2,4-PDCA) and its diethyl ester (diethyl-2,4-PDC) were studied in chick-embryo calvaria, which predominantly synthesize type I collagen. Half-maximal inhibition of tissue hydroxyproline formation required 650 microM-2,4-PDCA, whereas the Ki with respect to chicken prolyl 4-hydroxylase in vitro was 2 microM. In contrast, half-maximal inhibition was caused by 10 microM-diethyl-2,4-PDC in the intact calvaria, although chicken prolyl 4-hydroxylase in vitro was not inhibited even at 1 mM. The collagenous material produced in the presence of diethyl-2,4-PDC showed an altered 'melting' profile and a lowering of the transition temperature by 10 degrees C, indicating misalignment and thermal instability of its triple-helical structure. Amount and electrophoretic mobility of procollagen type I chains were increased in a dose-dependent manner. The amounts of partially processed species and alpha-chains were decreased, without change in mobility. This marked effect on procollagen-collagen conversion in the intact calvaria suggests that the underhydroxylated collagenous material generated in the presence of diethyl-2,4-PDC is resistant to or acts as endogenous secondary inhibitor of type I procollagen N-proteinase. Electron microscopy of treated calvaria cells showed dilated rough endoplasmic reticulum and numerous phagolysosomes, indicating intracellular retention and lysosomal degradation of the newly synthesized underhydroxylated collagenous material. In summary, these results identify 2,4-PDCA and diethyl-2,4-PDC as the first prolyl 4-hydroxylase-directed inhibitor/proinhibitor pair that affects intra- and extra-cellular events during collagen formation.
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PMID:Inhibition of prolyl hydroxylation and procollagen processing in chick-embryo calvaria by a derivative of pyridine-2,4-dicarboxylate. Characterization of the diethyl ester as a proinhibitor. 185 Sep 89

Incorporation rates of 14C-proline into collagen hydroxyproline in cultured Ito cells and hepatocytes isolated from chronically alcohol-treated rats were studied in order to clarify the role of Ito cells in the development of alcoholic liver fibrosis pathogenesis. In the cultured Ito cells isolated from alcohol-treated rats, prolyl hydroxylase activity significantly increased. Total collagen synthesis tended to increase in the alcohol group, and the increase in intracellular intact collagen was statistically significant. More than half of the 14C-radioactivity in intact collagen in cultured Ito cells from control rats was found in collagen other than types I and III collagen (mainly type IV collagen). In Ito cells from alcohol-treated rats, synthesis of collagen other than type I and III significantly increased and type I collagen synthesis tended to be decreased. No significant difference was found in collagen synthesis between the cultured hepatocytes from alcoholic and control rats. These results suggest that chronic alcohol consumption stimulates collagen synthesis in Ito cells, especially type IV collagen. This stimulation of Ito cells may play a role in the development of alcoholic liver fibrosis.
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PMID:Collagen synthesis by cultured rat liver cells isolated from chronically alcohol-treated rats. 196 91

Connective tissue components were detected immunohistochemically in cultured rat hepatocytes and sinusoidal lining cells. In the Ito and endothelial cells, the staining reactions to prolyl hydroxylase were strong. The reaction in the hepatocytes, however, was weaker, and there was no staining reaction to prolyl hydroxylase in the Kupffer cells. In the Ito cells, types III and IV collagen were clearly positive, whereas reactions to type I collagen were very weak. In the endothelial cells, type IV collagen stained clearly, whereas the reaction for type I collagen was very weak, and there was no reaction for III. Laminin was clearly positive in the Ito and endothelial cells. Connective tissue components were not detectable in the Kupffer cells. The hepatocytes were positive for types I, III, and IV collagen, but the staining reactions to type IV collagen were weak. Laminin staining was almost negative. These results suggest that type IV collagen is produced mainly by nonparenchymal cells and that types I and III collagen are produced by both parenchymal and nonparenchymal liver cells.
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PMID:Connective tissue components in cultured parenchymal and nonparenchymal cells of rat liver. Immunohistochemical studies. 282 83

The in vitro effects of dexamethasone on condylar cartilage from normal newborn mice were tested by measuring protein and DNA content, collagen synthesis, prolyl hydroxylase activity, collagen chains and by immunofluorescence the localization of type I and II collagen and fibronectin. The biochemical assays were complemented by structural studies of hormone-treated and control cultured specimens. It became apparent that both the protein and DNA content of the tissue decreased immediately following the addition of dexamethasone of the incubation system. Protein synthesis was significantly decreased by the hormone by 24 h. The degree of collagen hydroxylation was decreased by 24 h. Dexamethasone-treated condyles did not reveal a significant increase in the percentage of cold hydroxyproline of the total protein. Using the indirect immunofluorescence method, hormone-treated condyles revealed an enhancement of positive reactivity for type I collagen and fibronectin. SDS-gel electrophoresis of 3H-labeled collagen chains isolated by CM-cellulose chromatography indicated that dexamethasone did not significantly affect the ratios of the collagen chains. For further characterization, each chain was subjected to cyanogen bromide cleavage showing that the peptide maps of alpha 1(I) and alpha 1(II) chains were not different in dexamethasone-treated tissues in comparison to controls.
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PMID:Dexamethasone impairs growth and collagen synthesis in condylar cartilage in vitro. 284 91

Dimethylnitrosamine (DMN)-induced hepatic fibrosis was used as an experimental model to study collagen-gene expression during liver fibrogenesis. Increase in the concentrations of the mRNAs for type I, III, and IV collagens was found to be an early event in the development of hepatic fibrosis, as the mRNAs for all three collagen types showed a definite increasing tendency by day 7 of DMN treatment. Prolyl 4-hydroxylase (EC 1.14.11.2) and galactosylhydroxylysyl glucosyltransferase (EC 2.4.1.66) activities were also distinctly elevated at this stage, whereas no increase could be detected in the liver collagen content. The increase in the mRNAs for type I collagen was the smallest and that for type IV collagen the greatest at all the time points studied. The relative concentrations of the mRNAs for the three collagen types on day 21 of DMN treatment were 350% of the control mean for type I collagen, 490% for type III and 660% for type IV. The data further indicate that the proportions of the mRNAs for the three collagen types are 1.0:0.9:0.2 in normal rat liver, 1.0:1.4:0.8 on day 14 of DMN treatment, and 1.0:1.3:0.5 on day 21. The early marked increase in the mRNA for type IV collagen suggests that enhanced production of basement-membrane collagen may be an early event in the development of hepatic fibrosis.
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PMID:Gene expression of type I, III and IV collagens in hepatic fibrosis induced by dimethylnitrosamine in the rat. 366 19

Three possible mechanisms are considered to account for the variations of post-translational modifications in different collagen types. 1) The cells have different amounts of post-translational modifying enzymes, 2) the rate of prolylhydroxylation of different procollagen types is varied, and 3) the rate of chain association of pro-alpha chains of different collagen types is modulated. In an attempt to examine the three possibilities, we have determined the activities of prolyl hydroxylase and lysyl hydroxylase, and we have examined the kinetics of the secretion of procollagens and the kinetics of pro-gamma chain formation of different procollagen types in matrix-free cells isolated from tissues of 17-day-old chick embryos. Type II collagen synthesized by cartilage cells contains more hydroxylysine than type I collagen synthesized by tendon and cornea cells. It was found, however, that cartilage cells contain significantly less lysyl hydroxylase than tendon and cornea cells. In contrast, we found only a small difference in the amount of prolyl hydroxylase in tendon, cornea, and cartilage cells. The secretion of type I procollagen by tendon and cornea cells can be described by two first order processes. In contrast, the secretion of type II procollagen by cartilage cells, type IV procollagen by lens cells, and type V procollagen by cornea cells can be described by single first order processes. Examination of the formation of pro-gamma components of procollagen types I and II revealed that it occurs via intermediate dimers of two pro-alpha chains. The formation or pro-gamma(I) chains in tendon and cornea cells is about three times faster than the formation of pro-gamma(II) chains in cartilage cells. These results are consistent with the hypothesis that the rate of association of pro-alpha chains regulates the synthesis of procollagens with different degrees of post-translational modifications.
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PMID:Mechanism for the regulation of post-translational modifications of procollagens synthesized by matrix-free cells from chick embryos. 630 52

Based on the finding that prolyl hydroxylase, a key enzyme in collagen biosynthesis, is a constituent of the hepatic parenchymal cell, we have suggested that the hepatocyte may synthesize collagen (Exp. Cell Res. 123: 269-279, 1979). We now report that, consistent with this idea, collagen formation has been detected in primary nonproliferating cultures of isolated rat hepatocytes prepared from either normal liver or regenerated liver four days after partial hepatectomy. The characteristics of the radiolabeled collagen formed in two-day old cultures incubated for 24 hours in the presence of either [3H]-proline or [35S]-cystine were its resistance to pepsin and its susceptibility to degradation by highly purified, protease-free bacterial collagenase. The presence of fibroblasts in the hepatocyte cultures was excluded as an explanation for these results because we detected no type I collagen, a universal product of the cultured fibroblast. The initial low rates of synthesis of collagen relative to total cellular protein (0.1-0.4 percent) increased dramatically upon continued incubation of the cells reaching 0.31 and 0.81 percent in nine-day old cultures of normal or regenerated hepatocytes, respectively. This change was accompanied by the synthesis of an additional 100,000 molecular weight from of collagen, possibly type I or A, B. Morphologically, the hepatocytes progressively flattened and overlapped adjacent cells with time in culture. However, their identify as hepatocytes was confirmed by the fact that synthesis of fibrinogen, a liver-specific function, was maintained above initial levels throughout the experiment. We conclude that synthesis of collagen is a constitutive function of the hepatocyte. This function is linked to hepatocyte replication, is subject to phenotypic change in culture, and may be important in the pathogenesis of hepatic fibrosis or cirrhosis.
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PMID:Collagen synthesis by the hepatocyte: studies in primary cultures of parenchymal cells from adult rat liver. 734 23

The effect of beta-aminopropionitrile on collagen cross-links, lysyl oxidase and prolyl hydroxylase and particular collagen type content in rat lungs after bleomycin treatment was investigated. It was stated, that beta-aminopropionitrile significantly diminishes elevated dihydroxylysinonorleucine to hydroxylysinonorleucine ratio, prevented increase of lysyl oxidase activity and increase in type I collagen content in the lungs. It is suggested, that beta-aminopropionitrile may be useful in the treatment of lung fibrosis.
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PMID:The effect of beta-aminopropionitrile on bleomycin-induced lung injury in rats. 754 46


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