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)

Changes in the regulation of collagen post-translational modification in transformed cells were studied in three established human sarcoma cell lines and in chick-embryo fibroblasts freshly transformed by Rous sarcoma virus. The collagens synthesized by all but one of these and by all the control human and chick-embryo cell lines were almost exclusively of types I and/or III. The relative rate of collagen synthesis and the amounts of prolyl hydroxylase activity and immunoreactive protein were markedly low in all the transformed human cell lines. The other enzymes studied, lysyl hydroxylase, hydroxylysyl galactosyltransferase and galactosylhydroxylysyl glucosyltransferase, never showed as large a decrease in activity as did prolyl hydroxylase, suggesting a more efficient regulation of the last enzyme than of the three others. The chick-embryo fibroblasts freshly transformed by Rous sarcoma virus differed from the human sarcoma cells in that prolyl hydroxylase activity was distinctly increased, whereas the decreases in immunoreactive prolyl hydroxylase protein and the three other enzyme activities were very similar to those in the simian-virus-40-transformed human fibroblasts. It seems possible that this increased prolyl hydroxylase activity is only a temporary phenomenon occurring shortly after the transformation, and may be followed by a decrease in activity later. The newly synthesized collagens of all the transformed cells that produced almost exclusively collagen types I and/or III had high extents of lysyl hydroxylation, and there was also an increase in the ratio of glycosylated to non-glycosylated hydroxylysine. The data suggest that one critical factor affecting modification is the rate of collagen synthesis, which affects the ratio of enzyme to substrate in the cell.
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PMID:Regulation of collagen post-translational modification in transformed human and chick-embryo cells. 627 18

A high correlation was found between the activities of protein disulphide isomerase and prolyl 4-hydroxylase when assayed in cells synthesizing various collagen types or the same type at markedly different rates. The highest activities of both enzymes were found in freshly isolated chick-embryo tendon and cartilage cells, intermediate activities in confluent cultures of human skin and lung fibroblasts and mouse 3T6 fibroblasts, and the lowest values in three human sarcoma cell lines, the difference in protein disulphide isomerase activity between the freshly isolated tendon cells and confluent simian-virus-40-transformed human lung fibroblasts being about 25-fold. All these differences are in good agreement with differences reported between the various cells in their rates of collagen synthesis. A great similarity was also found between the changes in the two enzyme activities measured per cell during the growth of 3T6 fibroblast cultures from the early logarithmic phase to the stationary phase. No correlation was found between protein disulphide isomerase activity and the type of collagen synthesized. The data suggest that protein disulphide isomerase may be involved in the formation of intra-chain and inter-chain disulphide bonds in procollagens, but there is no collagen type-related variation in this enzyme activity of a magnitude that would explain the marked differences in the rates of formation of inter-chain disulphide bonds between the various collagen types.
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PMID:Protein disulphide-isomerase activity in various cells synthesizing collagen. 686 63

Prolyl 4-hydroxylase is the key enzyme of synthesis of collagens. Hydroxylation of a sufficient number of proline residues to hydroxyproline is necessary for the stability of triple helices in collagenous proteins, because non-hydroxylated non-triple-helical collagen polypeptide chains are degraded intracellularly. We studied 15 primary chondrosarcomas and osteosarcomas, 17 benign bone tumours and one case of fibrous dysplasia and chordoma using immunofluorescence staining with antibodies against the alpha(I) and alpha(II) subunits of type I and II prolyl 4-hydroxylases, and with antibodies against collagen types I and II. Type I prolyl 4-hydroxylase was found to be the predominant isoenzyme in both types of bone sarcoma, whereas the type II enzyme was more readily expressed by benign tumours. A feature of collagen staining, that was common to both sarcoma types, was that collagen types I and II were mainly found within cancer cells and were rarely present extracellularly. Extracellular collagen staining was more obvious in benign tumours. The results show that expression of prolyl 4-hydroxylase isoenzymes is altered in bone sarcomas as compared with normal bone tissue. Chondrous cells, which normally express mainly the type II isoenzyme, switch their expression pattern to that of type I. The findings provide evidence that type I is the major isoenzyme in malignant bone tumours, and probably in malignant neoplasms in general. The pattern of enzyme expression is considered to be associated with dedifferentiation of cancer cells.
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PMID:Immunofluorescence localization of prolyl 4-hydroxylase isoenzymes and type I and II collagens in bone tumours: type I enzyme predominates in osteosarcomas and chondrosarcomas, whereas type II enzyme predominates in their benign counterparts. 1514 32

Alveolar soft-part sarcoma (ASPS) is a rare neoplasm with chromosomal translocation that results in ASPL-TFE3 fusion. It is a slow-growing lesion associated with a high incidence of pulmonary and brain metastases indicating poor survival. We demonstrated that the ASPS metastases include also stromal myofibroblasts. These cells proliferate, express smooth-muscle genes, and synthesize extracellular matrix proteins, all of which are characteristics of activated myofibroblasts. The tumor cells also exhibited stromal components such as transforming growth factor beta (TGFbeta)-dependent, hypoxia-regulated cytoglobin (stellate cell activation association protein, cytg/STAP) and prolyl 4-hydroxylase, a collagen cross-linking enzyme. The pulmonary ASPS myofibroblasts synthesize serum response factor (SRF), a repressor of Smad3-mediated TGFbeta signaling essential for myofibroblast differentiation and Smad3. The phosphorylated active Smad3 was found mostly in the tumor cells. The brain tumor cells express cytg/STAP, but in contrast to the lung metastases, they also express SRF, Smad3, and phospho-Smad3. Halofuginone, an inhibitor of myofibroblasts' activation and Smad3 phosphorylation, inhibited tumor development in xenografts derived from renal carcinoma cells harboring a reciprocal ASPL-TFE3 fusion transcript. This inhibition was associated with the inhibition of TGFbeta/SRF signaling, with the inhibition of myofibroblasts' activation, and with the complete loss in TFE3 synthesis by the tumor cells. These results suggest that the myofibroblasts may serve as a novel target for treatment of ASPS metastases.
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PMID:Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: a novel target for treatment? 1871 94