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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphorylation of G0/G1-arrested Chinese hamster lung fibroblasts (CC139 line) has been analyzed following stimulation by fetal calf serum (FCS) or by a variety of growth factors. FCS stimulated the phosphorylation of three major polypeptides separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis: a nuclear protein with a Mr of 62,000 daltons, the ribosomal protein S6, and a cytosoluble peptide of 27,000 daltons. These phosphorylations occurred rapidly after serum stimulation (1 min for the 27,000-dalton peptide, 5 min for S6 and the 62,000-dalton proteins) and were maximal after 30 min. In nonstimulated cells the 27,000-dalton phosphopeptide exists in two forms with isoelectric points of 5.7 and 6.0; serum increased the amount of the most acidic form. At low concentrations, the "commitment" growth factors, alpha-thrombin, eye-derived growth factor (EDGF), platelet-derived growth factor (PDGF), stimulated phosphorylation of the 27,000-dalton peptide. At higher concentrations, these factors alone reinitiated DNA synthesis and, like FCS, stimulated phosphorylation of the three major peptides. In contrast, and suggesting a different mechanism of action, "progression" factors such as insulin (1-10 micrograms/ml) and multiplication-stimulating activity (MSA) are unable to stimulate phosphorylation of the 27,000-dalton peptide. However, insulin or MSA which are known to potentiate the mitogenic action of alpha-thrombin, PDGF, EDGF, ... were also found to potentiate phosphorylation of the ribosomal protein S6. These results support the existence of two classes of growth factors and suggest that protein phosphorylation is an early event involved in the control of the cellular G0 leads to G1 transition.
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PMID:Growth factor-stimulated protein phosphorylation in G0/G1-arrested fibroblasts. Two distinct classes of growth factors with potentiating effects. 682 30

To investigate serum requirements for optimal erythropoiesis in vitro, we studied the response of erythroid progenitor cell proliferation in culture to platelet-derived growth factor (PDGF). Human bone marrow cells cultured with platelet-poor plasma-derived serum (PDS) form fewer erythroid colonies than do cells cultured with human whole blood serum or fetal calf serum (P less than 0.05). Treatment of washed platelets with thrombin releases a low molecular weight (less than 100,000) factor that enhances colony growth. This secreted factor appears to be PDGF, based upon the ability of partially purified and electrophoretically pure PDGF to restore colony-forming capacity of PDS-containing cultures to 70-96% of the level found in control cultures with whole blood serum or fetal calf serum. Enhancement of colony growth by PDGF was noted only in marrow cultures supplemented with erythropoietin and PDS. Presence of bioactive erythropoietin in PDGF preparations was excluded by assay in hypertransfused, polycythemic mice, and in fasted rats. Although PDGF stimulates erythroid burst formation in marrow cultures containing optimal concentrations of burst-promoting activity (BPA), it does not influence proliferation of circulating erythroid bursts, regardless of BPA concentration added to culture. We conclude that PDGF is a serum determinant of optimal erythroid progenitor cell proliferation in marrow culture. The activity of PDGF is distinct from that of the apparent erythroid specific growth factors erythropoietin and BPA.
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PMID:Platelet-derived growth factor promotes proliferation of erythropoietic progenitor cells in vitro. 685 8

Platelet basic protein (PBP) (isoelectric point, 10.0-10.5; apparent Mr, 11,000-15,000) has been purified to homogeneity from material secreted by fresh human platelets after stimulation by thrombin. The purification, using preparative isoelectric focusing and chromatography on heparin-Sepharose, yielded two additional peptides with antiheparin activity that were immunologically identical with PBP: low-affinity platelet factor 4 and beta-thromboglubulin. The purity of the peptides was confirmed by immuoelectrophoresis and by NH2-terminal amino acid analysis. Dansyl chloride-treated PBP yielded a single dansylated amino acid residue (glycine). By using a specific radioimmunoassay it was shown that 10(9) human platelets contain 2-3 microgram of PBP which can be released in response to specific stimulation. PBP is associated with mitogenic activity as assayed in Swiss 3T3 mouse cells cultured in low-serum (0.4-1.5%) medium at levels of about 1 ng/ml and saturating at 10-40 ng/ml. The biological activity of different PBP preparations was variable, presumably due to inhibition by the varying amounts of ampholytes that interfered with the mitogenic activity of the peptide. Mitogenic activity was eluted from NaDodSO4/polyacrylamide gels and shown to comigrate with immunoreactive material and with conventional marker proteins of 14,000-17,000 daltons or with histones of 11,000-15,000 daltons. Evidence is presented that PBP is different from cationic platelet-derived growth factor which has an apparent Mr of 30,000.
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PMID:Human platelet basic protein associated with antiheparin and mitogenic activities: purification and partial characterization. 693 22

The hormones which support growth, in vitro, of normal, neonatal human foreskin fibroblasts were determined. Whereas thrombin and hydrocortisone were major growth stimulants, platelet-derived growth factor was not. Human foreskin fibroblasts grew in a serum-free, biochemically defined medium consisting of epidermal growth factor (100 ng/ml), insulin (100 ng/ml), transferrin 10 micrograms/ml), thrombin (1 microgram/ml), ascorbic acid (10 micrograms/ml), and hydrocortisone (5 x 10(-5) M) in a 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12, supplemented with ovalbumin (1 mg/ml) and trace elements. The growth achieved was comparable to that achieved with 5% fetal bovine serum. Neither platelet-derived growth factor, fibroblast growth factor, nor somatomedin activity increased proliferation. This serum-free medium, designated Defined Medium F, provides a biochemically defined system for growth and limited subcultivation of human foreskin fibroblasts in vitro.
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PMID:Growth of human foreskin fibroblasts in a serum-free, defined medium without platelet-derived growth factor. 704 Apr 23

Induction of NO synthase expression by interleukin-1 beta in cultured vascular smooth muscle cells from rat aortas was accompanied by simultaneous induction of GTP: cyclohydrolase I. This enzyme regulates the de novo synthesis pathway for tetrahydrobiopterin, an essential cofactor for the catalytic conversion of L-arginine to L-citrulline and NO by inducible NO synthase. Inhibition of GTP: cyclohydrolase attenuated NO production by interleukin-1 beta-stimulated smooth muscle cells. Peptide growth factors such as fibroblast growth factor, platelet-derived growth factor and transforming growth factor beta 1 and the protease thrombin have been shown to modulate the production NO by cytokine-treated smooth muscle cells. These peptide agonists also regulated the induction of NO synthase and GTP: cyclohydrolase mRNA expression.
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PMID:Growth factor regulation of interleukin-1 beta-induced nitric oxide synthase and GTP: cyclohydrolase expression in cultured smooth muscle cells. 750 72

This brief overview discusses the ability of mediators associated with vascular injury, such as interleukin-1 beta and tumour necrosis factor alpha, to activate vascular smooth muscle cells to produce nitric oxide or a related donor of nitric oxide. The cytokines cause the synthesis of nitric oxide synthase(s), which catalyzes the conversion of L-arginine to nitric oxide and L-citrulline. The production of nitric oxide can be modulated by factors produced by vascular cells and formed elements of the blood (e.g. platelet-derived growth factor, transforming growth factor beta), but also by those generated at sites of vascular injury from inactive precursors circulating in the blood (e.g. thrombin, plasmin). The production of nitric oxide by vascular smooth muscle cells may contribute to the homeostasis of blood vessels at sites of injury. In particular, nitric oxide may prevent the local development of vasospasms, unwanted proliferation of smooth muscle cells, and also help to control coagulation and the formation of the thrombus.
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PMID:Role of the L-arginine-nitric oxide pathway in vascular smooth muscle. 750 37

Using a rat pulmonary artery smooth muscle cell line (PAC1), detailed analysis of polyphosphoinositide (PPI) metabolism reveals receptor type-selective patterns in the formation of inositol phosphates and 3-hydroxyphosphorylated PPIs. Responses to several agonists that stimulate hypertrophy or proliferation were examined, and distinct categories of response profile were observed. Thrombin and angiotensin II stimulated the hydrolysis of phosphatidylinositol (PI) 4,5-bisphosphate and the formation of several cytosolic species of inositol phosphates without the activation of PI 3-hydroxykinase. The response to thrombin was distinctive because a very large production of inositol 1,4-bisphosphate was accompanied by hydrolysis of PI 4-phosphate. The response to platelet-derived growth factor (PDGF) was distinguished by the production of the PI 3-hydroxykinase product, PI 3,4,5-trisphosphate, and the appearance of PI 3-hydroxykinase activity in immunoprecipitates. PDGF treatment of PAC1 cultures did not produce accumulation of detectable amounts of inositol 1,4,5-trisphosphate, although a small sustained elevation in the level of inositol monophosphate and a gradual accumulation of inositol 1,3,4-trisphosphate were observed. Characterization of these distinctive responses permitted us to correlate agonist-regulated PPI metabolism with induction of immediate-early genes and stimulation of hypertrophy or proliferation of PAC1 cultures (Rothman, A., Wolner, B., Button, D., and Taylor, P. (1994) J. Biol. Chem. 269, 6399-6404). Thrombin-stimulated PPI turnover and the production of a high level of inositol bisphosphate may be early signals linked to the induction of fosB and PAC1 cell hypertrophy, whereas the activation of PI 3-hydroxykinase and the accumulation of PI 3,4,5-trisphosphate in response to PDGF appear to be associated with mitogenesis.
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PMID:Agonist-selective regulation of polyphosphoinositide metabolism in pulmonary artery smooth muscle cells. 750 2

Nitric oxide is a multifunctional regulator of the vascular system. In healthy blood vessels, nitric oxide is produced from L-arginine by the constitutive nitric oxide synthase in endothelial cells. In addition, vascular injury or inflammation cause the production of nitric oxide in most types of vascular cells, including vascular smooth muscle. This response to injury is due to the induction of a second type of nitric oxide synthase by cytokines such as interleukin-1 beta or tumor necrosis factor-alpha. Factors derived from blood (thrombin, plasmin) and from vascular cells (platelet-derived growth factor, transforming growth factor beta, insulin-like growth factor, epidermal growth factor and basic fibroblast growth factor), regulate the induction of nitric oxide synthesis in vascular smooth muscle cells. The endogenous production of nitric oxide by vascular smooth muscle at sites of injury may contribute to the local control of blood flow, vascular tone and blood fluidity. It may participate also to the remodeling of the injured blood vessel wall.
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PMID:Inducible nitric oxide synthase in vascular smooth muscle. 751 15

Recent studies have shown that the synthetic peptides SFL LRN and SFL LRN PND KYEPF (thrombin receptor-activating peptides (TRAP)) derived from the deduced sequence of the new amino terminus of the cleaved thrombin receptor can mimic thrombin receptor activation, act as full agonists for platelet activation, and induce prostaglandin I2 production as well as cytosolic Ca2+ increase in human umbilical vein endothelial cells (HUVEC). Here, we have compared the ability of these synthetic peptide ligands and thrombin to stimulate platelet-derived growth factor (PDGF) production by, and monocyte adhesion to, HUVEC. Thrombin (50 units/ml) and TRAP (25 microM) maximally stimulated monocyte adhesion. Furthermore, the stimulation of E-selectin cell surface expression and the steady-state E-selectin mRNA levels by thrombin and TRAP were comparable. Thrombin (50 units/ml) stimulated PDGF production 400% above the basal level in 24 h, whereas the 6-mer and 14-mer TRAP, even at 200 microM, did not significantly stimulate PDGF production. Northern analysis, however, revealed that TRAP at 100 microM stimulated PDGF-A and -B chain mRNA expression to a level similar to that induced by thrombin. These results suggest that activation of cell signaling by TRAP can mimic thrombin and is sufficient for the stimulation of monocyte adhesion to HUVEC; however, thrombin-stimulated PDGF production by HUVEC may require mechanisms in addition to the signaling events initiated by TRAP or may require the participation of a novel thrombin receptor.
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PMID:Thrombin receptor-activating peptides differentially stimulate platelet-derived growth factor production, monocytic cell adhesion, and E-selectin expression in human umbilical vein endothelial cells. 751 96

Thrombin elicits multiple biological effects on a variety of cells. We have previously shown that thrombin is a potent mitogen for human glomerular mesangial cells. This mitogenic effect of thrombin is associated with activation of phospholipase C (PLC) and induction of platelet-derived growth factor (PDGF) gene expression. The thrombin receptor, which belongs to the guanine nucleotide binding protein (G protein)-coupled receptor family, has recently been shown to induce rapid tyrosine phosphorylation of cellular proteins. In the present study, we investigated the role of protein-tyrosine phosphorylation in mediating the cellular responses elicited by thrombin in human glomerular mesangial cells. Amino acid labeling followed by immunoprecipitation with phosphotyrosine antibodies demonstrate that thrombin stimulates tyrosine phosphorylation of a set of cellular proteins. Treatment of mesangial cells with thrombin followed by immunoblotting with phosphotyrosine antibodies showed three major bands of tyrosine-phosphorylated proteins approximately 130, 70, and 44-42 kDa. Phosphorylation of these proteins was inhibited by two tyrosine kinase inhibitors, herbimycin A and genistein. Both compounds inhibited DNA synthesis and PDGF B-chain gene expression but had no effect on inositol phosphates production or increases in cytosolic calcium in response to thrombin. These data demonstrate that protein-tyrosine phosphorylation is not required for thrombin-induced PLC activation with inositol phosphate formation and subsequent intracellular calcium release, but it is an absolute requirement for thrombin-induced DNA synthesis and PDGF B-chain gene expression.
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PMID:Mitogenic signaling of thrombin in mesangial cells: role of tyrosine phosphorylation. 752 56


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