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:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphatidylinositol 3-phosphate (PtdIns(3)P), a recently described phospholipid, has been linked to polyoma virus-induced cellular transformation and platelet-derived growth factor-mediated mitogenesis. PtdIns(3)P, in contrast to phosphatidylinositol, phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), is resistant to hydrolysis by bovine brain phospholipase C gamma. We present here the identification of a phosphomonoesterase activity from the soluble fraction of NIH 3T3 cells which removes the phosphate from the D-3 position of PtdIns(3)P. This enzyme is specific as it has little or no activity on the monoester phosphates of PtdIns(4)P, PtdIns(4,5)P2, or inositol 1,3-bisphosphate and is tentatively designated phosphatidylinositol 3-phosphatase (PtdIns 3-phosphatase). The enzyme does not require added metal ions for activity and is maximally active in the presence of EDTA. It is inhibited by Ca2+, Mg2+, Zn2+, and the phosphatase inhibitor VO4(3-). In addition, there is no phospholipase C activity toward PtdIns(3)P in the soluble fraction of NIH 3T3 cells. In view of the absence of a phospholipase C activity that hydrolyzes PtdIns(3)P, we propose that PtdIns(3)P is not a precursor for a soluble inositol phosphate messenger but that it instead may act directly to control certain cellular processes or as a precursor for other phosphatidylinositols. PtdIns 3-phosphatase may thus terminate a metabolic signal or regulate precursor levels for other phosphatidylinositols that are phosphorylated in the D-3 position.
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PMID:The discovery of a 3-phosphomonoesterase that hydrolyzes phosphatidylinositol 3-phosphate in NIH 3T3 cells. 255 36

Recent techniques have been devised for the culture of bone cells derived from human bone explants. These cells, which are thought to represent several stages in the osteoblast lineage, respond to PTH with an increase in cyclic AMP content, and have high basal alkaline phosphatase activity which is increased on exposure to 1,25-dihydroxyvitamin D3 and decreased by PTH. Such characteristics distinguish these cells from fibroblasts. In this study, we demonstrate that human bone-derived cells also differ from fibroblasts in their growth characteristics. Bone-derived cells proliferated in basal medium supplemented with platelet-poor plasma. The rate of proliferation was enhanced by additional supplementation with platelet-derived growth factor (PDGF), and further increased when a combination of growth factors was added (PDGF, TGF-beta and EGF). In contrast, fibroblasts did not proliferate in basal medium supplemented with platelet-poor plasma and the addition of PDGF alone stimulated fibroblast proliferation to the same extent as 10% fetal bovine serum. Supplementation with other growth factors did not further enhance the response of fibroblasts to PDGF. These results emphasize the differences in proliferative responses between human bone-derived cells and human fibroblasts, and indicate that the factors responsible for osseous regeneration in vivo may differ from those factors which regulate repair of soft tissue wounds.
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PMID:Study of the growth factor requirements of human bone-derived cells: a comparison with human fibroblasts. 278 49

The presence of many types of polypeptide growth factors in the mineralized extracellular matrix of bone is now well established. These factors are generally referred to as bone-derived growth factors (BDGFs), and are similar, or possibly identical, to the following species; platelet-derived growth factor (PDGF); acidic and basic forms of fibroblast growth factor (aFGF, bFGF); transforming growth factor beta (TGF-beta); and insulin-like growth factor 1 (IGF-1). Several osteoinductive factors, such as bone morphogenetic protein (BMP) and osteogenin, a skeletal growth factor (SGF), and osteoblast-derived BDGFs, have also been identified. Complete description of the biological functions of these BDGFs which are relevant to bone will ultimately require specific bioassays involving specific cell types in vitro, as well as in vivo animal implant models. Studies with primary rat osteoblast-like cells exposed either to mixed BDGFs, pure TGF-beta, or heparin-purified PDGF, aFGF, or bFGF from bovine bone have shown a general dose-dependent mitogenic effect. Phenotypic changes which accompany the BDGF-induced wave of proliferation include: decreased osteocalcin secretion and a reduction in 1,25-(OH)2 vitamin D3-stimulated osteocalcin synthesis; reduced alkaline phosphatase specific activity; decreased cyclic AMP responsiveness to parathyroid hormone (PTH); and increased collagen synthesis. Bone exhibits the most complex spectrum of growth factor activities of any tissue yet described. In bovine bone powder free of blood and cartilage contamination, the volume concentration of mitogens is up to 20 times greater than that in serum. Bone cells and other indigenous cell types must be considered as possible sources of the BDGFs, in addition to sequestration from blood. Mechanisms for the unmasking or release of BDGFs from the mineralized matrix that result in local action on osteoblasts, endothelial cells, and other target cells are undoubtedly important for the development and maintenance of bone tissue.
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PMID:Polypeptide growth factors in bone matrix. 306 10

Subcutaneous implantation of demineralized bone matrix induces the local formation of cartilage and bone. In this study we have investigated the influence of adding various growth factors to the implant. Cartilage formation was monitored by measuring collagen II mRNA levels, and bone formation in the implant was assessed from alkaline phosphatase activity and calcium content. Supplements of the platelet-derived growth factor to implants in older rats increased and production of mRNA for collagen II, alkaline phosphatase activity, and the calcium content of the implant, whereas the other growth factors tested were without effect. The data suggest that under some conditions bone induction is submaximal and can be increased by local supplement of platelet-derived growth factor (PDGF). The present observations may have important therapeutic implications in the treatment of nonunions of fractures and impaired bone formation in the aged.
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PMID:Platelet-derived growth factor enhances demineralized bone matrix-induced cartilage and bone formation. 312 65

We have noted two previously undescribed inositol polyphosphates in neutral methanol extracts from Swiss mouse 3T3 cells that were grown in [3H]inositol and stimulated with platelet-derived growth factor. They have been identified as 1-monomethylphosphoinositol 4,5-bisphosphate and 1-monomethylphosphoinositol 4-phosphate by comparison to a synthesized standard using HPLC chromatography, paper electrophoresis, and enzymatic dephosphorylation with inositol polyphosphate 5-phosphomonoesterase and intestinal alkaline phosphatase [orthophosphoric-monoester phosphohydrolase (alkaline optimum), EC 3.1.3.1]. We propose that these compounds are formed by methanolysis of inositol 1,2-(cyclic)-4,5-trisphosphate and inositol 1,2-(cyclic)-4-bisphosphate present in the cells. Inositol cyclic phosphates did not react with neutral methanol in the absence of the cells, which are required for the methanolysis reaction. These findings suggest a role for inositol cyclic phosphates as reactive compounds that are added to as yet unidentified cellular acceptors.
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PMID:Isolation of 1-monomethylphosphoinositol 4,5-bisphosphate [a product of methanolysis of inositol 1,2-(cyclic)-4,5-trisphosphate] from Swiss mouse 3T3 cells. 342 29

Skeletal growth factor (SGF) activity was extracted from human bone matrix by demineralization and purified under dissociative conditions using hydroxyapatite, HPLC gel-filtration and HPLC reverse-phase chromatography. Human SGF thus purified was characterized chemically and biologically. Purified human SGF stimulated chick embryo bone cell proliferation at picomolar concentrations (half maximum at 2-3 ng/ml) and had little or no activity on other cell types tested (mouse 3T3 and normal rat kidney fibroblasts, embryonic chick intestinal and human placental cells). Human SGF did not displace 125I-labeled epidermal growth factor binding to normal rat kidney cells and did not stimulate normal rat kidney cell colony formation in soft agar. Human SGF activity was sensitive to trypsin, chymotrypsin, papain, dithiothreitol and performic acid but was resistant to heat (upto 70 degrees C), pH (3-10), cyanogen bromide, alkaline phosphatase and neuraminidase and did not bind jack bean concanavalin A or kidney bean lectin. From our chemical and biological studies it appears that human SGF is different from other known polypeptide growth factors: epidermal growth factor, fibroblast growth factor, insulin, insulin-like growth factor-I, platelet-derived growth factor and transforming growth factor.
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PMID:Chemical and biological characterization of low-molecular-weight human skeletal growth factor. 349 Feb 78

The mineralized matrix of osseous tissue harbors abundant mitogenic activity which is extractable by demineralizing solvents. In bovine bone powder free of blood and cartilage contamination, the volume concentration of mitogens is up to 20 times greater than in serum. Growth factor activity in bone extracts was quantitated on quiescent mouse BALB/c/3T3 fibroblasts, where [3H]thymidine incorporation for 48 h was stimulated up to 200-fold in a linear, dose-dependent manner. Six distinct bone-derived growth factors (BDGFs) have been resolved and partially purified (up to 44,000-fold) on heparin-Sepharose using NaCl gradient elution. Provisionally named by the NaCl molarity at which they elute, these BDGFs include BDGF-0.45 (25% of total activity). This factor is heat-stable and sensitive to dithiothreitol, and displaces 125I-labelled bovine platelet-derived growth factor in a radioreceptor assay. BDGF-0.45 (approximately 50 ng/g of bone) is closely related or identical to bovine platelet-derived growth factor. BDGF-1.1 (10%) has a pI of 5.2 and shows a 16,600-dalton doublet on sodium dodecyl sulfate-polyacrylamide gel electrophoresis Western blots stained with antiserum to bovine anionic fibroblast growth factor. Two activities with high heparin affinity resemble cationic forms of fibroblast growth factor. BDGF-1.5 is the dominant factor in fetal membranous bone (50%), but is less abundant in adult bone (20%). BDGF-1.7, a 17,500-18,400-dalton triplet, is virtually absent in fetal bone (7%) but abundant (30%) in adult bone and may be related to cartilage derived growth factor. Two minor activities, BDGF-0.1 (10%) and BDGF-2.0 (7%) have not been characterized. Proliferation of bovine capillary endothelial cells was strongly supported by BDGFs 1.1, 1.5, and 1.7, but not by 0.45. These four purified BDGFs and the crude bone extract were also strongly mitogenic for rat osteoblasts while depressing alkaline phosphatase specific activity by 2-3-fold. Bone exhibits the most complex spectrum of growth factor activities of any tissue yet described. Bone cells and other indigenous cell types must be considered as possible sources of the BDGFs, in addition to sequestration from blood. Mechanisms for unmasking or release of BDGFs from the mineralized matrix resulting in local action on target cells are undoubtedly important for the development and maintenance of bone tissue.
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PMID:Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. 374 6

The effects of platelet-derived growth factor (PDGF) on DNA synthesis and mRNA expression of osteoblast markers in marrow stromal cells derived from adult (6 months) and old (24 months) rats were examined. Treatment of stromal cells from adult rats with dexamethasone induced the appearance of osteoblast-like cells. PDGF partially also inhibited the differentiation of stromal cells induced by dexamethasone. In cultures of serum-starved stromal cells, PDGF stimulated [3H]-thymidine incorporation into DNA in a dose-dependent manner with a maximum stimulation of 15-fold at 500 ng/ml. By comparison, insulin-like growth factor (IGF-I) has a small effect on [3H]-thymidine incorporation. The effect of PDGF and IGF-I on DNA synthesis was additive. Treatment of the confluent stromal cells from adult rats with PDGF increased the mRNA level of osteopontin fourfold without any significant effect on alkaline phosphatase and type I collagen mRNAs. In contrast, dexamethasone stimulated the mRNA expression of alkaline phosphatase, type I collagen, and osteopontin 2.1-, 2.3-, and 14-fold, respectively. Addition of PDGF to dexamethasone-treated cells failed to induce any further increase in osteopontin expression whereas the expression of alkaline phosphatase and type I collagen was partially reduced. The expression of osteocalcin mRNA was negligible in stromal cells but stimulated several fold by dexamethasone and 1,25(OH)2D3. PDGF inhibited drastically the elevation of osteocalcin mRNA. In contrast, IGF-I stimulated type I collagen expression 100% without any appreciable effect on the expression of osteopontin and alkaline phosphatase. The stimulatory effect of PDGF on osteopontin expression was augmented by IGF-I. Furthermore, PDGF attenuated the stimulatory effect of IGF-I on type I collagen expression. The responses of cultured cells from old rats to growth factors were also examined. PDGF or PDGF plus IGF-I increased [3H]-thymidine incorporation in stromal cells from old rats but to a lesser extent. However, PDGF was equally effective in stimulating osteopontin expression in cells from both adult and old rats. We concluded that PDGF is a potent mitogen but that the response of stromal cells from old rats is impaired. In addition, PDGF stimulates osteopontin expression in stromal cells and this effect is not age dependent.
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PMID:Effect of platelet-derived growth factor on DNA synthesis and gene expression in bone marrow stromal cells derived from adult and old rats. 762 82

The expression of the B-chain of platelet-derived growth factor (PDGF) was analyzed in 29 human brain tumors (4 astrocytomas, 7 glioblastomas, 3 medulloblastomas, 3 oligodendrogliomas, 7 meningiomas, and others) using monoclonal antibody after digestion with alkaline phosphatase, and compared with proliferative activities measured by in vivo uptake of bromodeoxyuridine. Medulloblastomas contained the highest amounts of PDGF B-chain, some four to eight times more than that in control brain tissue. The most predominant PDGF molecule of the medulloblastoma was 17 kd. Astrocytomas, glioblastomas, oligodendrogliomas, and meningiomas contained predominantly 30 and/or 22-24 kd molecules. Glioblastoma and meningioma proliferative activities correlated closely to PDGF concentrations, with only a few exceptions. Tumors that contained a high level of PDGF B-chain showed high proliferative activity, while tumors with high proliferative activity did not always contain a high level of PDGF B-chain. Tumors that contain many PDGF B-chains may thus indicate malignancy.
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PMID:Expression of the B-chain of platelet-derived growth factor and proliferative activity of human brain tumors. 768 50

Insulin stimulation of differentiated 3T3-L1 adipocytes or Chinese hamster ovary cells expressing high levels of the insulin receptor resulted in a time-dependent decrease in the electrophoretic mobility of SOS on sodium dodecyl sulfate-polyacrylamide gels. The reduction in SOS mobility was completely reversed by alkaline phosphatase treatment, and the in vitro phosphorylation of SOS by mitogen-activated protein kinase resulted in a decrease of electrophoretic mobility identical to that following in vivo insulin stimulation. Immunoprecipitation of Grb2 followed by SOS immunoblotting demonstrated a disassociation of the SOS-Grb2 complex that paralleled the decrease in SOS electrophoretic mobility. Similarly, SOS immunoprecipitation followed by Grb2 immunoblotting also indicated an uncoupling of the SOS-Grb2 complex. Further, incubation of whole-cell extracts with glutathione-S-transferase-Grb2 fusion proteins demonstrated that insulin stimulation resulted in a decreased affinity of SOS for Grb2. In contrast, the dissociation of SOS from Grb2 did not affect the interactions between Grb2 and tyrosine-phosphorylated Shc. In addition to insulin, several other agents which activate the mitogen-activated protein kinase pathway (platelet-derived growth factor, serum, and phorbol ester) also resulted in the uncoupling of the SOS-Grb2 complex. Consistent with these results, expression of v-ras and v-raf resulted in a constitutive decrease in the association between SOS and Grb2. Together, these data suggest a molecular mechanism accounting for the transient activation of ras due to the uncoupling of the SOS-Grb2 complex following SOS phosphorylation.
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PMID:Insulin-stimulated disassociation of the SOS-Grb2 complex. 773 60


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