Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of proto-oncogene fos is induced in response to a variety of growth factors and differentiation-specific agents. However, the induction of fos gene expression is not influenced by inhibition of protein synthesis. We, therefore, entertained the notion that expression of the fos gene may be governed by posttranslational modification of cellular transcriptional factors. We report here that transcription of the human c-fos gene is modulated by negatively and positively acting cellular factors. The nuclear protein products of the resident oncogene of the FBJ-murine osteosarcoma virus (v-fos) and its corresponding cellular proto-oncogene (c-fos) are stoichiometrically phosphorylated on serine and threonine residues. The c-fos protein is more highly phosphorylated than the v-fos protein due to the phosphorylation of unique sites tentatively localized to the c-terminal 20 amino acid residues. The protein kinase C agonist, TPA, stimulates phosphorylation of the c-fos, but not the v-fos protein.
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PMID:Proto-oncogene fos: factors affecting expression and covalent modification of the gene product. 283 Aug 21

We have investigated the covalent modification of the proteins encoded by the murine fos proto-oncogene (c-fos) and that of the corresponding gene product of FBJ murine osteosarcoma virus (v-fos). Both proteins are posttranslationally processed in the cell, resulting in forms with lower electrophoretic mobilities than that of the initial translation product on sodium dodecyl sulfate-polyacrylamide gels. Treatment with alkaline phosphatase indicates that most, if not all, of this electrophoretic shift is due to phosphoesterification of both proteins. These phosphoryl groups stoichiometrically modify the v-fos and c-fos proteins on serine residues and turn over rapidly in vivo in the presence of protein kinase inhibitors (half-life, less than 15 min). Direct quantitative comparison of steady-state labeling studies with L-[35S]methionine and [32P]phosphate reveals that the c-fos protein is four- to fivefold more highly phosphorylated than the v-fos protein is. Comparison of tryptic fragments from [32P]phosphate-labeled proteins indicates that although the two proteins have several tryptic phosphopeptides in common, the c-fos protein contains unique major tryptic phosphopeptides that the v-fos protein lacks. These unique sites of c-fos phosphorylation have been tentatively localized to the carboxy-terminal 20 amino acid residues of the protein. Phosphorylation of the c-fos protein, but not the v-fos protein, can be stimulated at least fivefold in vivo by the addition of either 12-tetradecanoyl-phorbol-13-acetate or serum. This increase in the steady-state degree of phosphorylation of c-fos appears to be independent of protein kinase C since phosphorylation is Ca2+ and diacylglycerol independent. The possible role of phosphorylation of these proteins in cellular transformation is discussed.
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PMID:Modification of fos proteins: phosphorylation of c-fos, but not v-fos, is stimulated by 12-tetradecanoyl-phorbol-13-acetate and serum. 311 Jun 3

The effects of 12-O-tetraadecanoyl phorbol-13-acetate (TPA), 1-oleoyl-2-acetyl-glycerol (OAG), and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) on the parathyroid hormone (PTH) degrading activity in a PTH-responsive osteoblast-like rat osteosarcoma cell line UMR106 were investigated to assess the role of Ca2+-activated. Phospholipid dependent protein kinase (protein kinase C) on the degradation of hormones. TPA and OAG, activators of protein kinase C, enhanced the PTH degrading activity dose-dependently, whereas H-7, an inhibitor of protein kinase C, exhibited a dose-dependent inhibition on this activity. These data suggest that protein kinase C activation may enhance PTH degrading activity by UMR106 cells as a possible regulator of PTH degradation.
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PMID:Possible involvement of protein kinase C in parathyroid hormone degradation by osteoblast-like rat osteosarcoma cell line UMR106. 347 Dec 17

To test directly whether protein kinase C activation is one of the required events leading to stimulation of prostaglandin production by bone cells, protein kinase C activity and prostaglandin E2 release were measured in monolayer cultures of the clonal human osteosarcoma cell lines G-292 and SaOS-2 after exposure to phorbol myristate acetate (PMA). Both cell lines have specific receptors for PMA but only G-292 cells respond with increased prostaglandin E2 production (M. A. Shupnik and A. H. Tashjian, Jr., J. Biol. Chem., 257: 12161-12164, 1982). The subcellular distribution of protein kinase C in both unstimulated osteosarcoma cell lines was similar; in an EDTA- and leupeptin-containing homogenization buffer, between 70 and 80% of the total enzyme activity was cytosolic. Short (less than 60 min) incubations with PMA induced marked decreases in cytosolic enzyme activity and parallel increases in particulate protein kinase C; thereafter, total measured cellular protein kinase C activity declined, mediated by decreases in both cytosolic and particulate protein kinase C specific activities. By 24 h cytosolic, particulate, and total protein kinase C activities were less than 10% of basal. Because the protein kinase C responses in both cell types were essentially the same, but only G-292 cells give a prostaglandin response to PMA, we conclude that protein kinase C activation by PMA is itself insufficient to stimulate prostaglandin E2 production and that the lack of a prostaglandin response in SaOS-2 cells cannot be explained by lack of protein kinase C activation.
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PMID:Time-dependent changes in protein kinase C distribution and disappearance in phorbol ester-treated human osteosarcoma cells. 347 24

Phorbol 12-myristate 13-acetate (PMA) induces time-dependent changes in protein kinase C subcellular distribution and enzymatic activity in the human osteosarcoma cell line SaOS-2. Short (less than 60 min) incubations with PMA caused decreased cytosolic enzyme activity and a concomitant increase in particulate protein kinase; after 3 h, particulate protein kinase C activity also declined to reach less than 10% of basal activity by 24 h (Krug, E., and Tashjian, Jr., A. H., (1987) Cancer Res. 47, 2243-2246). In order to determine whether the loss in enzyme activity was due to decreased enzyme protein, Western blot analyses were performed using a polyclonal antibody against protein kinase C raised in rabbits. This approach confirmed the previously reported time-related changes: 80-kDa immunoreactive protein kinase C initially translocated from the cytosol to the particulate cell fraction and later disappeared completely from the particulate fraction. Loss of protein kinase C enzymatic activity thus results from actual loss of the 80-kDa protein; we found no evidence for generation of a calcium/phospholipid-independent protein kinase C-like form of the enzyme. Membrane association was confirmed by immunoprecipitation experiments using [35S]methionine-labeled cells. Brief exposure to PMA caused a marked loss in the [35S]methionine-labeled cytosolic protein kinase C band and an increase in the labeled particulate band. Protein kinase C immunoprecipitated from cells treated with PMA for 14 h displayed an increase in [35S]methionine label despite a greater than 80% loss of enzyme activity. The high specific radioactivity of the remaining 80-kDa protein leads us to conclude that long term treatment with PMA causes an increase in the rate of protein kinase C synthesis accompanied by a still greater increase in the rate of enzyme degradation in SaOS-2 cells.
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PMID:Evidence for increased synthesis as well as increased degradation of protein kinase C after treatment of human osteosarcoma cells with phorbol ester. 347 87

We present evidence for the presence of specific, high-affinity binding sites for tritiated phorbol 12,13-dibutyrate on osteosarcoma-derived (HT-3) cells. Activation of protein kinase C by a phorbol ester resulted in an inhibition of alkaline phosphatase activity and the accumulation of prostaglandin E2. Indomethacin blocked prostaglandin E2 production and enhanced alkaline phosphatase activity. These data suggest that prostaglandin E2 is enhanced by activation of protein kinase C, and in turn, alkaline phosphatase activity is reduced.
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PMID:Activation of protein kinase C and the involvement of prostaglandin E2 in the inhibition of osteosarcoma-derived cell alkaline phosphatase activity. 766 74

The effect of the tumor promoter 4 beta-phorbol 12-myristate 13-acetate and of the phosphatases inhibitor okadaic acid on the binding of tumor necrosis factor-alpha (TNF-alpha) to a human osteogenic sarcoma cell line (Saos-2) was investigated. Both substances prevented almost completely TNF binding to its receptors. The effect of 4 beta-phorbol 12-myristate 13-acetate was reversed by the protein kinase C inhibitors staurosporine and calphostin C or by protein kinase C depletion. Vinblastine, under conditions causing full microtubule disassembly, produced only a 50% decrease of TNF binding. Vinblastine plus PMA was additive in fully preventing TNF binding. It is suggested that the degree of binding of TNF-alpha to its receptors in Saos-2 cells is under the control of a microtubule-dependent and of a microtubule-independent regulatory pathway.
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PMID:Regulation of the TNF-alpha receptor in human osteosarcoma cells: role of microtubules and of protein kinase C. 767 25

Cell interaction with extracellular matrix (ECM) modulates cell growth and differentiation. By using in vitro culture systems, we tested the effect of type I collagen (Coll-I) on signal transduction mechanisms in the osteosarcoma cell line UMR-106 and in primary cultures from neonatal rat calvariae. Cells were cultured for 72 h on Coll-I gel matrix and compared with control cells plated on plastic surfaces. Agonist-dependent and voltage-dependent rises in cytosolic Ca2+ concentration ([Ca2+]i; measured by fura 2 fluorometry) were significantly blunted in cells cultured on Coll-I compared with cells grown on plastic. In UMR-106 cells, the collagen matrix effect was mimicked by 24-h incubation with soluble Coll-I or short peptides containing the arginine-glycine-aspartate motif. Accumulation of cellular adenosine 3',5'-cyclic monophosphate (cAMP) stimulated by parathyroid hormone, cholera toxin, and forskolin was augmented (50-150%) in cells plated on Coll-I vs. control. The collagen effect on both [Ca2+]i- and adenylate cyclase-signaling pathways in UMR-106 cells was abrogated in the presence of protein kinase C (PKC) depletion or inhibition. Also, Coll-I induced a twofold increase in membrane-bound PKC without changing cytosolic PKC activity. Thus, by altering PKC activity, Coll-I modulates the [Ca2+]i- and cAMP-signaling pathways in osteoblasts. This, in turn, may influence bone remodeling processes.
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PMID:Cell-matrix interaction in bone: type I collagen modulates signal transduction in osteoblast-like cells. 776 1

The rat osteosarcoma cell line UMR-106 has an osteoblast-like phenotype and possesses parathyroid hormone (PTH)-responsive dual signal transduction systems [adenosine 3',5'-cyclic monophosphate-dependent protein kinase (PKA) and calcium-protein kinase C (Ca-PKC)]. These cells transport inorganic phosphate (Pi) by a Na(+)-dependent carrier under stimulation by PTH. The present study aimed to clarify PTH-responsive signal transduction mechanisms in the regulation of Na(+)-dependent Pi transport by PTH in UMR-106 cells. Exposure of these cells to 10(-7) mol/l PTH induced a significant increase in Pi uptake within 30 min of incubation and it became maximal after 2 h. Parathyroid hormone (10(-9)-10(-7) mol/l) stimulated Pi uptake dose dependently. Activation of PKC by 12-O-tetradecanoyl phorbol-13-acetate (TPA) also increased Pi uptake in time- and dose-dependent manners similar to PTH. In contrast, neither PKA activation by 10(-4) mol/l forskolin or by 10(-4) mol/l dibutyryladenosine 3',5'-cyclic monophosphate nor calcium ionophore treatment with 10(-7) mol/l A23187 or with 10(-7) mol/l ionomycin during 3-h incubations affect Pi uptake, except its increase by 10(-4) mol/l forskolin at a 3-h incubation. These agents had no influence on Pi uptake even in combined treatments with TPA. The PTH-induced increase in Pi uptake was abolished almost completely by pretreating cells with PKC inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H-7) (50 mumol/l) or staurosporin (10 and 50 nmol/l), and by down-regulating PKC with a prolonged TPA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of protein kinase C in the stimulation of sodium-dependent phosphate transport by parathyroid hormone in osteoblast-like cells. 780 49

The regulation of vitamin D receptor (VDR) abundance in MC3T3-E1 mouse osteoblasts and UMR 106-01 rat osteosarcoma cells by rat PTH 1-34, human PTH-related protein 1-34, and agents that activate specific signal transduction pathways was studied. Treatment of these cells with forskolin (FSK) caused up-regulation of VDR, whereas treatment with phorbol esters suppressed VDR levels. PTH or PTH-related protein treatment induced a 2- to 3-fold increase in VDR, which was equivalent to that elicited by FSK in UMR 106-01 cells but less than the FSK-induced increase (approximately 8-fold) in MC3T3-E1 cells. PTH treatment of MC3T3-E1 cells resulted in an approximately 3-fold increase in VDR levels with maximum stimulation occurring at 10(-9) M PTH after 4 h of treatment. In UMR 4-7 cells, a subclone of UMR 106-01 cells that express cAMP resistance due to regulated expression of a mutant form of the type 1 regulatory subunit of the cAMP-dependent protein kinase A (PKA), the up-regulation of VDR abundance due to FSK and PTH treatment was mostly prevented. Pretreatment of MC3T3-E1 cells with staurosporine, an inhibitor of PKC, resulted in an approximately 3-fold increase in basal VDR levels but did not enhance the PTH-mediated up-regulation of VDR. Collectively, these data suggest that the increase in VDR abundance observed in these target cells is mainly due to the activation of the PKA signal transduction pathway. Treatment of UMR 106-01 cells with PTH for 4 h before exposure of the cells to 1,25-dihydroxyvitamin D3 resulted in a 2-fold increase in the induction of 25-hydroxyvitamin D3-24 hydroxylase messenger RNA. Thus, exposure of target cells to PTH augments their response to 1,25-dihydroxyvitamin D3 due to up-regulation of VDR abundance.
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PMID:Regulation of 1,25-dihydroxyvitamin D3 receptors by parathyroid hormone in osteoblastic cells: role of second messenger pathways. 783 3


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