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Query: UNIPROT:P06889 (Mol)
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The 8.2-kilobase (kb) unintegrated circular DNA form of the FBJ murine leukemia virus (FBJ-MLV) was linearized by cleavage at the single HindIII site, molecularly cloned into bacteriophage Charon 30, and subsequently subcloned into pBR322 (pFBJ-MLV-1). Both FBJ-MLV virion RNA and pFBJ-MLV-1 DNA were used to investigate the arrangement of helper virus sequences in the FBJ murine osteosarcoma virus genome (FBJ-MSV) by heteroduplex formation with cloned FBJ-MSV proviral DNA. The results showed that the FBJ-MSV genome contained 0.8 kb of helper virus sequence at its 5' terminus and 0.98 kb at its 3' terminus. Approximately 6.8 kb of helper virus sequence had been deleted, and 1.7 kb of unrelated sequence was inserted into the FBJ-MSV genome. This substituted region contains v-fos, the transforming gene of FBJ-MSV. Using a probe specific for v-fos, we have cloned homologous sequences (c-fos) from mouse and human chromosomal DNA. Heteroduplex analysis of FBJ-MSV DNA with these recombinant clones showed that both the c-fos(mouse) and the c-fos(human) sequences hybridized to the entire 1.7-kb v-fos region. However, five regions of homology of 0.27, 0.26, 0.14, 0.5, and 0.5 kb were separated by four regions of nonhomology of 0.76, 0.55, 0.1, and 0.1 kb from 5' to 3' with respect to the FBJ-MSV genome. The size of these sequences showed striking similarity in both c-fos(mouse) and c-fos(human).
Mol Cell Biol 1983 May
PMID:Structure of the FBJ murine osteosarcoma virus genome: molecular cloning of its associated helper virus and the cellular homolog of the v-fos gene from mouse and human cells. 630 48

Rat osteosarcoma 17/2.8 cells (Ros 17/2.8 cells) were labeled with [32P]PO4(2-), and their levels of inositol lipids were determined after stimulation with thrombin. Thrombin stimulated a pertussis toxin-sensitive rapid accumulation of phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] with lesser increases in levels of phosphatidylinositol-3,4-bisphosphate [PtdIns(3,4)P2] and phosphatidylinositol-3-phosphate [PtdIns3P] that were slower in onset. Ros 17/2.8 cell homogenates contained phosphatase activities that hydrolyzed PtdIns(3,4,5)P3 to PtdIns(3,4)P2 and PtdIns3P. Phosphoinositide-3-kinase activity was determined in Ros 17/2.8 cell homogenates using exogenously provided PtdIns(4,5)P2. Guanosine-5'-3-O-(thio)triphosphate caused an approximately 3-fold increase in phosphoinositide-3-kinase activity in a manner that was blocked by high concentrations of guanosine-5'-2-O-(thio)diphosphate. Purified bovine brain G protein beta gamma subunits also increased phosphoinositide-3-kinase activity modestly in Ros 17/2.8 cell homogenates. Ros 17/2.8 cell homogenates contained phosphatase activities that sequentially dephosphorylated PtdIns(3,4,5)P3 to PtdIns(3,4)P2 and PtdIns3P. Two peaks of phosphoinositide-3-kinase activity were resolved by anion exchange chromatography of a Ros 17/2.8 cell cytosolic extract. The later elution of these was selectively activated by beta gamma subunits (16-fold activation with 16 microM beta gamma subunits). Half-maximal effects of the beta gamma subunits were observed at a concentration of 0.6 microM, and activation was blocked by preincubation of the beta gamma subunits with an excess of recombinant Gi alpha 2. beta gamma Subunits did not activate the p85 alpha/p110 beta form of phosphoinositide-3-kinase purified from sf9 cells after expression with the use of baculovirus vectors.
Mol Pharmacol 1995 Sep
PMID:Regulation of phosphoinositide-3-kinase by G protein beta gamma subunits in a rat osteosarcoma cell line. 756 35

Human osteosarcoma and fibrosarcoma cell lines were investigated for alterations in oncogenes, tumor suppressor genes, and growth factors, all of which have been implicated in tumor formation. Characterization of oncogenes that are involved in osteosarcoma formation, including the c-fos and c-myc oncogenes, indicated that all six osteosarcoma cell lines examined had 5- to 20-fold amplification of the c-myc oncogene, whereas neither of two fibrosarcoma cell lines c-myc amplification. Interestingly, only three of six osteosarcoma cell lines displayed altered c-myc immediate-early gene function. c-fos was found to be normal, both at the gene and functional levels, in all six osteosarcoma and both fibrosarcoma cell lines tested. Characterization of two tumor suppressor genes, p53 and RB1, that have been implicated in osteosarcoma formation indicated that p53 was altered in five of six osteosarcoma cell lines, whereas RB1 was altered in only two or six of these cell lines. Neither RB1 nor p53 was found to be altered in the fibrosarcoma cell lines tested. An additional transformation marker, autocrine growth-factor production, was observed in all six osteosarcoma cell lines and both fibrosarcoma cell lines examined. Finally, the differentiation state of the osteosarcoma cell lines was investigated via the bone differentiation markers alkaline phosphates and osteocalcin. Alkaline phosphatase activity was observed in four of six osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined. The alkaline phosphatase activity was a result of the expression of the bone/liver/kidney alkaline phosphatase isoform. High-level osteocalcin expression was observed in one of the osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined, although all cell lines demonstrated low-level osteocalcin expression. Together, these data demonstrate that relatively undifferentiated osteosarcomas commonly display c-myc amplification, p53 and RB1 mutation, and autocrine growth-factor production, all of which may play a role in osteosarcomagenesis.
Mol Carcinog 1995 Nov
PMID:Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines. 757 9

A mutation in the tumor suppressor p53 gene resulting in an Arg-->Ser substitution in position 249 is found frequently in human hepatocellular carcinomas associated with hepatitis B infection and with aflatoxin exposure. To determine the significance of this mutation in an in vivo experimental model using transgenic mice, we introduced a two-nucleotide change in the mouse p53 gene at amino-acid position 246, which is equivalent to position 249 in human p53, by the recombinant polymerase chain reaction mismatched primer method. This p53 mutation resulted in the same change, an Arg-->Ser substitution, as in the human p53 gene at position 249. We now report that the protein product of this mutant mouse p53ser246 had properties similar to those of the wild-type protein when tested by binding to (i) monoclonal antibodies PAb246 and PAb240, ii) simian virus 40 large T antigen, and (iii) heat-shock protein. However, it had mutant-type transforming properties when tested for colony formation with an osteosarcoma cell line. It was not active, as is wild-type p53, in transcription activation of the muscle creatine kinase promoter. These properties are the same as those found in the p53trp248 product of the p53 mutation associated with the Li-Fraumeni syndrome. Although less is known about the human p53ser249 product associated with hepatocellular carcinoma, the mutant murine p53ser246 protein shares the known properties of the human gene product.
Mol Carcinog 1995 Jun
PMID:Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. 760 78

To clarify the possible action of adrenal androgen on bone cell, the existence, characteristics and regulation of aromatase in human osteoblast-like osteosarcoma cells (HOS) and primary cultured osteoblast-like cells from normal human bones (HO) were examined in this study. Significant positive correlation between bone mineral density (BMD) and serum dehydroepiandrosterone sulfate (DHEA-S) was found in 120 postmenopausal women (51-99 years old) but no correlation was seen between BMD and serum estradiol (E2). In subset analysis, strongly positive correlation of serum DHEA-S and estrone (E1) with BMD was observed in postmenopausal women aged less than 69 years old. Administration of DHEA to ovariectomized rat significantly increased BMD and decreased relative osteoid volume in femur. These in vivo findings strongly suggested that serum adrenal androgen may be converted to estrogen in peripheral organ, especially, osteoblast and be important steroids to maintain BMD. [3H]DHEA was converted to [3H]androstenedione and [3H]androstenedione to [3H]estrone in primary cultured human osteoblast. Osteoblast-like cells showed aromatase activity, and an apparent Km and the Vmax were 4.74 +/- 0.78 nM (mean +/- SD, n = 3) and 0.83 +/- 0.79 fmol/mg protein/h for HOS, and 4.6 +/- 2.9 nM and 279 +/- 299 fmol/mg protein/h (mean +/- SD, n = 19) for HO, respectively. The aromatase activity was significantly increased by dexamethasone in a dose-dependent manner. Reverse transcription-polymerase chain reaction analysis revealed that dexamethasone increased the transcript of P450AROM gene. Osteoblast-specific promoters were also determined. Dexamethasone and 1 alpha,25-dihydroxyvitamin D3 synergistically enhanced aromatase activity and P450AROM mRNA expression. These results demonstrate that adrenal androgen, DHEA, is converted to E1 in osteoblast by P450AROM which is positively regulated by glucocorticoid and 1 alpha,25-dihydroxyvitamin D3 and important to maintain BMD in the 6 to 7th decade, after menopause.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Aromatase in bone cell: association with osteoporosis in postmenopausal women. 762 49

2 mM Ascorbic acid has a potent cytotoxic effect on neuroblastoma, osteosarcoma, retinoblastoma, and rhabdomyosarcoma cells cultured in vitro. At a lower concentration (0.2 mM), ascorbic acid remains highly cytotoxic for neuroblastoma, osteosarcoma and retinoblastoma cells, but it has a stimulatory effect on the growth of rhabdomyosarcoma cells.
Biochem Mol Biol Int 1994 Nov
PMID:Ascorbic acid is cytotoxic for pediatric tumor cells cultured in vitro. 770 4

All the factors that influence prognosis in patients with osteosarcomas have not been fully determined. One reported predictor of poor outcome is increased multi-drug resistant gene (mdr-1) expression, as measured by reverse transcription and polymerase chain reaction (RT-PCR). We examined whether immunostaining for p-glycoprotein, the protein product of mdr-1, could be used instead of RT-PCR to indicate the presence of the multidrug-resistant phenotype. The sensitivity of the immunostaining was determined using KB cell sublines. For 13 cases of osteosarcoma, samples were immunostained for p-glycoprotein and the levels of mdr-1 expression quantitated with use of RT-PCR. Three osteosarcomas with undetectable levels of mdr-1 expression by RT-PCR were negative immunohistochemically. Ten cases showed mdr-1 expression ranging from approximately 1 to 32 copies of mdr-1 mRNA/cell. Of these cases, five cases contained occasional tumour cells with positive immunostaining. There was no correlation between levels of expression and the presence or number of immunoreactive cells. These results indicate that the presence of p-glycoprotein immunostaining does not reliably correlate with the level of mdr-1 expression. However it may be useful in conjunction with RT-PCR to further define different subgroups of osteosarcomas that may have different prognoses, and this is currently under investigation.
Diagn Mol Pathol 1995 Mar
PMID:Correlation of p-glycoprotein detection by immunohistochemistry with mdr-1 mRNA levels in osteosarcomas. Pilot study. 773 58

Transforming growth factor beta (TGF-beta), a potent regulator of bone formation, has bifunctional effects on osteoblast replication and biochemical activity that appear differentiation dependent. We now show that cell surface binding sites for TGF-beta vary markedly among fibroblasts, bone-derived cells, and highly differentiated osteosarcoma cultures from fetal rats. Expression of betaglycan and type II receptors decline relative to type I receptor expression in parallel with an increase in osteoblast-like activity, predicting that the ratio among various TGF-beta binding sites could influence how its signals are perceived. Bone morphogenetic protein 2 (BMP-2), which induces osteoblast function, does not alter TGF-beta binding or biochemical activity in fibroblasts and has only small effects in less differentiated bone cells. In contrast, BMP-2 rapidly reduces TGF-beta binding to betaglycan and type II receptors in osteoblast-enriched primary cell cultures and increases its relative binding to type I receptors in these cells and in ROS 17/2.8 cultures. Pretreatment with BMP-2 diminishes TGF-beta-induced DNA synthesis in osteoblast-enriched cultures but synergistically enhances its stimulatory effects on either collagen synthesis or alkaline phosphatase activity, depending on the present state of bone cell differentiation. Therefore, BMP-2 shifts the TGF-beta binding profile on bone cells in ways that are consistent with progressive expression of osteoblast phenotype, and these changes distinguish the biochemical effects mediated by each receptor. Our observations indicate specific stepwise actions by TGF-beta family members during osteoblast differentiation, developing in part from changes imprinted by BMP-2 on TGF-beta receptor stoichiometry.
Mol Cell Biol 1995 Jun
PMID:Independent changes in type I and type II receptors for transforming growth factor beta induced by bone morphogenetic protein 2 parallel expression of the osteoblast phenotype. 776 Aug 23

We investigated the contribution of c-fos protooncogene in the mitogenic effect of transforming growth factor-beta (TGF beta) in serum-deprived, confluent rat calvaria osteoblastic cells. The TGF beta-induced growth in these cells was associated with an immediate and transient c-fos mRNA accumulation, similar to the inductive effect of fetal calf serum. To assess the role of c-fos in the response to TGF beta, we used a c-fos antisense (AS) oligonucleotide displaying duplex formation with rat c-fos mRNA. Studies of AS and sense (S) uptake by osteoblastic cells demonstrated that incorporation of labeled oligomers was maximal at 2 h, and the incorporated AS oligonucleotide remained intact for 24 h. Immunofluorescence analysis of c-Fos-labeled cells demonstrated that AS, but not S, oligonucleotide reduced c-Fos protein expression, suggesting specific efficient inhibition of c-fos translation by the AS oligomer. Proliferation assays showed that cell growth induced by fetal calf serum was inhibited by the AS, but not by the S oligonucleotide, in both normal rat osteoblasts and ROS 17/2.8 osteosarcoma cells, demonstrating efficient and specific blockage of cell growth by the AS oligomer. The mitogenic effect of TGF-beta was abolished in cells cultured in the presence of AS, whereas S had no effect, showing that c-fos is required for TGF beta-induced osteoblast cell growth. The results show that the induction of c-fos is implicated in the mitogenic effect of TGF beta in osteoblastic cells and provide a cellular mechanism involved in the response of these cells to TGF beta.
Mol Endocrinol 1995 Feb
PMID:c-fos protooncogene is involved in the mitogenic effect of transforming growth factor-beta in osteoblastic cells. 777 69

A pertussis toxin-sensitive G protein has been reported to play a role in the mitogenic response to insulin-like growth factor-I (IGF-I) in mouse fibroblasts, and diacylglycerol generation has been shown to accompany growth stimulation by IGF-I of several cell lines. We have examined the roles of pertussis toxin sensitive G proteins and diacylglycerol generation in signaling by the insulin-like growth factor-I receptor in a cell line that is very responsive to IGF-I, the human osteosarcoma cell line, MG-63. Pertussis toxin failed to inhibit IGF-I induced [3H]-thymidine incorporation into DNA. Furthermore, the stable analog GTP gamma S had no effect on the binding of 125I-labelled IGF-I to MG-63 membrane preparations. Following addition of IGF-I to growth-arrested MG-63 cells there was no increase in diacylglycerol levels over 30 min. We conclude that the activated IGF-I receptor does not use pertussis toxin sensitive G proteins or diacylglycerol generation in a pathway leading to DNA synthesis in MG-63 cells.
Mol Cell Endocrinol 1994 Oct
PMID:Evidence against roles for pertussis toxin sensitive G proteins or diacylglycerol generation in insulin-like growth factor-1 stimulated DNA synthesis in MG-63 osteosarcoma cells. 782 13


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