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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MYC proto-oncogene has been shown to be overexpressed in several types of sarcomas, including some osteosarcomas. In most cases, the overexpression is due to gene amplification. The total number of osteosarcoma patients studied, however, remains too small to derive any conclusions regarding the true prevalence and the possible clinical significance of MYC gene amplification. To address the issue more thoroughly, we studied 27 specimens from 25 patients with high-grade osteosarcoma (16 primary, 11 metastatic; 11 adult, 14 pediatric) for MYC gene alterations by Southern blot analysis. Two of 27 specimens (7%) showed MYC gene amplification: a primary fibrohistiocytic osteosarcoma of the femur in a 37-year-old man showed threefold amplification, and a primary Paget's osteosarcoma of the tibia in a 60-year-old man showed fourfold amplification. None of the specimens tested showed MYC gene rearrangement (zero of 27) or activating point mutations at the PvuII site in MYC exon-1 (zero of 26). Hence, the MYC gene is amplified in a subset of osteosarcomas. The possible clinical or biological significance of MYC gene amplification in osteosarcoma may warrant further investigation.
Diagn Mol Pathol 1993 Sep
PMID:Sporadic amplification of the MYC gene in human osteosarcomas. 828 30

The retinoblastoma gene product, p110RB1, appears to regulate cell growth by modulating the activities of nuclear transcription factors. The elements that specify the transport of p110RB1 into the nucleus have not yet been explored. We now report the identification of a basic region, KRSAEGGNPPKPLKKLR, in the C terminus of p110RB1, which has sequence similarity to known bipartite nuclear localization signals (NLSs). A two-amino-acid mutation introduced into this putative NLS [to give mutant NLS(NQ)] or deletion of the entire NLS (delta NLS) abrogated exclusive nuclear localization, yielding proteins which were distributed either equally throughout the cell or predominantly in the cytoplasm. A mutant protein [NLS(NQ)/delta 22] containing both the mutated NLS and a deletion of exon 22, previously shown to disrupt the interaction of p110RB1 with several cellular transcription factors and oncoproteins, accumulated only in the cytoplasm. When fused to the C terminus of Escherichia coli beta-galactosidase, the RB1 NLS directed this protein to the nucleus, indicating that the motif is not only necessary but also sufficient for nuclear transport. Neither NLS(NQ) nor delta NLS was hyperphosphorylated in vivo, but both retained their abilities to interact, in vitro, with simian virus 40 large T antigen, adenovirus E1a, and the cellular transcription factor E2F. When transfected at multiple copy number, the NLS mutant alleles displayed reduced biological activity, measured by inhibition of growth of the osteogenic sarcoma cell line Saos-2, which has no wild-type RB1. Naturally occurring mutations and deletions in exon 25 of RB1 which disrupt the NLS may lead to partial or complete inactivation of p110RB1 and may be responsible for some retinoblastoma and other tumors.
Mol Cell Biol 1993 Aug
PMID:A bipartite nuclear localization signal in the retinoblastoma gene product and its importance for biological activity. 833 4

The oncogene mdm2 has been found to be amplified in human sarcomas, and the gene product binds to the tumor suppressor p53. In this report, we describe the dissection of the MDM2-binding domain on p53 as well as the p53-binding domain on MDM2. We also demonstrate that the oncoprotein simian virus 40 T antigen binds to the product of cellular oncogene mdm2. We have constructed several N- and C-terminal deletion mutants of p53 and MDM2, expressed them in vitro, and assayed their in vitro association capability. The N-terminal boundary of the p53-binding domain on MDM2 is between amino acids 1 and 58, while the C-terminal boundary is between amino acids 221 and 155. T antigen binds to an overlapping domain on the MDM2 protein. On the other hand, the MDM2-binding domain of p53 is defined by amino acids 1 and 159 at the N terminus. At the C terminus, binding is progressively reduced as amino acids 327 to 145 are deleted. We determined the effect of human MDM2 on the transactivation ability of wild-type human p53 in the Saos-2 osteosarcoma cell line, which does not have any endogenous p53. Human MDM2 inhibited the ability of human p53 to transactivate the promoter with p53-binding sites. Thus, human MDM2 protein, like the murine protein, can inactivate the transactivation ability of human p53. Interestingly, both the transactivation domain and the MDM2-binding domain of p53 are situated near the N terminus. We further show that deletion of the N-terminal 58 amino acids of MDM2, which eliminates p53 binding, also abolishes the capability of inactivating p53-mediated transactivation. This finding suggests a correlation of in vitro p53-MDM2 binding with MDM2's ability in vivo to interfere with p53-mediated transactivation.
Mol Cell Biol 1993 Nov
PMID:The tumor suppressor p53 and the oncoprotein simian virus 40 T antigen bind to overlapping domains on the MDM2 protein. 841 78

Alkaline phosphatase (AP) activity and expression of bone Gla protein (BGP), c-fos, and c-jun were compared in two transplantable osteosarcomas with high potentials for metastasis to the lung. The original spontaneous osteosarcoma (SOS) gradually became histologically undifferentiated, losing its osteogenic activity during serial transfer, whereas the chemical (4-hydroxyaminoquinoline 1-oxide)-induced osteosarcoma (COS) retained osteogenesis. The two osteosarcomas showed similar doubling times and levels of lung metastasis, and strong AP activity was detected on the cell membranes of both. Northern blot analysis revealed that lack of BGP mRNA expression was associated with expression of both c-fos and c-jun proto-oncogenes in SOS. In contrast, neither c-fos nor c-jun mRNAs were detected but BGP mRNA was expressed in the case of COS. These results suggest that the c-fos and c-jun genes may suppress the expression of BGP mRNA relevant to differentiation and osteoid formation in rat osteosarcomas. However, this does not appear to be directly related to proliferative or metastatic biological behavior.
Mol Carcinog 1993
PMID:Correlation between lack of bone Gla protein mRNA expression in rat transplantable osteosarcomas and expression of both c-fos and c-jun proto-oncogenes. 845 89

The present study was undertaken to examine oncogene abnormalities in human bone and soft tissue tumors. Twenty four tumor tissues and one human cell strain established from an osteosarcoma were examined by Southern blot analysis using a recessive oncogene (p0.9R and p3.8R derived from a cDNA of the Rb gene) and eight dominant oncogenes (c-myc, c-K-ras, c-fos, c-raf-1, c-fms, c-sis, N-myc, and c-erb B) as probes. Homozygous deletions or other alterations within the Rb locus were found in 3 of 6 osteosarcomas, 1 osteosarcoma cell line, 1 of 3 malignant fibrous histiocytomas and 1 of 2 Ewing's sarcomas. On the other hand, amplification of c-myc was found in 2 osteosarcomas and 1 osteosarcoma cell line. All cases with c-myc amplification had alterations in the structure of the Rb locus, and these patients showed rapid clinical malignancy progression and a probable tendency to bone metastases. Results of this study suggest that structural alterations of the Rb gene and amplification of c-myc might play an important role in the clinical course and pathogenesis of osteosarcoma.
Cell Mol Biol (Noisy-le-grand) 1993 Mar
PMID:Alterations of retinoblastoma susceptible gene accompanied by c-myc amplification in human bone and soft tissue tumors. 851 77

U2OS Dr1 cells, originating from a human osteosarcoma, are resistant to the intracellular action of diphtheria toxin but contain toxin receptors on their surfaces. These cells do not have detectable amounts of fibroblast growth factor receptors. When these cells were transfected with fibroblast growth factor receptor 4, the addition of acidic fibroblast growth factor to the medium induced tyrosine phosphorylation, DNA synthesis, and cell proliferation. A considerable fraction of the cell-associated growth factor was found in the nuclear fraction. When the growth factor was fused to the diphtheria toxin A fragment, it was still bound to the growth factor receptor and induced tyrosine phosphorylation but did not induce DNA synthesis or cell proliferation, nor was any fusion protein recovered in the nuclear fraction. On the other hand, when the fusion protein was associated with the diphtheria toxin B fragment to allow translocation to the cytosol by the toxin pathway, the fusion protein was targeted to the nucleus and stimulated both DNA synthesis and cell proliferation. In untransfected cells containing toxin receptors but not fibroblast growth factor receptors, the fusion protein was translocated to the cytosol and targeted to the nucleus, but in this case, it stimulated only DNA synthesis. These data indicate that the following two signals are required to stimulate cell proliferation in transfected U2OS Dr1 cells: the tyrosine kinase signal from the activated fibroblast growth factor receptor and translocation of the growth factor into the cell.
Mol Cell Biol 1996 Jan
PMID:Stimulation of proliferation of a human osteosarcoma cell line by exogenous acidic fibroblast growth factor requires both activation of receptor tyrosine kinase and growth factor internalization. 852 4

Although numerous studies have shown potent antiproliferative and differentiation-inducing effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and its analogs on cells not directly related to bone metabolism, only few reports focussed on the effects of these analogs on bone. We compared the action of several recently developed analogs with that of 1,25-(OH)2D3 on human (MG-63) and rat (ROS 17/2.8) osteoblast-like cells and on in vitro bone resorption. In MG-63 cells the analogs EB1089 and KH1060 were about 166,000 and 14,000 times more potent than 1,25-(OH)2D3 in stimulating type I procollagen and 100 and 6,000 times more potent in stimulating osteocalcin production, respectively. Also in ROS 17/2.8 cells EB1089 and KH1060 were most potent in inducing osteocalcin synthesis. In vitro bone resorption was 2.3 and 17.5 times more potently stimulated by EB1089 and KH1060, respectively. In MG-63 cells, 1,25-(OH)2D3 and the analogs inhibited cell proliferation, whereas both 1,25-(OH)2D3 and the analogs stimulated the growth of ROS 17/2.8 cells. Differences in potency could neither be explained by affinity for the vitamin D receptor nor by a differential involvement of protein kinase C in the action of the analogs. Together, these data show that also in bone the analogs EB1089 and KH1060 are more potent than 1,25-(OH)2D3 but that the potency of the analogs compared to 1,25-(OH)2D3 is dependent on the biological response. On the basis of these observations it can be concluded that the reported reduced calcemic effect in vivo is not the result of a decreased responsiveness of bone to these analogs. Lastly, in view of eventual clinical application of 1,25-(OH)2D3-analogs, the observed stimulation of in vitro bone resorption and growth of an osteosarcoma cell line warrant in vivo studies to further examine these effects.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Differential effects of 1,25-dihydroxyvitamin D3-analogs on osteoblast-like cells and on in vitro bone resorption. 854 Dec 30

Defects of the respiratory chain carrying out oxidative phosphorylation (OXPHOS) are the biochemical hallmark of human mitochondrial disorders. Faulty OXPHOS can be due to mutations in either nuclear or mitochondrial genes, that are involved in the synthesis of individual respiratory subunits or in their post-translational control. The most common mitochondrial disorder of infancy and childhood is Leigh's syndrome, a severe encephalopathy, often associated with a defect of cytochrome c oxidase (COX). In order to demonstrate which genome is primarily involved in COX-deficient (COX(-))-Leigh's syndrome, we generated two lines of transmitochondrial cybrids. The first was obtained by fusing nuclear DNA-less cytoplasts derived from normal fibroblasts, with mitochondrial DNA-less (rho degree) transformant fibroblasts derived from a patient with COX(-))-Leigh's syndrome. The second cybrid line was obtained by fusing rho degree cells derived from 143B.TK- human osteosarcoma cells, with cytoplasts derived from the same patient. The first cybrid line showed a specific and severe COX(-) phenotype, while in the second all the respiratory chain complexes, including COX, were normal. These results indicate that the COX defect in our patient is due to a mutation of a nuclear gene. The use of cybrids obtained from 'customized', patient-derived rho degree cells can have wide applications in the identification of respiratory chain defects originated by nuclear DNA-encoded mutations, and in the study of nuclear DNA-mitochondrial DNA interactions.
Hum Mol Genet 1995 Nov
PMID:Nuclear DNA origin of cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence based on patient's-derived rho degrees transformants. 858 77

Previous studies identified several glucocorticoid response elements (GREs) in the 5'-promoter region of the rat osteocalcin (OC) gene by purified receptor binding. The present study addresses functionality of the GRE sequences in the proximal promoter at nucleotide (nt) -16 to -1 downstream of the TATA element together with the GRE half-element in the OC box at nt -86 to -81. This was done by assaying glucocorticoid responsiveness [at 10(-6) M dexamethasone (DEX)], and in combination with 10(-8) M 1,25-dihydroxyvitamin D3, of a series of deleted and mutated OC promoter reporter constructs (OCCAT) in osteoblast-like cells, the ROS 17/2.8 rat osteosarcoma line. Promoter deletion analysis revealed an additional GRE in the distal promoter at nt -697 to -683 that functions to suppress OC transcription. In the absence of this upstream negative GRE (nGRE), the -531 OCCAT construct exhibited enhanced promoter activity in response to DEX (1.8-fold DEX/Control), but further deletion (-348 and -108 OCCAT constructs) restored DEX suppression to OC promoter activity (0.6- and 0.8-fold DEX/Control, respectively). Mutations introduced in both the proximal GRE (nt -16 to -1) and the half-GRE in the OC box, or in the proximal GRE alone, nearly abrogated DEX responsiveness of OC promoter activity. Both distal and proximal GREs specifically bound glucocorticoid receptor present in ROS 17/2.8 nuclear extracts as shown by competition with wild type and mutated oligonucleotides and antibody inhibition of binding. Furthermore, both GREs, independently, conferred DEX-responsive transcriptional repression to the heterologous thymidine kinase basal promoter. We also report that glucocorticoid suppression of 1,25-dihydroxyvitamin D3-stimulated transcription occurs independently of distal or proximal GREs. Taken together, these results demonstrate that in vivo responsiveness of OC to DEX involves the integrative activities of several functional promoter elements.
Mol Endocrinol 1995 Jun
PMID:Contributions of distal and proximal promoter elements to glucocorticoid regulation of osteocalcin gene transcription. 859 14

We have shown earlier that 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] induces cell growth suppression and cell differentiation of a human megakaryoblastic leukemia cell line, HIMeg. However, the molecular mechanism of 1,25(OH)2 D3 action is still unknown. Prompted by this, we have searched here for the presence of 1,25(OH)2 D3 receptor (VDR) expression in HIMeg cells by reverse transcription-polymerase chain reaction (RT-PCR). The amplified product showed an identical size to the product amplified from the control human VDR cDNA and hybridized specifically with the digoxigenin-labeled human VDR cDNA fragment. As expected, VDR mRNA is also expressed in HOS-8603, a human osteosarcoma cell line. These results represent the first reported evidence that VDR mRNA is expressed in megakaryoblastic cells. In addition, the regulation of VDR mRNA expression in HIMeg cells was studied by quantitative RT-PCR. It was found that [correction of the] VDR mRNA expression in HIMeg cells could be down-regulated rapidly by 1,25(OH)2 D3 (10 nM) in a time-dependent manner, reaching a maximal reduction to about 15% of control. However, VDR mRNA expression in HOS-8603 cells was not regulated by 1,25(OH)2 D3 at any time-point tested. Treatment of HIMeg cells with forskolin (1 microM), an activator of adenylate cyclase, caused an increase in VDR mRNA levels. Similarly, VDR mRNA expression in HOS-8603 cells was also up-regulated by forskolin. Consistent with the functionality of the VDR in other target cells, we found that the up-regulation of VDR expression in HIMeg cells by forskolin was accompanied by an increased responsiveness of HIMeg cells to 1,25(OH)2 D3 even though forskolin alone had no effects. Exposure to 1,25(OH)2 D3 in combination with forskolin resulted in a much more significant inhibition of cell proliferation than to 1,25(OH)2 D3 alone. Similarly, forskolin could also augment the differentiation induced by 1,25(OH)2 D3 reflected by a more evident morphological change and a higher percentage of development of cells with multilobular nuclei. These alterations were accompanied by a loss of clonogenic capacity and a decrease in the number of cells in the S phase. These data establish that HIMeg cells express functional VDR, which served to mediate actions of its ligand on the proliferation and differentiation of these cells.
J Steroid Biochem Mol Biol 1996 Mar
PMID:Demonstration of vitamin D receptor expression in a human megakaryoblastic leukemia cell line: regulation of vitamin D receptor mRNA expression and responsiveness by forskolin. 863 62


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