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)

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder of enchondral bone formation characterized by multiple bony outgrowths (exostoses), with progression to osteosarcoma in a minority of cases. The exclusive involvement of skeletal abnormalities distinguishes EXT from the clinically more complex Langer-Giedion syndrome (LGS), which is associated with deletions at chromosome 8q24. Previously, linkage analysis has revealed a locus for EXT in the LGS region on chromosome 8q24. However, locus heterogeneity was apparent with 30% of the families being unlinked to 8q24. We report on two large pedigrees segregating EXT in which linkage to the LGS region was excluded. To localize the EXT gene(s) in these families we performed a genome search including 254 microsatellite markers dispersed over all autosomes and the X chromosome. In both families evidence was obtained for linkage to markers from the proximal short and long arms of chromosome 11. Two-point analysis gave the highest lod score for D11S554 (Zmax = 7.148 at theta = 0.03). Multipoint analysis indicated a map position for the EXT gene between D11S905 and D11S916, with a peak multipoint lod score of 8.10 at 6 cM from D11S935. The assignment of a second locus for EXT to the pericentromeric region of chromosome 11 implicates an area that is particularly rich in genes responsible for developmental abnormalities and neoplasia.
Hum Mol Genet 1994 Jan
PMID:Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. 816 19

Although loss of cell surface fibronectin (FN) is a hallmark of many oncogenically transformed cells, the mechanisms responsible for this phenomenon remain poorly understood. The present study utilized the nontumorigenic human osteosarcoma cell line TE-85 to investigate the effects of induced Ha-ras oncogene expression on FN biosynthesis. TE-85 cells were stably transfected with metallothionein-Ha-ras fusion genes, and the effects of metal-induced ras expression on FN biosynthesis were determined. Induction of the ras oncogene, but not proto-oncogene, was accompanied by a decrease in total FN mRNA and protein levels. Transfection experiments indicated that these oncogene effects were not due to reduced FN promoter activity, suggesting that a posttranscriptional mechanism was involved. The most common mechanism of posttranscriptional regulation affects cytoplasmic mRNA stability. However, in this study the down-regulation of FN was identified as a nuclear event. A component of the ras effect was due to a mechanism affecting accumulation of processed nuclear FN RNA. Mechanisms that would generate such an effect include altered RNA processing and altered stability of the processed message in the nucleus. There was no effect of ras on FN mRNA poly(A) tail length or site of polyadenylation. There was also no evidence for altered splicing at the ED-B domain of FN mRNA. This demonstration of nuclear posttranscriptional down-regulation of FN by the Ha-ras oncogene identifies a new level at which ras oncoproteins can regulate gene expression and thus contribute to development of the malignant phenotype.
Mol Cell Biol 1994 May
PMID:A novel mechanism of Ha-ras oncogene action: regulation of fibronectin mRNA levels by a nuclear posttranscriptional event. 816 64

Cytosine methylation at CpG dinucleotides is thought to cause more than one-third of all transition mutations responsible for human genetic diseases and cancer. We investigated the methylation status of the CpG dinucleotide at codon 248 in exon 7 of the p53 gene because this codon is a hot spot for inactivating mutations in the germ line and in most human somatic tissues examined. Codon 248 is contained within an HpaII site (CCGG), and the methylation status of this and flanking CpG sites was analyzed by using the methylation-sensitive enzymes CfoI (GCGC) and HpaII. Codon 248 and the CfoI and HpaII sites in the flanking introns were methylated in every tissue and cell line examined, indicating extensive methylation of this region in the p53 gene. Exhaustive treatment of an osteogenic sarcoma cell line, TE85, with the hypomethylating drug 5-aza-2'-deoxycytidine did not demethylate codon 248 or the CfoI sites in intron 6, although considerable global demethylation of the p53 gene was induced. Constructs containing either exon 7 alone or exon 7 and the flanking introns were transfected into TE85 cells to determine whether de novo methylation would occur. The presence of exon 7 alone caused some de novo methylation to occur at codon 248. More extensive de novo methylation of the CfoI sites in intron 6, which contains an Alu sequence, occurred in cells transfected with a vector containing exon 7 and flanking introns. With longer time in culture, there was increased methylation at the CfoI sites, and de novo methylation of codon 248 and its flanking HpaII sites was observed. These de novo-methylated sites were also resistant to 5-aza-2'-deoxycytidine-induced demethylation. The frequent methylation of codon 248 and adjacent Alu sequence may explain the enhanced mutability of this site as a result of the deamination of the 5-methylcytosine.
Mol Cell Biol 1994 Jun
PMID:Ubiquitous and tenacious methylation of the CpG site in codon 248 of the p53 gene may explain its frequent appearance as a mutational hot spot in human cancer. 819 60

The proto-oncogene transcription factors Fos and Jun form a heterodimeric complex that binds to DNA and regulates expression of specific target genes. Continuous expression of c-fos causes transformation of cultured fibroblasts and induces osteogenic sarcoma in mice. To investigate the molecular basis of fos-mediated oncogenesis, we developed a conditional cell transformation system in which Fos expression was regulated by isopropyl-beta-D-thiogalactopyranoside (IPTG). Synthesis or repression of Fos in L1-3c-fos cells occurred rapidly, within 30 min, after the removal or addition of IPTG to the culture medium. However, there was a significant delay between the induction of Fos expression and the appearance of morphological transformation. No effect was observed after 12 h of Fos expression, partial transformation was detected after 24 h, and full transformation required approximately 3 days of continuous Fos expression. Similarly, the transformed cell morphology persisted for at least 2 days after repression of Fos, and a normal phenotype was observed only after 3 days. Fos-Jun complexes, capable of binding to AP-1 sequences, were present continuously during the delay in morphological transformation. Furthermore, increased expression of several candidate Fos target genes, including those encoding Fra-1, transin (stromelysin), collagenase, and ornithine decarboxylase, was detected shortly after Fos induction. The induction of morphological transformation was not dependent on the cell cycle, as it occurred in both cycling and noncycling cells. Thus, the Fos-Jun complexes present before L1-3c-fos cells become fully transformed are transcriptionally active. These complexes disappeared, and the Fos target genes were repressed at least 2 days prior to reversion. Our results suggest that cell transformation by Fos requires increased expression of a target gene(s) with a long-lived product(s) that must reach a critical level.
Mol Cell Biol 1994 Jun
PMID:Cell transformation by c-fos requires an extended period of expression and is independent of the cell cycle. 819 66

A 27 kDa heat shock (HSP27) has been analysed by immunoassay and immunoblotting in oestradiol sensitive and insensitive cells. Oestradiol growth responsive MCF7 and T47D human breast cancer cells and growth unresponsive variants derived therefrom have unaltered levels of HSP27 as well as retaining their oestradiol receptor phenotype. MCF7 cells induced to become doxorubicin resistant in culture lose both HSP27 and oestradiol receptor. Thus, in these three pairs of cells, HSP27 content parallels oestradiol receptor (ER). Analysis of a range of ER positive and negative human cell lines supports the positive relationship between HSP27 and ER. This included six ER positive and two ER negative breast tumour lines, one ER positive and one ER negative endometrial tumour cell line and seven ER negative human lines from other sites. One ER negative osteosarcoma line (HTB96) had appreciable levels of HSP27 that were unaffected after stable transfunction with an ER cDNA. Heat shock increases HSP27 levels in some but not all cell lines tested, the effect being inversely proportional to the basal (37 degrees C) content. In a mouse mammary tumour cell line, loss of androgen sensitivity was accompanied by loss of HSP27. Loss of HSP27 occurred in MCF7 cells made drug resistant to Novatrone, vincristine and etoposide as well as doxorubicin; no detectable change was seen in cells made resistant by 5 fluorouracil or X-irradiation. In ER positive ZR75 human breast tumour cells and in both ER negative and positive variants of the HTB96 human osteosarcoma line, the intracellular distribution of HSP27 was analysed. Over 96% of the HSP27 was in the cytosol fraction and the distribution was unaffected by incubation with oestradiol. HSP27 has been discussed in the literature under three different names p29, p24 and HSP27. The data presented in this paper are reviewed in the context of the previous data. It is concluded that there is a good but not absolute correlation between the presence of ER and high amounts of HSP27 but that low amounts of HSP27 are present in many ER negative cells. The correlations between HSP27 and drug resistance are more complex.
J Steroid Biochem Mol Biol 1993 Oct
PMID:Relationship of HSP27 and oestrogen receptor in hormone sensitive and insensitive cell lines. 821 77

The osteoblast-like osteosarcoma cell line ROS 17/2.8, which expresses very low levels of estrogen receptor (ER), was stably transfected with the mouse ER in order to more easily evaluate the physiological role of estrogens in bone cell homeostasis. These transfected ROS.SMER 14 cells are highly responsive to estrogenic stimulation at subconfluence, but become refractory to estrogenic stimulation when postconfluency is reached. The purpose of these studies was to determine the mechanisms underlying this loss of responsiveness in these ER stably transfected cells at postconfluence. When proliferative capacity was evaluated by bromodeoxyuridine immunocytochemistry, approximately 70% of the subconfluent cells were actively dividing, whereas none of the postconfluent cells underwent division. Subconfluent cells were found to contain 2500-3000 ER-binding sites/cell, whereas the ER in postconfluent cells was low and often undetectable. Steady state ER mRNA levels were not significantly modified by postconfluency. ER protein levels were also unaffected by confluency status. Since protein kinase-C (PKC) has been reported to influence cell proliferation and steroid hormone receptor binding, PKC activity was measured in sub- and postconfluent cells. Calcium-dependent PKC activity was approximately about 2-fold higher in postconfluent compared to subconfluent cells, whereas no differences were discerned in calcium-independent PKC activity. In an effort to examine the role of PKC in greater detail, postconfluent cells were treated with PKC inhibitors (H-7 or staurosporine) or with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate) to down-regulate PKC activity, and changes in ER were evaluated. Inhibition or down-regulation of the PKC activity in postconfluent cells enhanced ER-binding capacity in a dose-dependent manner and estrogen responsiveness of an exogenous reporter gene and of the endogenous alkaline phosphatase, representing an endogenous estrogen-stimulated gene. These data indicate that there is an interaction between the PKC and ER signaling systems in bone cells and that this interaction may be influenced by the proliferative and/or differentiative state of the cells, resulting in modulation of hormone responsiveness.
Mol Endocrinol 1993 Sep
PMID:Endogenous protein kinase-C activation in osteoblast-like cells modulates responsiveness to estrogen and estrogen receptor levels. 824 15

Immunostaining methods were used to detect viral T-antigen and the cellular protein p53 in pathological tissues obtained from transgenic mice carrying JC-SV40 hybrid viral DNAs. A transgenic mouse carrying the SV40 regulatory region and JC virus (JCV) T-antigen-coding sequences exhibited an SV40-characteristic choroid plexus papilloma that expressed JCV T-antigen and p53. JCV-associated pathology was observed in two other mice in which the JCV regulatory signals directed SV40 T-antigen-induced adrenal neuroblastomas and brain neoplastic cells. However, these mice also exhibited an SV40-characteristic osteosarcoma and abdominal lymphoma that contained SV40 T-antigen and p53-positive cells. Contrasting thymic pathology was observed in the two types of mice where the SV40 regulatory region directed a JCV T-antigen-induced thymoma in one mouse, and the JCV regulatory region directed SV40 T-antigen-induced thymic hypoplasia in two other mice.
Mol Chem Neuropathol 1993 Sep
PMID:Expression of viral T-antigen in pathological tissues from transgenic mice carrying JC-SV40 chimeric DNAs. 825 Oct 33

Uncontrolled cell growth is at the basis of neoplastic proliferation and arteriosclerotic lesions. In vitro proliferation of vascular smooth muscle cells, Balb c/3T3 fibroblasts, retinal neuroepithelial cells and neuroblastoma cells is inhibited by d-alpha-tocopherol. On the contrary Chinese hamster ovary cells, osteosarcoma cells and macrophages are not sensitive. PDGF-BB activated proliferation is highly d-alpha-tocopherol sensitive while lysophosphatidic acid induced growth is poorly inhibited. d-beta-Tocopherol, an analogue of d-alpha-tocopherol, with similar antioxidant properties, does not inhibit proliferation. Protein kinase C activity is inhibited by d-alpha-tocopherol but not by d-beta-tocopherol, suggesting a central role of this enzyme in the control of cell proliferation by d-alpha-tocopherol. Activation of the transcription activation complex AP-1 (but not NFKB) is prevented by d-alpha-tocopherol and not by d-beta-tocopherol.
Mol Aspects Med 1993
PMID:d-alpha-tocopherol control of cell proliferation. 826 42

A regulatory mechanism for the vitamin D receptor (VDR) in rat osteosarcoma cells (ROS 17/2.8) is stabilization of the receptor through binding of its ligand, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Increased transcription of the gene encoding VDR does not occur upon treatment of these osteoblast-like cells with 1,25-(OH)2D3. When 10 nM 1,25-(OH)2D3 was administered to confluent cultures of ROS 17/2.8 cells, no change in receptor mRNA was detected, as measured by a ribonuclease protection assay. VDR abundance was measured using an immunoradiometric assay at varying time points within a 24-h period after 1,25-(OH)2D3 treatment. Receptor protein levels increased rapidly and continued to rise over 24 h. By 2 h, the level of receptor increased 2.5-fold, achieving a maximum level of 8-fold above the baseline at 18 h. The half-life of the receptor protein is 2 h in the absence of hormone, as determined by blockage of translation in cycloheximide-treated cells. In the presence of hormone, however, receptor levels were unchanged for at least 6 h. The administration of 1,25-(OH)2D3 stabilizes the receptor, thereby resulting in its accumulation in ROS 17/2.8 cells.
Mol Endocrinol 1993 Oct
PMID:Stabilization of the vitamin D receptor in rat osteosarcoma cells through the action of 1,25-dihydroxyvitamin D3. 826 62

The p53 gene undergoes rearrangement in a high percentage of osteosarcomas, resulting in loss of its expression. A p53-null murine osteosarcoma cell line F6 was transfected with either a wild-type or a mutant p53 gene. Stably transfected cell lines were obtained, and their differentiation capabilities were compared in vitro with the parental cell line. Alkaline phosphatase and osteocalcin expression were measured as early and late differentiation markers, respectively. Induction of alkaline phosphatase expression was not affected by the presence of either p53 gene, whereas osteocalcin expression was seen in cells containing the wild-type p53 gene but not in the parental p53-null or mutant-expressing cell lines. That the induction of osteocalcin was intrinsically dependent on the presence of wild-type p53 was also indicated by the use of a temperature-sensitive Val 135 p53 mutant at 32 degrees C; predominant expression of p53 in the wild-type conformation resulted in osteocalcin expression. While the wild-type p53 gene could suppress tumor formation in vivo, the tumors expressing the mutant p53 gene grew two to three times as large as the tumors that did not express p53. Therefore, the absence of end-point differentiation in bone due to p53 rearrangements may contribute to the maintenance of the tumorigenic phenotype in osteosarcomas.
Mol Carcinog 1993
PMID:Dependence of induction of osteocalcin gene expression on the presence of wild-type p53 in a murine osteosarcoma cell line. 828 Mar 78


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