UMLS:C0029463 - FACTA Search

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

p53 tumor suppressor is activated by phosphorylation and acetylation on DNA damage. One of unknown p53 early transcripts was identified to be histone deacetylase-5 (HDAC5). We tested a hypothesis that HDAC5 is a p53 down-stream target gene that on induction by p53 inactivates p53 by removal of acetyl group in p53 molecule, thus functioning as an auto-regulatory negative feedback loop in analogue to p53-murine double minute 2 interaction. Six p53 binding consensus sites were identified in the promoter of HDAC5. p53 binds to one of the sites weakly. However, luciferase constructs driven by the HDAC5 promoter containing three to six potential binding sites were not activated by p53, nor was the expression of HDAC5 mRNA induced by p53-activating agents. Furthermore, HDAC5 does not bind to p53 nor reduces etoposide-induced p53 acetylation. Thus, HDAC5 is not a p53 target gene and may act in a p53-independent manner. We next studied the effect of HDAC5 on tumor cell growth and apoptosis. Transfection of HDAC5 inhibited growth of multiple tumor cell lines including U2OS osteogenic sarcoma cells, SY5Y neuroblastoma cells, and MCF breast carcinoma cells. The growth suppression seen in HDAC5-overexpressing cells appears to be attributable partly to a reduced growth rate as revealed by cell growth assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and mainly to spontaneous apoptosis as shown by DNA fragmentation ELISA and morphological appearance. Mechanistically, repression of three cell proliferation genes in mitogen-activated protein kinase pathway and induction of seven apoptosis-related genes were identified by microarray profiling in HDAC5-overexpressed cells. Among induced genes, four (TNFR1, TNFSF7, caspase-8, and DAPK1) were associated with the tumor necrosis factor ligand-receptor death pathway. Induction of TNFR1, TNFSF7, and caspase-8 were confirmed by Northern and Western analyses. Thus, activation of tumor necrosis factor death receptor pathway appears to be associated with HDAC5-induced spontaneous apoptosis.
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PMID:Histone deacetylase 5 is not a p53 target gene, but its overexpression inhibits tumor cell growth and induces apoptosis. 1201 72

Mutation in the BRCA1 gene is associated with an increased risk of breast and ovarian cancer. Recent studies have shown that the BRCA1 gene product may be important in mediating responses to DNA damage and genomic instability. Previous studies have indicated that overexpression of BRCA1 can induce apoptosis or cell cycle arrest at the G(2)/M border in various cell types. Although the activation of JNK kinase has been implicated in BRCA1-induced apoptosis, the role of other members of the mitogen-activated protein kinase family in mediating the cellular response to BRCA1 has not yet been examined. In this study, we monitored the activities of three members of the MAPK family (ERK1/2, JNK, p38) in MCF-7 breast cancer cells and U2OS osteosarcoma cells after their exposure to a recombinant adenovirus expressing wild type BRCA1 (Ad.BRCA1). Overexpression of BRCA1 in MCF-7 cells resulted in arrest at the G(2)/M border; however, BRCA1 expression in U2OS cells induced apoptosis. Although BRCA1 induced JNK activation in both cell lines, there were marked differences in ERK1/2 activation in response to BRCA1 expression in these two cell lines. BRCA1-induced apoptosis in U2OS cells was associated with no activation of ERK1/2. In contrast, BRCA1 expression in MCF-7 cells resulted in the activation of both ERK1/2 and JNK. To directly assess the role of ERK1/2 in determining the cellular response to BRCA1, we used dominant negative mutants of MEK1 as well as MEK1/2 inhibitor PD98059. Our results indicate that inhibition of ERK1/2 activation resulted in increased apoptosis after BRCA1 expression in MCF-7 cells. Furthermore, BRCA1-induced apoptosis involved activation of JNK, induction of Fas-L/Fas interaction, and activation of caspases 8 and 9. The studies presented in this report indicate that the response to BRCA1 expression is determined by the regulation of both the JNK and ERK1/2 signaling pathways in cells.
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PMID:BRCA1-induced apoptosis involves inactivation of ERK1/2 activities. 3110 59

Tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 have growth-stimulating activity for a wide range of cell types. Ras, which comprises a family of three members, i.e, Ha-Ras, Ki-Ras, and H-Ras, is known to participate in growth control in all its facets, including cell proliferation, transformation, differentiation, and apoptosis. In this study, we tested the hypothesis that Ras might be involved in the cell growth-promoting activity of TIMPs. Using MG-63 human osteosarcoma cells, we demonstrated that both TIMP-1 and TIMP-2 caused an increase in the Ras-GTP level in a dose-dependent manner. Our previous results indicated that TIMP-1 activity is mediated through the tyrosine kinase (TYK)/mitogen-activated protein kinase (MAPK) pathway. Here, we demonstrated that Ras activation by TIMP-1 was inhibited by a specific TYK inhibitor, herbimycin A, suggesting that the TYK/MAPK signaling pathway was involved in Ras activation by TIMP-1. However, the activation of Ras by TIMP-2 was inhibited by an inhibitor specific for cyclic AMP-dependent protein kinase (PKA), H89, suggesting the involvement of the PKA-mediated pathway. Furthermore, TIMP-2 promoted the formation of a complex between Ras-GTP and phosphoinositide 3-kinase.
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PMID:Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways. 1214 51

Previously, we have shown that parathyroid hormone (PTH) transactivation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) requires both serine 129 (S129) and serine 133 (S133) in rat osteosarcoma cells UMR 106-01 (UMR) cells. Furthermore, although protein kinase A (PKA) is responsible for phosphorylation at S133, glycogen synthase kinase 3beta (GSK-3beta) activity is required and may be responsible for phosphorylation of CREB at S129. Here, we show, using the GAL4-CREB reporter system, that epidermal growth factor (EGF) can transactivate CREB in UMR cells in addition to PTH. Additionally, treatment of UMR cells with both PTH and EGF results in greater than additive transactivation of CREB. Furthermore, using mutational analysis we show that S129 and S133 are required for EGF-induced transcriptional activity. EGF activates members of the MAPK family including p38 and extracellular signal-activated kinases (ERKs), and treatment of UMR cells with either the p38 inhibitor (SB203580) or the MEK inhibitor (PD98059) prevents phosphorylation of CREB at S133 by EGF but not by PTH. Treatment of cells with either SB203580 or PD98059 alone or together significantly inhibits transactivation of CREB by EGF but not by PTH, indicating that EGF regulates CREB phosphorylation and transactivation through p38 and ERKs and PTH does not. Finally, the greater than additive transactivation of CREB by PTH and EGF is significantly inhibited by the PKA inhibitor H-89 or by cotreatment with SB203580 and PD98059. Thus, several different signaling pathways in osteoblastic cells can converge on and regulate CREB activity. This suggests, in vivo, that circulating agents such as PTH and EGF are acting in concert to exert their effects.
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PMID:Induction of transcriptional activity of the cyclic adenosine monophosphate response element binding protein by parathyroid hormone and epidermal growth factor in osteoblastic cells. 1216 94

Activation of the mitogen-activated protein kinases ERK1/2 by the chemotherapeutic agent cisplatin has been shown to result in either survival or cell death. The downstream mediators of these opposing effects are unknown, as are the upstream signaling molecules. Activation of ERK is required for accumulation and phosphorylation of p53 following cisplatin treatment. We studied the role of ERK activation after cisplatin treatment under p53-negative and p53-positive conditions using a tetracycline-dependent expression vector in Saos-2 osteosarcoma cells. Dose-dependent activation of ERK first occurred 3-6 h after a 2-h cisplatin incubation and declined after 12-24 h in several tumor cell lines. Incubation of cell lines with the MEK1 inhibitors PD98059 or UO126 after, but not during, cisplatin treatment completely inhibited cisplatin-induced activation of ERK. The activation of ERK by cisplatin was inhibited by transient transfection with dominant-negative Ras-N17 in Saos-2 cells. Treatment of cells with PD98059 or UO126 after cisplatin incubation or inhibition of signaling through ERK by tetracycline-regulated expression of dominant-inhibitory ERK enhanced resistance to cisplatin in p53-negative osteosarcoma cells and reduced cisplatin-induced apoptosis. P53 was stabilized and phosphorylated in a MEK1-dependent manner after cisplatin incubation in Kelly neuroblastoma cells. Inhibition of signaling through ERK increased cell survival after cisplatin treatment in these cells as well. Expression of functional p53 did not change the proapoptotic effects of ERK activation in response to cisplatin in Saos-2 cells. Our results suggest that cisplatin-induced activation of ERK is mediated by Ras. ERK activation increased cisplatin-induced cell death independently of p53 in osteosarcoma and neuroblastoma cell lines.
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PMID:Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. 1243 98

Cellular stress activates multiple mitogen-activated protein kinase (MAPK) cascades and immediate-early gene (IEG) transcription. To address how these events are linked, we investigated the endogenous signaling/transcription factor network driving IEG activation by arsenite and anisomycin in the human osteosarcoma cell line HOS/TE-85. Induction of IEG transcription by both stresses corresponded temporally with the phosphorylation of the regulatory factors Elk-1 and cAMP response element-binding protein (CREB), along with activation of the extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK) and p38 MAPK cascades. To assess the role of the different cascades, they were selectively inhibited with PD98059, SP600125 and SB203580, respectively. This implicated all three cascades in Elk-1 phosphorylation after arsenite treatment, whereas ERK and SAPK inhibition diminished this, and IEG mRNA levels, downstream of anisomycin. SB blocked phosphorylation of both serum response factor (SRF) and CREB, and strongly reduced IEG activation by both stresses. Combining PD with SB further reduced arsenite induction of IEG transcription. Thus, all three MAPK cascades mediate anisomycin- and arsenite-induced signaling to IEG promoters in HOS cells through the differential targeting of Elk-1, SRF and CREB.
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PMID:Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF. 1266 Aug 19

Osteosarcomas represent the most common primary malignant bone tumors; however, comprehension of the molecular mechanisms underlying their pathogenesis is far from thorough. Studies in cultured cells have demonstrated that the c-Jun N-terminal kinase (JNK) signal transduction pathway participates in the proliferation, differentiation, and apoptosis of osteoblasts. Phosphorylated JNKs activate the oncoprotein c-Jun, which is known to form the activator protein-1 (AP-1) transcription factor as a homo- or heterodimer. c-Jun's principal dimerization partner is c-Fos, which participates in the differentiation and function of osteoblasts and in the pathogenesis of osteosarcomas. A similar role for the JNK cascade in the malignant transformation of human osteoblasts and in the generation of osteosarcomas has not been documented. Our study addressed the possibility that a functional upregulation of the JNK pathway is implicated in the pathogenesis of osteosarcomas. To this end, we employed immunohistochemistry to examine normal bone and osteosarcoma cells in paraffin-embedded sections from 56 patients with high-grade tumors and 15 patients with low-grade tumors. We assessed the protein levels of the two major JNK isoforms (JNK1 and JNK2); their phosphorylated-hence activated-species, p-JNK; their substrate, c- Jun; its phosphorylated (activated) form, pc-Jun; and c-Jun's heterodimeric partner, c-Fos. We also examined the immunohistochemical profile of the alpha chain of the nascent polypeptide-associated complex (alpha-NAC), an osteoblast-specific AP-1 coactivator that potentiates the transcriptional activity of the c-Jun/c-Jun homodimer. Positive immunostaining for JNK1, JNK2, p-JNK, c-Jun, pc-Jun, c-Fos, and alpha-NAC was observed in 86, 93, 94, 99, 97, 99, and 97.5% of the samples, respectively, whereas normal bone was devoid of these immunoreactivities. The cellular levels of all proteins were significantly correlated to each other (P < 0.001 for each correlation). Moreover, significantly higher expression levels of all proteins were detected in high-grade tumors compared to levels in low-grade ones. The observed expression profile of alpha-NAC implies that the active AP-1 in human osteosarcomas most likely comprises c-Jun/c-Jun homodimers. When cellular levels of the JNK pathway components and c-Fos were evaluated as possible biological markers of tumor grade, high expression of c-Jun and abundant pc-Jun predicted a high-grade tumor. Our findings provide novel evidence that the JNK signaling pathway is functionally operative in the malignant transformation of osteoblasts and the subsequent development and progression of human osteosarcomas. Evaluation of c-Jun expression and JNK-dependent activation may facilitate an improved prediction of the tumor's clinical behavior and potentially be exploited in designing patient-tailored treatment regimens.
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PMID:Activation of the JNK-AP-1 signal transduction pathway is associated with pathogenesis and progression of human osteosarcomas. 1268 79

Signal transduction downstream HGF receptor (MET) activation involves multiple pathways that account for mitogenesis, motility and morphogenesis in a cell type-dependent fashion. MET receptor is aberrantly expressed in almost 100% of human osteosarcomas. We analyzed the effect of the MET receptor activation in five human osteosarcoma cell lines evaluating the levels of HGF-dependent activation of MAPK and PKB/AKT as biochemical readouts of mitogenic and invasive responses, respectively. All the cell lines tested expressed high levels of the MET proto-oncogene. Four cell lines showed activation of the MAPK cascade upon HGF stimulation, suggesting that this growth factor serves a common proliferative function in osteosarcomas. Two lines showed activation of PKB/AKT that is known to be involved in migration mediated by HGF receptor. Accordingly, cell lines where MAPK cascade was activated responded to HGF with increased proliferation, while induction and inhibition of PKB/AKT activity corresponded to acquisition or block of the invasive-motile response to HGF, respectively. Both the HGF dependent responses were reverted by the specific MET inhibitor K252a. These data show that HGF activates both the mitogen and motogen machinery in osteosarcoma cells and suggest that HGF might promote their malignant behavior by concomitant activation of different pathways and biological functions.
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PMID:Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma. 1270 13

Recently cloned leukotactin-1 (Lkn-1) that belongs to CC chemokine family has not been characterized. To understand the intracellular events following Lkn-1 binding to CCR1, we investigated the activities of signaling molecules in response to Lkn-1 in human osteogenic sarcoma cells expressing CCR1. Lkn-1-stimulated cells showed elevated phosphorylation of extracellular signal-related kinases (ERK1/2) with a distinct time course. ERK activation was peaked in 30 min and 12 h showing biphasic activation of ERK. Pertussis toxin, an inhibitor of G(i)/G(o) protein, and phospholipase C (PLC) inhibitor blocked Lkn-1-induced activation of ERK. Protein kinase C delta (PKC delta) specific inhibitor rottlerin inhibited ERK activation in Lkn-1-stimulated cells. The activities of PLC and PKC delta were also enhanced by Lkn-1 stimulation. Dominant negative Ras inhibited activation of ERK. Immediate early response genes such as c-fos and c-myc were induced by Lkn-1 stimulation. Lkn-1 affected the cell cycle progression by cyclin D(3) induction. These results suggest that Lkn-1 activates the ERK pathway by transducing the signal through G(i)/G(o) protein, PLC, PKC delta and Ras, and it may play a role for cell proliferation, differentiation, and regulation of gene expression for other cellular processes.
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PMID:Leukotactin-1-induced ERK activation is mediated via Gi/Go protein/PLC/PKC delta/Ras cascades in HOS cells. 1275 39

Extracellular regulated kinases (ERKs)-1 and -2 are members of the MAPK family of protein kinases involved in the proliferation, differentiation and apoptosis of bone cells. The purpose of the present study investigated the biocompatibility role, and signaling pathways of components of mineral trioxide aggregate (MTA) by culturing human osteosarcoma cell line (U2OS) in the presence of materials. Biocompatibility effects were assessed using the MTT assay for mitochondrial enzyme activity. The statistical analysis of the survival rate was performed using one-way analysis of variance (ANOVA) with p<0.05 shown statistical difference. The signaling pathway of MTA-treated U2OS cells were assessed by the western blotting methods. Dose-dependent and time-dependent tests were conducted. The results showed that the survival rates of the MTA extract experimental groups were higher than that of the control group (p<0.05). ERKs activity was dose-dependent, decreasing as the concentrations of the MTA extract decreased, and was time-dependent, decreasing as the treatment time increased. Suppression of ERK pathway by PD98059 resulted in dose-dependent and time-dependent decreases. The findings suggest that MTA is a biocompatible material to U2OS cells, and the ERK kinase pathway plays a signal transduction role in the MTA treated U2OS cells.
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PMID:Effects of mineral trioxide aggregate (MTA) extracts on mitogen-activated protein kinase activity in human osteosarcoma cell line (U2OS). 1283 85

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