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

Deregulated overexpression of c-Myc (Myc) confers susceptibility to apoptosis in several cell types, but the molecular regulation of these processes has not been well established. Here we have characterized several molecular changes that may modulate Myc-dependent apoptosis. Ectopic overexpression of Myc in both Rat1 fibroblasts and human osteosarcoma cells causes a dramatic increase of cellular p53 mRNA and protein, and this induction of p53 correlates with apoptosis triggered by withdrawal of serum. Stable transfection of a wild-type human p53 gene into Myc-transformed cells further potentiates apoptosis. Anticancer agents vinblastine and nocodazole also induce apoptosis in Myc-transformed Rat1 fibroblasts but are cytostatic to the same cells without Myc overexpression. We demonstrate that induction of Myc-dependent apoptosis in these cells is specifically associated with an activation of p46 c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activity, whereas this JNK/SAPK activation is absent in stress-treated cells without Myc overexpression. Moreover, overexpression of the Mdm-2 gene in Rat1-myc cells significantly inhibits apoptosis induced by low serum but has little effect on apoptosis triggered by chemotherapeutic drugs. Interestingly, differential inhibition by Mdm-2 paralleled differential activation of p46 JNK/SAPK. Thus, our data support a functional involvement of p53 in Myc-dependent apoptosis and implicate potential regulatory roles for JNK/SAPK and Mdm-2 pathways in the regulation of apoptosis in Myc-transformed tumor cells.
 ...
PMID:Regulation of Myc-dependent apoptosis by p53, c-Jun N-terminal kinases/stress-activated protein kinases, and Mdm-2. 921 67

Members of the protein inhibitor of activated signal transducer and activator of transcription (STAT) family (PIAS family) of proteins act as negative regulators of STATs in cytokine signaling. We report here that PIAS proteins have proapoptotic activity. PIAS1 induced apoptosis in both human 293T cells and human osteosarcoma U2OS cells. PIAS1 is localized in the nucleus as distinct nuclear dots. Ectopic expression of PIAS1 in U2OS cells activated JNK1 (c-Jun NH(2)-terminal kinase). A dominant-negative JNK1, capable of inhibiting PIAS1-induced JNK1 activation, blocked PIAS1-mediated apoptosis. Furthermore, a mutant PIAS1, lacking the first 9 amino acid residues, failed to repress Stat1-mediated gene activation although it retained its ability to activate JNK and to trigger apoptosis. Our results identify a novel function of PIAS1 in the induction of JNK-dependent apoptosis, independent of the previously known inhibitory activity of PIAS1 in STAT-mediated gene activation.
 ...
PMID:Induction of apoptosis by protein inhibitor of activated Stat1 through c-Jun NH2-terminal kinase activation. 1145 46

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.
 ...
PMID:BRCA1-induced apoptosis involves inactivation of ERK1/2 activities. 3110 59

In a series of experimental studies, it was shown that repetitive mild heat stress has antiaging hormetic effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. We have reported the hormetic effects of repeated challenge at the levels of maintenance of stress protein profile; reduction in the accumulation of oxidatively and glycoxidatively damaged proteins; stimulation of the proteasomal activities for the degradation of abnormal proteins; improved cellular resistance to ethanol, hydrogen peroxide, and ultraviolet-B rays; and enhanced levels of various antioxidant enzymes. Detailed analysis of the signal transduction pathways to determine alterations in the phosphorylation and dephosphorylation states of ERK, JNK, and p38 MAP kinases as a measure of cellular responsiveness to mild and severe heat stress is in progress. Furthermore, comparative studies using nonaging immortal cell lines, such as SV40-transformed human fibroblasts, spontaneous osteosarcoma cells, and telomerase-immortalized human bone marrow cells are also in progress for establishing differences in normal and cancerous cells for their responsiveness to mild and severe stresses.
 ...
PMID:Mechanisms of hormesis through mild heat stress on human cells. 1524 85

Syndecans are cell surface heparan sulfate proteoglycans that serve as co-receptors and modulate the actions of a number of extracellular ligands. Syndecans thereby regulate cell adhesion, proliferation, and differentiation. Studies in cancer cells suggest that syndecans may also modulate cell viability. We previously showed that syndecan-2 controls the growth of normal human osteoblastic cells. In this study, we examined the role of syndecan-2 in osteosarcoma cell proliferation and apoptosis. To this goal, MG63 osteosarcoma cells which express low syndecan-2 levels were transfected to overexpress full-length syndecan-2 or truncated syndecan-2 lacking its cytoplasmic domain. Determination of cell growth by cell counting and 3H-thymidine incorporation showed that truncated syndecan-2 inhibited MG63 cell proliferation. Flow cytometry analysis of DNA content and colony forming test revealed that syndecan-2, but not truncated syndecan-2, induced MG63 cell death. We show that characteristic features of apoptosis such as caspase activation, PARP cleavage, cytochrome c release, increased Bax expression, and DNA fragmentation were associated with syndecan-2-induced cell death. We further show that expression of full-length or truncated syndecan-2 induced differential activation of MAPK phosphorylation in MG63 cells. Notably, syndecan-2 but not truncated syndecan-2 overexpression increased JNK phosphorylation. Moreover, SP600125, a specific inhibitor of JNK, suppressed Bax expression induced by syndecan-2 overexpression, indicating that JNK activation mediates syndecan-2-induced apoptosis. The results show that syndecan-2 induces osteoblastic cell apoptosis through the JNK/Bax apoptotic pathway and that the cytoplasmic domain of syndecan-2 is required for this action. This supports a role for syndecan-2 in the regulation of osteosarcoma cell fate and identifies one signaling pathway by which syndecan-2 induces apoptosis in osteosarcoma cells.
 ...
PMID:Syndecan-2 overexpression induces osteosarcoma cell apoptosis: Implication of syndecan-2 cytoplasmic domain and JNK signaling. 1593 98

Selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants, are generally used for treatment of various mood and anxiety disorders. There has been much research showing the anti-tumor and cytotoxic activities of some antidepressants; but the detailed mechanisms were unclear. In cultured human osteosarcoma cells (MG63), paroxetine reduced cell viability in a concentration- and time-dependent manner. Paroxetine caused apoptosis as assessed by propidium iodide-stained cells and increased caspase-3 activation. Although immunoblotting data revealed that paroxetine could activate the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), only SB203580 (a p38 MAPK inhibitor) partially prevented cells from apoptosis. Paroxetine also induced [Ca(2+)](i) increases which involved the mobilization of intracellular Ca(2+) stored in the endoplasmic reticulum and Ca(2+) influx from extracellular medium. However, pretreatment with BAPTA/AM, a Ca(2+) chelator, to prevent paroxetine-induced [Ca(2+)](i) increases did not protect cells from death. The results suggest that in MG63 cells, paroxetine caused Ca(2+)-independent apoptosis via inducing p38 MAPK-associated caspase-3 activation.
 ...
PMID:Paroxetine-induced apoptosis in human osteosarcoma cells: activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation. 1717 98

Previous studies have shown that oridonin, a diterpenoid isolated from Rabdosia rubescens, was able to inhibit proliferation and induce apoptosis in several cell types. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effect and mechanisms of action of oridonin in human osteosarcoma cells. Our results demonstrated that oridonin induced concentration- and time-dependent suppression of proliferation and activation of apoptosis in U2OS, MG63 and SaOS-2 osteosarcoma cell lines. Oridonin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). These events were all inhibited by z-VAD-fmk, a universal inhibitor of caspases. Oridonin treatment dephosphorylated constitutively active AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). In addition, oridonin decreased the phosphorylation of ERK and increased the phosphorylation of p38 MAPK and JNK. Furthermore, oridonin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in osteosarcoma cells. All together, our results suggested that oridonin is able to inactivate Akt and ERK and activate p38 MAPK and JNK signalling pathways in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.
 ...
PMID:Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells. 1721 75

The effect of anandamide on human osteoblasts is unclear. This study examined the effect of anandamide on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca2+ levels in MG63 osteosarcoma cells. Anandamide at 50-200 microM decreased cell viability via apoptosis as demonstrated by propidium iodide staining and activation of caspase-3. Immunoblotting suggested that anandamide induced expression of ERK, JNK and p38 MAPK. Anandamide-induced cell death and apoptosis were reversed by SB203580, but not by PD98059 and SP600125, suggesting that anandamide's action was via p38 MAPK, but not via ERK and JNK. Anandamide at 1-100 microM induced [Ca2+]i increases. Removal of extracellular Ca2+ decreased the anandamide response, indicating that anandamide induced Ca2+ influx and Ca2+ release. Chelation of intracellular Ca2+ with BAPTA reversed anandamide-induced cell death and p38 MAPK phosphorylation. Collectively, in MG63 cells, anandamide induced [Ca2+]i increases which evoked p38 MAPK phosphorylation. This p38 MAPK phosphorylation subsequently activated caspase-3 leading to apoptosis.
 ...
PMID:Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. 1722 95

The molecular mechanisms underlying antiproliferative actions of the steroid 1alpha,25-dihydroxy vitamin D(3) (1,25D) in human osteosarcoma cells are known only partially. To better understand the signaling involved in 1,25D anti-tumorigenic properties in bone, we stably silenced vitamin D receptor (VDR) expression in the human osteosarcoma SaOS-2 cell line. We found that 1,25D treatment reduced cell proliferation by approximately 25% after 3 days only in SaOS-2 cells expressing native levels of VDR protein, and involved activation of MAPK/AP-1/p21(waf1) pathways. Both sustained (3 days) and transient (15min) 1,25D treatment activated JNK and ERK1/2 MAPK signaling in a nongenomic VDR-dependent manner. However, only sustained exposure to hormone led to upregulation of p21 and subsequent genomic control of the cell cycle. Specific blockade of MEK1/MEK2 cascade upstream from ERK1/2 abrogated 1,25D activation of AP-1 and p21, and subsequent antiproliferative effects, even in the presence of a nuclear VDR. We conclude that 1,25D-induced inhibition of human osteosarcoma cell proliferation occurs via sustained activation of JNK and MEK1/MEK2 pathways downstream of nongenomic VDR signaling that leads to upregulation of a c-Jun/c-Fos (AP-1) complex, which in turn modulates p21(waf1) gene expression. Our results demonstrate a cross-talk between 1,25D/VDR nongenomic and genomic signaling at the level of MAP kinase activation that leads to reduction of cell proliferation in human osteosarcoma cells.
 ...
PMID:1alpha,25-Dihydroxyvitamin D(3) antiproliferative actions involve vitamin D receptor-mediated activation of MAPK pathways and AP-1/p21(waf1) upregulation in human osteosarcoma. 1741 93

Integrins play significant roles in mechanical responses of cells on extracellular matrix (ECM). We studied the roles of integrins and ECM proteins (fibronectin [FN], type I collagen [COL1], and laminin [LM]) in shear-mediated signaling and the expression of bone formation-related genes (early growth response-1 [Egr-1], c-fos, cyclooxygenase-2 [Cox-2], and osteopontin [OPN]) in human osteosarcoma MG63 cells. MG63 cells on FN, COL1, and LM were kept as controls or subjected to shear stress (12 dynes/cm(2)), and the association of alpha(v)beta(3) and beta(1) integrins with Shc, phosphorylation of mitogen-activated protein kinases (MAPKs, i.e., extracellular signal-regulated kinase [ERK], c-jun-NH(2)-terminal kinase [JNK], and p38), and expressions of Egr-1, c-fos, Cox-2, and OPN were determined. In MG63 cells, shear stress induces sustained associations of alpha(v)beta(3) and beta(1) with Shc when seeded on FN, but sustained associations of only beta(1) with Shc when seeded on COL1/LM. Shear inductions of MAPKs and bone formation-related genes were sustained (24 h) in cells on FN, but some of these responses were transient in cells on COL1/LM. The shear activations of ERK, JNK, and p38 were mediated by integrins and Shc, and these pathways differentially modulated the downstream bone formation-related gene expression. Our findings showed that beta(1) integrin plays predominant roles for shear-induced signaling and gene expression in osteoblast-like MG63 cells on FN, COL1, and LM and that alpha(v)beta(3) also plays significant roles for such responses in cells on FN. The beta(1)/Shc association leads to the activation of ERK, which is critical for shear induction of bone formation-related genes in osteoblast-like cells.
 ...
PMID:Integrin-mediated expression of bone formation-related genes in osteoblast-like cells in response to fluid shear stress: roles of extracellular matrix, Shc, and mitogen-activated protein kinase. 1833 55


1 2 3 4 5 6 7 8 Next >>