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)

p21 (WAF1/CIP1) is a downstream effector of p53 and mediates growth arrest by inhibiting the action of G(1) cyclin-dependent kinases. However, it has been reported that the p21 expression was triggered by multiple differentiation-inducing agents by a p53-independent pathway. These agents induced expression of p21 by binding to specific DNA elements and modulating transcriptional initiation. We demonstrated that the gene encoding p21 was not only a vitamin D(3) target gene but also a vitamin K(2) target gene in the cells and that their differentiation was well related to the transcriptional activation of the p21 gene. Transient overexpression of p21, using adenovirus-driven p21 expression plasmid, in MG-63 cells in the absence of vitamins D(3) and K(2) resulted in their differentiation. The transcriptional activation of p21 by vitamin D(3) or vitamin K(2) in p53-deficient osteosarcoma cells demonstrated the p53-independent role of p21 in human osseous differentiation. HUM PATHOL 32:410-416.
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PMID:Transcriptional activation of p21 by vitamin D(3) or vitamin K(2) leads to differentiation of p53-deficient MG-63 osteosarcoma cells. 1133 58

RB, p53 and p21(Sdi1/WAF1/Cip1) interact in the induction of G1 arrest. We established osteosarcoma cell lines in which a tetracycline-regulatable promoter controls the induction of RB, p53 and p21. By using these cell lines, we investigated whether RB, p53 or p21 regulates, in the same manner or differently, expression and function of E2F-1 and its responsive genes. E2F-1 gene products and transcripts of the E2F-responsive genes decreased in response to RB. Similar changes occurred to p53 and p21 when RB is present. However, in the absence of RB, some of the E2F-responsive genes decreased in response to p53 but not to p21. Thus, RB is a critical component for regulating the E2F-responsive genes, while p53 alone affects only a subset of these genes.
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PMID:Alterations in expression of E2F-1 and E2F-responsive genes by RB, p53 and p21(Sdi1/WAF1/Cip1) expression. 1143 20

A noninvasive method for molecular imaging of the activity of different signal transduction pathways and the expression of different genes in vivo would be of considerable value. It would aid in understanding the role specific genes and signal transduction pathways have in various diseases, and could elucidate temporal dynamics and regulation at different stages of disease and during various therapeutic interventions. We developed and assessed a method for monitoring the transcriptional activation of endogenous genes by positron-emission tomography (PET) imaging. The HSV1-tk/GFP (TKGFP) dual reporter gene was used to monitor transcriptional activation of p53-dependent genes. A retrovirus bearing the Cis-p53/TKGFP reporter system was constructed in which the TKGFP reporter gene was placed under control of an artificial cis-acting p53-specific enhancer. U87 glioma and SaOS-2 osteosarcoma cells were transduced with this retrovirus and used to establish xenografts in rats. We demonstrated that DNA damage-induced up-regulation of p53 transcriptional activity correlated with the expression of p53-dependent downstream genes, such as p21, in U87 (wild-type p53), but not in SaOS-2 osteosarcoma (p53 -/-) cells. We showed that PET, with [(124)I]FIAU (2'-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-[(124)I]iodouracil) and the Cis-p53TKGFP reporter system, is sufficiently sensitive to image the transcriptional regulation of genes in the p53 signal transduction pathway. These imaging results were confirmed by independent measurements of p53 activity and the expression levels of downstream genes (e.g., p21) by using conventional molecular-biological assays. PET imaging of p53 transcriptional activity in tumor xenografts by using the Cis-p53TKGFP reporter system may be useful in assessing novel therapeutic approaches.
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PMID:Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo. 1148 88

Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid into prostanoids which are involved in apoptosis and inflammation. Two distinct COXs have been identified: COX-1 which is constitutively expressed and COX-2 which is induced by different products such as tumor promoters or growth factors. Previously, we demonstrated that a plant steroid, diosgenin, was a new megakaryocytic differentiation inducer of human erythroleukemia cells. In our study, we investigated the effect of diosgenin on the proliferation rate, cell cycle distribution and apoptosis in the human osteosarcoma 1547 cell line. The effects of this compound were also tested on COX expression and COX activities. Diosgenin treatment caused an inhibition of 1547 cell growth with a cycle arrest in G1 phase and apoptosis induction. Moreover, we found a correlation between p53, p21 mRNA expression and nuclear factor-kappaB activation and we observed a time-dependent increase in PGE2 synthesis after diosgenin treatment.
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PMID:A plant steroid, diosgenin, induces apoptosis, cell cycle arrest and COX activity in osteosarcoma cells. 1160 50

The mouse double minute 2 (MDM2) oncogene has been suggested as a target for cancer therapy. It is amplified or overexpressed in many human cancers, including breast cancer, and MDM2 levels are associated with poor prognosis of several human cancers, including breast cancer, ovarian cancer, osteosarcoma, and lymphoma. In the present study, we investigated the functions of MDM2 oncogene in the growth of breast cancer and the potential value of MDM2 as a drug target for cancer therapy by inhibiting MDM2 expression with a specific antisense antihuman-MDM2 oligonucleotide (oligo). The selected antisense mixed-backbone oligo was evaluated for its in vitro and in vivo antitumor activity in human breast cancer models: MCF-7 cell line containing wild-type p53 and MDA-MB-468 cell line containing mutant p53. In MCF-7 cells, p53 and p21 levels were elevated, resulting from specific inhibition of MDM2 expression by the antisense oligo (AS). In MDA-MB-468 cells, after inhibition of MDM2 expression, p21 levels were elevated, although p53 levels remained unchanged. After i.p. administration of the antisense anti-MDM2 oligo, in vivo antitumor activity occurred in a dose-dependent manner in nude mice bearing MCF-7 or MDA-MB-468 xenografts. In both models, in vivo synergistically or additive therapeutic effects of MDM2 inhibition and the clinically used cancer chemotherapeutic agents irinotecan, 5-fluorouracil, and paclitaxel (Taxol) were observed. These results suggest that MDM2 have a role in tumor growth through both p53-dependent and p53-independent mechanisms. We speculate that MDM2 inhibitors, such as ASs, have a broad spectrum of antitumor activities in human breast cancers, regardless of p53 status. This study should provide a basis for future development of anti-MDM2 ASs as cancer therapeutic agents used alone or in combination with conventional chemotherapeutics.
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PMID:Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: in vitro and in vivo activities and mechanisms. 1170 84

The present study was performed to identify a potent and sequence-specific antisense oligonucleotide (ASO), to inhibit Hdm2 expression in human cancer cell lines and to study the downstream consequences. Ten chimeric 2'-O-methoxyethyl (MoE)-modified hemimers were synthesized that targeted various regions from the 5'- to the 3'-end of Hdm2 mRNA. The IC50 of the most potent ASO, NCH-4401, was subsequently determined and compared to the IC50 of a 2'-MoE-modified ASO, with a complete phosphorothioate backbone (NCH-4668), and to a 3 bp mismatched ASO (NCH4529). NCH4401 inhibited Hdm2 expression in SJSA-1 cells with an IC50 of 120 nm, whereas NCH-4668 was less potent with an IC50 of 180 nm. The mismatched control ASO was completely inactive, indicating a sequence-dependent mechanism of action of NCH-4401. NCH4401 was subsequently used to study the consequences of inhibiting Hdm2 expression in human osteosarcoma cells. NCH-4401 completely inhibited Hdm2 protein expression in SJSA-1 cells at a concentration of 300 nm, already 4 h after start of ASO treatment. At an ASO concentration of 300 nM, p53 protein was induced 12.5-fold and p21 was induced 8-fold over background levels, 24 h after start of ASO treatment. The dramatic induction of p53 in SJSA-1 cells prompted us to investigate whether the accumulation of p53 in these cells was followed by induction of apoptosis. However, no signs for apoptosis were detected in SJSA-1 cells, following induction of wild-type p53 using the Yopro method and the induction of caspase-3 activity. SJSA-1 cells were subsequently treated with NCH-4401 at different concentrations in combination with two well-known DNA-damaging agents, i.e. carboplatin and mitomycin C. Apoptosis induction following treatment of cells with DNA-damaging agents and NCH4401 was determined in parallel by measuring caspase-3 activation and uptake of the DNA dye Yopro. Carboplatin and mitomycin C together only slightly induced apoptosis in SJSA-1 cells to a factor of approximately 2-fold, as measured by the induction of caspase-3 activity. The downregulation of Hdm2 expression by NCH4401 did not induce apoptosis on its own and did not potentiate the mitomycin C/carboplatin-induced programmed cell death.
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PMID:Consequences of the inhibition of Hdm2 expression in human osteosarcoma cells using antisense oligonucleotides. 1171 35

Expression of the cyclin-dependent kinase inhibitor gene p21 is induced after DNA damage and plays a role in cell survival. The exact mechanism of induction is not known, but enhancement of mRNA stability has recently been implicated as an important factor. To obtain further insight into the dynamics of p21 gene expression at the individual cell level, normal fibroblasts, GM1492 fibroblasts from a Bloom's syndrome patient, and U2OS osteosarcoma cells were UVC irradiated, fixed at different time points, and subjected to mRNA fluorescence in situ hybridization (FISH) and immunocytochemical staining. In mock-irradiated normal fibroblasts, a subfraction of cells revealed low levels of p21 mRNA synthesis. After UVC treatment, p21 transcripts accumulated over time in nuclear locations other than transcription foci. At 6 hr after irradiation, almost 50% of the cells displayed p21 mRNA in three different distribution patterns within the nuclei. The highest frequency of cells with cytoplasmic accumulation of p21 mRNA was seen at 17 hr after UVC treatment. We conclude that increased p21 gene transcription and possibly stabilization of newly synthesized p21 mRNA contribute to elevated levels of p21 protein after UVC irradiation. (J Histochem Cytochem 50:81-89, 2002)
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PMID:Induction of p21 mRNA synthesis after short-wavelength UV light visualized in individual cells by RNA FISH. 1174 97

We characterized a new signaling pathway leading to the activation of cAMP-responsive element-binding protein (CREB) in several cell lines affected by mitochondrial dysfunction. In vitro kinase assays, inhibitors of several kinase pathways and overexpression of a dominant-negative mutant for calcium/calmodulin kinase IV (CaMKIV), which blocks the activation of CREB, showed that CaMKIV is activated by a mitochondrial activity impairment. A high calcium concentration leading to the disruption of the protein interaction with protein phosphatase 2A explains CaMKIV activation in these conditions. Transcrip tionally active phosphorylated CREB was also found in a rho0 143B human osteosarcoma cell line and in a MERRF cybrid cell line mutated for tRNA(Lys) (A8344G). We also showed that phosphorylated CREB is involved in the proliferation defect induced by a mitochondrial dysfunction. Indeed, cell proliferation inhibition can be prevented by CaMKIV inhibition and CREB dominant-negative mutants. Finally, our data suggest that phosphorylated CREB recruits p53 tumor suppressor protein, modifies its transcriptional activity and increases the expression of p21(Waf1/Cip1), a p53-regulated cyclin-dependent kinase inhibitor.
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PMID:CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation. 1178 25

p73 shares high sequence homology with the tumor suppressor p53. Like p53, ectopic overexpression of p73 induces cell cycle arrest and/or apoptosis, and these biological activities are linked to its sequence-specific transactivation function. The COOH-terminal region of p73 is unique and has a function to modulate DNA-binding ability and transactivation activity. To identify and characterize cellular proteins that interact with the COOH-terminal region of p73 alpha and regulate its activity, we employed a yeast-based two-hybrid screen with a human fetal brain cDNA library. We found MM1, a nuclear c-Myc-binding protein, was associated with p73 alpha in both yeast two-hybrid and in vitro pull-down assays. In mammalian cells, MM1 co-immunoprecipitated with p73 alpha, whereas p73 beta and tumor suppressor p53 did not interact with MM1. Overexpression of MM1 in p53-deficient osteosarcoma SAOS-2 cells enhanced the p73 alpha-dependent transcription from the p53/p73-responsive Bax and PG13 promoters, whereas p73 beta- and p53-mediated transcriptional activation was unaffected in the presence of MM1. MM1 also stimulated the p73 alpha-mediated growth suppression in SAOS-2 cells. More importantly, we found that c-Myc was physically associated with p73 alpha and significantly impaired the transcriptional activity of p73 alpha on Bax and p21(waf1) promoters. Expression of MM1 strongly reduced the c-Myc-mediated inhibitory activity on p73 alpha. These results suggest that MM1 may act as a molecular partner for p73 to prevent the c-Myc-mediated inhibitory effect on its activity.
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PMID:Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function. 1184 94

WT1 was originally identified as a Wilms' tumor suppressor gene, but it may have oncogenic potential in leukemia and in some solid tumors. WT1 is a transcription factor that has been implicated in the regulation of target genes related to apoptosis, genitourinary differentiation, and cell cycle progression. Because induction of WT1 leads indirectly to increased p21 expression in osteosarcoma cells, we investigated the possibility that other genes involved in the G(1)/S phase transition might also be WT1 targets. Cyclin E plays a crucial role in the cell cycle by activating cyclin-dependent kinase 2, which phosphorylates Rb, leading to progression from G(1) into S phase. We identified several WT1 binding sites in the cyclin E promoter. We demonstrate that WT1 binds to these sites and that in transient transfection assays WT1 represses the cyclin E promoter. This activity is dependent on the presence of a binding site located downstream of the transcription start site. In intact cells, induction of WT1 expression down-regulates cyclin E protein levels. These results provide the first demonstration that WT1 can directly modulate the expression of a gene involved in cell cycle progression.
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PMID:Cyclin E is a target of WT1 transcriptional repression. 1191 96


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