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)

The carboxy-terminal portion of the p53 protein contains the tetramerization domain, and the introduction of multiple missense mutations in this domain disrupts the formation of p53 tetramers, resulting in the production of dimeric or monomeric forms of p53. It has recently been shown that a single missense or nonsense mutation in this domain affects the functional properties of p53 both in yeast and in mammalian cells. In this study, we tested the oligomerization of p53 with mutations in the oligomerization domain, when expressed in a human osteosarcoma cell line, Saos-2, in vivo. We found that single point mutations, including two missense and two nonsense mutations, in the alpha-helix of the oligomerization domain disrupted the oligomerization of p53, but that p53 still retained its ability to inhibit colony formation of cells to some degree. These results suggest that oligomerization and the carboxy-terminal basic domain are not prerequisite for p53-dependent tumor suppression, and this may explain why few of the tumor-derived p53 mutations that have been examined so far are carboxy-terminal mutations.
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PMID:Oligomerization is not essential for growth suppression by p53 in p53-deficient osteosarcoma Saos-2 cells. 912 51

Multiple genetic alterations, including concurrent inactivation of RB and p53, occur frequently in several human cancers. To investigate the biological significance of RB and p53 gene inactivations, a wild-type RB or p53 cDNA expression vector regulated by tetracycline was introduced by stable transfection into an osteosarcoma cell line Saos-2, in which both the RB and p53 genes were inactivated. Induction of introduced RB expression resulted in suppression of cell growth, increased percentage of cells at the G0/G1 phase, and enlargement of the cells. Furthermore, activity of alkaline phosphatase was increased and expression of fibronectin was decreased, suggesting the induction of cell differentiation by RB expression. Induction of p53 expression also resulted in significant suppression of cell growth with slight accumulation of cells at the G0/G1 and G2/M phases. The cells were detached from culture dishes and the dead cell fraction increased. Furthermore, condensation of chromatin and DNA fragmentation were observed, suggesting the induction of apoptosis by p53. These results suggest that RB and p53 play different roles in carcinogenesis of osteoblast; RB inactivation releases cells from G0/G1 arrest and suppresses cell differentiation while p53 inactivation assists the cells to proliferate by repressing both apoptosis and cell cycle arrest at G0/G1 and G2/M.
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PMID:Differentiation induced by RB expression and apoptosis induced by p53 expression in an osteosarcoma cell line. 913 82

We have examined whether the tumour suppressor p53 protein suppressed UV-induced mutations in the hypoxathine-guanine phosphoribosyl transferase (HPRT) gene and in the supF gene of the shuttle vector plasmid pMY189. We used human osteosarcoma Saos-LP12 cells, in which wild type (wt) p53 protein was induced by treatment with isopopyl-beta-D-thiogalactopyranoside. The induction of wt p53 protein suppressed UV-induced mutations but not spontaneous mutations in the HPRT gene. The frequency of UV-induced mutations induced by UV-irradiation of the plasmid was also significantly lower in cells with induced wt p53 protein than in the uninduced cells. In addition, we found that frequency of G : C to A : T transition mutations which occurred at the 3' base pair of dipyrimidine sites were significantly lower in the cells with induced wt p53 protein than in the uninduced cells. These findings suggest that wt p53 protein may play roles in modulating DNA repair pathway, resulting in the suppression of UV-induced mutations.
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PMID:Suppression of UV-induced mutations by wild-type p53 protein in human osteosarcoma cells. 917 47

The effect of overexpression of p21waf1 on drug sensitivity was studied in an osteosarcoma cell line (SaOs-2) lacking both p53 and functional retinoblastoma protein using a tetracycline (TC)-inducible expression system. p21waf1 expression was barely detectable in SaOS-2 cells incubated in the presence of TC. After TC withdrawal, high levels of p21waf1 were induced in these cells. These p21waf1-induced cells showed increased sensitivity to doxorubicin, tomudex, and methotrexate as compared to uninduced cells; this condition is associated with increased apoptosis. Expression of p21waf1 reduced cyclin A-associated kinase activity and, surprisingly, resulted in inhibition of phosphorylation of E2F-1 and increased E2F-1 binding activity. An S-G2 cell cycle arrest/delay and an increase in expression of E2F-responsive genes (dihydrofolate reductase and thymidylate synthase) was correspondingly observed. Overexpression of p21waf1 in cells lacking functional retinoblastoma protein may mediate sensitivity to anticancer drugs by inhibiting E2F-1 phosphorylation, which may contribute to increased S-G2 cell cycle delay and increased cell susceptibility to apoptosis.
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PMID:Overexpression of p21waf1 leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells. 918 20

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.
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PMID:Regulation of Myc-dependent apoptosis by p53, c-Jun N-terminal kinases/stress-activated protein kinases, and Mdm-2. 921 67

p21(Waf1/Cip1) is one of the key regulatory proteins in cell cycle, terminal differentiation, and apoptosis. Its promoter was shown to be transactivated by the wild-type p53 protein as well as in a p53-independent manner. In this report, we demonstrate that E1AF, an ets-related transcription factor, activates the human p21(Waf1/Cip1) promoter by interacting with the ets-binding sites located close to the two previously identified p53-responsive elements. Northern blot analysis revealed that p21(Waf1/Cip1) and E1AF were correlatively upregulated in response to cisplatin treatment in SiHa cells. Transient expression assays demonstrated that E1AF can activate the p21(Waf1/Cip1) promoter-driven luciferase reporter gene in SiHa cells. The p21(Waf1/Cip1) promoter activity was also increased in p53-null Saos2 osteosarcoma cells, but was markedly reduced when the ets-binding sites were deleted. These results indicate that E1AF positively regulates transcription from the p21(Waf1/Cip1) promoter in response to genotoxic stresses.
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PMID:Activation of the p21(Waf1/Cip1) promoter by the ets oncogene family transcription factor E1AF. 922 30

This study investigates the human oncoprotein MDM2, which interferes with regulation of cell division and apoptosis. Fifteen mixed-type follicular non-Hodgkin's lymphomas, ten leukaemias, two hepatocellular carcinomas, one osteosarcoma, and ten normal cell lines (fibroblasts, osteoblasts, mesothelium, peripheral lymphocytes) were tested for MDM2 expression and MDM2 gene mutation by reverse transcriptase-polymerase chain reaction (RT-PCR), immunocytochemistry, and nucleotide sequence analysis. Two follicular lymphomas, three leukaemias, both hepatocellular carcinomas, and the osteosarcoma sample showed transcription of the activated MDM2 gene. These samples lacked amplified MDM2 genes and carried mis-sense, non-sense and frame-shift mutations in a zinc finger region of MDM2, altering the amino acid sequence or causing premature termination of transcription. The mis-sense mutations were found in tumour cells that showed significant accumulation of MDM2 and lack of nuclear p53. Non-sense mutations and frame-shift mutations were found in tumours lacking MDM2 proteins. The mutations may affect the biological properties of MDM2 proteins.
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PMID:Point mutations and nucleotide insertions in the MDM2 zinc finger structure of human tumours. 922 42

The p53 tumor suppressor gene encodes a phosphoprotein which when overexpressed can induce growth arrest at the G1 and G2/M phases of the cell cycle, promote differentiation and apoptosis. This paper demonstrates that p53 can associate with trk tyrosine kinase. Expression of a murine temperature-sensitive (ts) p53 mutant in PC12 cells overexpressing trk (a model system to analyse cellular differentiation and signal transduction induced by NGF) induces morphological changes in the absence of NGF stimulation at 32 degrees C but not at 37 degrees C. In cells differentiated by p53, trk, but not EGFr, was hyperphosphorylated on tyrosine. Furthermore trk was not phosphorylated when expressed in Saos-2 cells (human osteosarcoma cells that lack expression of both endogenous trk and p53) at either temperature. However, transfection of ts p53 into these cells induces trk phosphorylation at 32 degrees C in the absence of NGF stimulation. Association of trk and p53 can be detected in NIH3T3 and PC12 cells co-expressing trk and the ts p53 mutant, in NIH3T3 and PC12 cells transfected with trk alone, and in untransfected PC12 cells, showing that overexpressed and/or endogenous trk associates with endogenous, low levels of p53. These data suggest a novel function for p53 which involves the stimulation of signal transduction pathways (mediating morphological properties of cells), possibly through association with and hyperphosphorylation of trk.
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PMID:P53 associates with trk tyrosine kinase. 923 59

Through cloning of functional p53-binding sites (p53-tagged sites) from the human genome, we isolated a novel gene inducible by wild-type p53. Its cDNA sequence contained an open reading frame encoding a 431-amino acid peptide that showed a significant homology with members of the P2X family. This protein also revealed a similarity to RP-2, a gene activated in thymocytes undergoing programmed cell death. Northern blot analysis showed that it was expressed predominantly in skeletal muscle. Hence, we designated the gene P2XM (P2X specifically expressed in skeletal muscle). P2XM was localized to chromosomal band 22q11, where frequent loss of heterozygosity has been observed in rhabdoid tumors. Although we detected no genetic alteration in the coding sequences, one of four rhabdomyosarcoma cell lines examined had completely lost expression of this gene. Furthermore, a minor splice variant lacking a part of exon 1 that would encode residues corresponding to transmembrane domain M1 was relatively more abundant in two of seven sarcoma cell lines, one of which was derived from a rhabdomyosarcoma, and the other was derived from an osteosarcoma. The results suggest that P2XM may play a significant role in the proliferation and/or differentiation of skeletal muscle cells and that its altered expression may be involved in the development of some sarcomas.
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PMID:Cloning of P2XM, a novel human P2X receptor gene regulated by p53. 924 61

The use of cytogenetics has led to significant improvement in the diagnoses and classification of sarcomas. Many of the major sarcomas have been to have characteristic tumor-specific chromosomal translocations that are currently used in the diagnosis of these tumors. In the past year, a subset of Ewing's family of tumors and myxoid liposarcomas, which lack one of the characteristic translocations, were found to carry related translocations. New technologies such as a spectral karyotyping will likely increase out ability to identify additional tumor-specific translocations. The emergence of genetic alterations as prognostic factors, as illustrated by Ewing's family of tumors, osteosarcoma, and p53 expression in soft tissue sarcomas in general, is discussed. The review concludes with laboratory applications derived from either tumor cytogenetic or gene function abnormalities that are related to tumor-specific translocations. It is anticipated that advances in diagnosis, prognosis, and modeling will translate into future therapeutic advances.
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PMID:Cytogenetics and experimental models. 925 84


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