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)

Human retinoblastomas can occur both as hereditary and as sporadic cases. Knudson's proposal that they result from two mutational events, of which one is present in the germ line in hereditary cases, has been confirmed by more recent molecular analysis, which has shown both events to involve loss or mutational inactivation of the same gene, RB-1 (ref. 2). RB-1 heterozygosity also predisposes to osteosarcoma, and RB-1 allele losses are seen in sporadic lung, breast, prostate and bladder carcinomas. RB-1 is expressed in most, if not all, tissues and codes for a nuclear phosphoprotein which becomes hypophosphorylated in the G0 growth arrest state and in the G1 phase of the cell cycle. To gain a further insight into the role of RB-1 we and other groups have generated mice carrying an inactivated allele of the homologous gene, Rb-1 (ref. 10), by gene targeting. We report here that young heterozygous mice do not appear abnormal and do not develop retinoblastoma at a detectable frequency. However, homozygous mutant embryos fail to reach term and show a number of abnormalities in neural and haematopoietic development. Broadly similar results are reported by the other groups.
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PMID:Requirement for a functional Rb-1 gene in murine development. 140 28

A class of cellular genes in which loss-of-function mutations are tumorigenic has been proposed. Such genes would normally act to suppress the cancer phenotype at the cellular or organism level. The gene determining susceptibility to hereditary retinoblastoma (RB) appears to operate in exactly this fashion, and is the first cancer suppressor gene to be molecularly cloned. The RB gene contains 27 exons dispersed over more than 200 kb and ubiquitously expresses a 4.7 kb mRNA. From sequence analysis of RB cDNA clones, the predicted RB protein has 928 amino acids. The RB protein is a nuclear phosphoprotein capable of binding to DNA and forming a complex with oncoproteins of several DNA tumor viruses. Consistent with its ubiquitous expression pattern, RB gene inactivation was found in many other cancers such as osteosarcoma, breast carcinoma, small cell lung carcinoma and prostate carcinoma. A cloned RB gene was introduced, via retrovirus-mediated gene transfer, into such tumor cells that have inactivated endogenous RB genes. Expression of the exogenous RB gene consistently suppressed their tumorigenicity in nude mice, suggesting that RB may act as a general cancer suppressor. In an attempt to address the potential cellular function of this gene, we have observed that RB protein phosphorylation oscillates with cell-cycle and the unphosphorylated form is present predominantly in the G0/G1 phase. Furthermore, when cells were induced to differentiate only the unphosphorylated form of RB could be detected, suggesting that RB protein was modulated through phosphorylation, may play an important role in these cellular functions. A hypothesis is proposed to explain how RB participates in cell proliferation and differentiation and its role in tumorigenesis.
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PMID:The molecular basis of cancer suppression by the retinoblastoma gene. 248 31

The nuclear phosphoprotein p53 occurs at elevated levels in many transformed cells. Mutant forms of mouse p53 possess enhanced transforming activity compared with wild type p53. Mutant mouse p53 proteins form complexes with the 70 kDa family of heat shock proteins (HSPs). We previously demonstrated an association between p53 and the 70 kDa HSPs in the human osteosarcoma (HOS) derived cell line HOS-SL. We report here the molecular cloning and sequencing of the p53 gene from HOS-SL cells, and demonstrate that it is in fact mutant. Further, analysis of similar HOS-derived cell lines demonstrates that they also encode the same mutant form of p53, whereas the wild type form of p53 appears to be lost in these cells. Stability studies demonstrate an increased half life of the p53 protein in these cells, in keeping with its association with the HSP 70 proteins. A potential role for this p53 mutant in the transformation process is discussed.
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PMID:Identification and characterization of a p53 gene mutation in a human osteosarcoma cell line. 253 55

The retinoblastoma (RB) susceptibility gene is one member of a putative "cancer suppressor gene" family in which loss of gene function is associated with tumor formation. Using antibodies generated against a trypE-RB fusion protein, we previously identified a nuclear phosphoprotein, pp110RB, as the RB gene product. Here we describe three additional polyclonal antibodies that were generated to separate epitopes of pp110RB with three synthetic peptides deduced from the RB cDNA sequence. All four antibodies could specifically recognize the same phosphoprotein in human cells. This protein was phosphorylated on serine and threonine, but not tyrosine, residues. RB homologous proteins with molecular masses of 105-128 kD were detected in other vertebrates, such as monkey, rodent, and chicken, by at least two antibodies, indicating evolutionary conservation of the RB gene. These antibodies were specific and sensitive for monitoring RB gene inactivation as demonstrated by screening several osteosarcoma and synovial sarcoma cell lines. Of nine cell lines examined, three expressed no immunoprecipitable normal RB protein. DNA rearrangement and abnormal RB mRNA were detected in two of these three cell lines, whereas RB protein was absent from one synovial sarcoma cell line in which normal-sized RB mRNA was clearly present. Therefore, direct immunoprecipitation of RB protein can reveal RB gene mutations that are undetectable by DNA and mRNA analysis. These results further support a crucial role for the RB gene in the oncogenesis of some mesenchymal tumors.
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PMID:Antibodies detecting abnormalities of the retinoblastoma susceptibility gene product (pp110RB) in osteosarcomas and synovial sarcomas. 274 Jan 44

The retinoblastoma susceptibility (RB) gene is unique among other cloned cancer genes because its causal role in a human cancer, retinoblastoma, was established by classical genetic methods before its isolation. Earlier hypotheses and experimental data suggested that inactivation of a gene in chromosome band 13q14 resulted in retinoblastoma formation. A gene in this region was identified as the RB gene on the basis of mutations found specifically in retinoblastoma tumors; however, its proposed biological activity in suppressing neoplasia has yet to be demonstrated. The RB gene product was identified as a nuclear phosphoprotein of 110 kD associated with DNA binding activity, suggesting that the RB protein may regulate other genes. Probes for the RB gene and gene product will be useful for genetic diagnosis of retinoblastoma susceptibility in affected families; for direct detection of mutant RB alleles; and, potentially, for genetic diagnosis of susceptibility to osteosarcoma and other tumors tentatively linked to RB-gene dysfunction. Continued study of the RB gene should yield further insight into mechanisms of oncogenesis, development, and gene regulation.
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PMID:Studies on the human retinoblastoma susceptibility gene. 306 32

The nuclear phosphoprotein c-Jun is a major component of the AP-1 transcription factor, whose activity is augmented by many oncogenes. An important mechanism to stimulate AP-1 function is N-terminal phosphorylation of c-Jun at the serine residues 63 and 73 by the c-JunN-terminal kinases (JNKs). Mice and cells harboring a mutant allele of c-jun, which has the JNK phosphoacceptor serines changed to alanines (junAA), were used to determine the function of c-Jun N-terminal phosphorylation (JNP) during oncogenic transformation in vitro and in vivo. JunAA immortalized fibroblasts expressing v-ras and v-fos showed reduced tumorigenicity in nude mice, but the efficiency of v-src transformation was unaffected by the lack of JNP. To assess the significance of JNP in tumour development in vivo, two transgenic mouse tumour models were employed. Skin tumour development caused by constitutive activation of the ras pathway by K5-SOS-F expression and c-fos-induced osteosarcoma formation were impaired in mice lacking JNP. Inhibition of JNP may, therefore, be a novel therapeutic strategy to inhibit tumour growth in vivo. Oncogene (2000).
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PMID:Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. 1085 Oct 65