Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Primary intracranial osteosarcoma not originating in the skull is a distinctly rare tumour, as is post-irradiation sarcoma of short latency. The authors report the case of a 56 year old caucasian male who underwent resection of a glioblastoma of the left temporal region and was subsequently administered partial field external beam radiation therapy (XRT) to a total dose of 5940 cGy. Seven months following the completion of XRT, an enhancing region adjacent to the surgical site was noted on followup magnetic resonance images (MRI), one which increased in size on serial studies. Initial biopsy of the dural lesion adjacent to the temporal resection site revealed a sarcoma with a suggestion of osseous differentiation. Subsequent reoperation with resection of the lesion showed it to be a primary meningeal tumour, and histological evaluation of the lesion demonstrated an osteosarcoma. Immunohistochemical staining for p53 protein performed on both the original glioblastoma and the subsequently resected osteosarcoma showed widespread nuclear positivity. The clinical, radiographic and pathologic features of this unusual case are discussed. Meningeal osteosarcoma should be included among the rare secondary sarcomas of the meninges which may be associated with malignant glioma.
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PMID:Osteosarcoma of the meninges in association with glioblastoma. 926 63

Exogenously introduced wild-type and mutant p53 have recently been reported to enhance the human epidermal growth factor receptor (EGF-R) gene promoter activity in p53-deficient Saos2 osteosarcoma cells. A p53 binding site residing at position -265/-239 in the EGF-R proximal promoter has also been identified. We investigated the p53 regulation of EGF-R core promoter activity in human cell lines with varying endogenour p53 status. Wild-type and mutant p53Ala143 enhanced the EGF-R core promotor activity in cells that were either p53-deficient or contained wild-type or mutant endogenous p53. Upon further characterization of the various deletion fragments of the EGF-R promoter, we identified a wild-type p53 responsive 62 bp region residing at position -167/-105. The -167/-105 segment was responsive only to wild-type p53 but not to mutant p53Ala143 or p53His273. The -167/-105 segment of the EGF-R promotor contains one perfect and several imperfect consensus p53-binding half sites; indeed in gel shift experiments the 62 bp -167/-105 segment as well as the oligonucleotides corresponding to two p53 consensus half-sites within the 62 bp fragment, exhibited binding to p53-containing protein complexes. Thus, we have identified an additional wild-type p53 responsive site in the human EGF-R promoter. This site containing consensus p53-binding sequences resides at position -167/-105 and is proximal to recently identified p53 binding element located at position -265/-239 in the EGF-R promotor.
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PMID:Identification of an additional p53-responsive site in the human epidermal growth factor receptor gene promotor. 928 64

Recent data suggest that deletion of p16INK4 and mutation of TP53 are among the most common genetic events in the development of human cancer, since the codified proteins act as brakes of the abnormal cell cycle. As the molecular events leading to the development of pediatric bone sarcomas remain unclear, we analyzed 75 osteosarcoma and Ewing sarcoma samples from 43 pediatric patients to search for alterations at the TP53 or p16INK4 tumor suppressor genes. By means of PCR-DGGE (polymerase chain reaction and denaturing gradient gel electrophoresis) we detected TP53 point mutations in 18.6% of the tumor samples, but no constitutional mutations. In the analysis of p16INK4, 7% of the samples harbored deletions of the gene but no point mutations were detected by SSCP (single strand conformation polymorphism) analysis, just the polymorphism Ala-->Thr at codon 148. These data support the hypothesis that TP53 alterations may play a role in the development of pediatric bone tumors and that the primary mechanism of inactivation of p16INK4 seems to be homozygous deletion rather than point mutation.
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PMID:Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients. 930 18

We used a yeast functional assay (functional analysis of separated alleles in yeast: FASAY) to determine the p53 gene status of human cell lines maintained in our laboratory. This assay enables the researcher to score wild-type p53 expression on the basis of the ability of expressed p53 to transactivate the reporter gene HIS 3 via the p53-responsive GAL 1 promoter in Saccharomyces cerevisiae. The cell lines examined were ten hepatoma, two hepatoblastoma, three in vitro immortalized fibroblast, two osteosarcoma, a chondrosarcoma, an ovarian teratocarcinoma and a colon cancer cell line. Out of 20 cell lines, 11 cell lines had mutations in both alleles of the p53 gene, and another 8 cell lines had no mutation in the p53 gene. Thus, 55% of the cell lines examined had mutations in the p53. Interestingly, PA-1 cells had both the normal and the mutant p53 alleles, showing that FASAY is a useful method for detecting the wild-type and mutated p53 genes simultaneously. As for the three liver cell lines harboring HBsAg, there was no relationship between their p53 gene status and the presence of HBsAg. Two cell lines were normal for p53 status, while the other had a mutation of the p53 gene.
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PMID:Yeast functional assay of the p53 gene status in human cell lines maintained in our laboratory. 935 23

Treatment of cultured cells with trichostatin A (TSA), a specific histone deacetylase inhibitor, induces the histone hyperacetylation and modulates expression of some mammalian genes. We examined the effects of TSA on cell growth arrest, and its relation to expression of the WAF1/Cip1 gene, a potent inhibitor of cyclin-dependent kinases, in a p53-mutated human osteosarcoma cell line MG63. TSA at 500 ng/ml induced growth arrest at both G1 and G2/M phases, and the expressions of the WAF1/Cip1 mRNA and protein. We also examined the changes of acetylated isoforms of histone H4. Dose-response and kinetic analysis suggest a close correlation between the level of histone acetylation and the induction of the WAF1/Cip1 expressions. Using several mutant WAF1/Cip1 promoter fragments, we found that the TSA responsive elements are two Sp1 sites at -82 and -69 relative to the transcription start site. These findings indicate that TSA induces the WAF1/Cip1 promoter through the typical Sp1 sites, in a p53-independent fashion. Furthermore, the Sp1-luc plasmid, containing SV40 promoter-derived three consensus Sp1 binding sites, was markedly activated by TSA, compared to the mutant Sp1-luc plasmid. These results demonstrate that transcriptional activation through the Sp1 sites of the WAF1/Cip1 promoter by TSA coincides with induced hyperacetylation of histone H4.
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PMID:Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites. 940 48

The objective of this study was to determine whether p53 expression correlated with clinicopathological and DNA ploidy in osteosarcoma of the jaw, a particular subtype of osteosarcoma associated with an older age at presentation, longer median survival, rare metastasis, and death due to uncontrolled local recurrence. Seventeen cases of osteosarcoma of the jaw were stained for p53 using CM1 antibody (Novocastra). Eight cases (47.5%) showed nuclear staining in more than 10% of the neoplastic nuclei. Ploidy analysis showed 13 aneuploid (eight p53+) and three diploid (none p53+) tumors. No significant relationship was found between p53 positivity and clinicomorphological features, DNA ploidy or survival. p53-positive cases were, however, more commonly associated with aneuploidy and chondroblastic differentiation. These results indicate that p53 immunostaining does not seem to provide prognostic information in osteosarcoma of the jaw.
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PMID:Analysis of p53 expression in osteosarcoma of the jaw: correlation with clinicopathologic and DNA ploidy findings. 941 91

Necdin is a nuclear protein expressed in virtually all postmitotic neurons, and ectopic expression of this protein strongly suppresses the proliferation of NIH3T3 cells. Simian virus 40 large T antigen targets both p53 and the retinoblastoma protein (Rb) for cellular transformation. By analogy with the interactions of the large T antigen with these nuclear growth suppressors, we examined the ability of necdin to bind to the large T antigen. Necdin was co-immunoprecipitated with the large T antigen from the nuclear extract of necdin cDNA-transfected COS-1 cells. Yeast two-hybrid and in vitro binding analyses revealed that necdin bound to an amino-terminal region of the large T antigen, which encompasses the Rb-binding domain. Moreover, necdin bound to adenovirus E1A, another viral oncoprotein that forms a specific complex with Rb. We then examined the ability of necdin to bind to the transcription factor E2F1, a cellular Rb-binding factor involved in cell-cycle progression. Intriguingly, necdin, like Rb, bound to a carboxyl-terminal domain of E2F1, and repressed E2F-dependent transactivation in vivo. In addition, necdin suppressed the colony formation of Rb-deficient SAOS-2 osteosarcoma cells. These results suggest that necdin is a postmitotic neuron-specific growth suppressor that is functionally similar to Rb.
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PMID:Necdin, a postmitotic neuron-specific growth suppressor, interacts with viral transforming proteins and cellular transcription factor E2F1. 942 23

Expression of the GML gene is regulated in a p53-dependent manner and is correlated with the sensitivity of esophageal cancer cells to anti-cancer drugs. To clarify the effect of GML expression on the sensitivity of cancer cells to ionizing radiation treatment, we established cell lines derived from p53-mutant human osteosarcoma HOS and esophageal carcinoma TE10 lines in which GML expression can be induced using the tetracycline-regulable system. Colony formation assay showed that the growth of cells expressing GML are inhibited in response to ionizing radiation, whereas cells not expressing GML were resistant to irradiation. Further investigation demonstrated that GML expression enhances G2/M arrest and apoptosis induced by gamma-irradiation. These results suggest that GML sensitizes cancer cells to ionizing radiation.
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PMID:Overexpression of GML promotes radiation-induced cell cycle arrest and apoptosis. 942 96

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred.
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PMID:Human prostate cancer progression models and therapeutic intervention. 943 28


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