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 study of in vitro cell transformation is valuable for understanding the multistep carcinogenesis of human cells. The difficulty in inducing neoplastic transformation of human cells by treatment with chemical or physical agents alone is due to the difficulty in immortalizing normal human cells. Thus, the immortalization step is critical for in vitro neoplastic transformation of human cells. We transfected a mutant p53 gene (mp53: codon 273Arg-His) into normal human fibroblasts and obtained two G418-resistant mp53-containing clones. These clones showed an extended life span but ultimately senesced. However, when they were treated with either 4-nitroquinoline 1-oxide or X-rays, they were immortalized. The immortalized cells showed both numerical and structural chromosome abnormalities, but they were not tumorigenic. The expression of mutant but not wild type p53 was detected in the immortalized cells by RT-PCR. Expression of p21, which is located downstream of p53, was remarkably reduced in the immortalized cells, resulting in increased cdk2 and cdc2 kinase activity. However, there was no significant difference between the normal and immortalized human cells in expression of another tumor suppressor gene, p16. These findings indicate that the p53-p21 cascade may play an important role in the immortalization of human cells.
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PMID:Immortalization of mutant p53-transfected human fibroblasts by treatment with either 4-nitroquinoline 1-oxide or X-rays. 933 45

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

Mutagenicity of 15 nitrated polycyclic aromatic hydrocarbons (nitro PAHs), which were detected in ambient air particles and/or combustion source emissions, were examined using a set of six Salmonella typhimurium tester strains (TA7001 to TA7006), and the mutational specificity was characterized by the comparison of the mutagenic potencies of nitro-PAHs in the tester strains. Each strain carries a unique missense mutation in the histidine operon and is reverted by only one specific base-substitution out of six possible changes. All nitro-PAHs tested were mutagenic in multiple strains, and were classified into four categories based on the strains predominantly reverted. 1-Nitropyrene (1-NPy), 2,7-dinitrofluoren-9-one and 1,3-, 1,6- and 1,8-dinitropyrene isomers exerted the highest mutagenicity in strain TA7005 (C.G-->A.T transversion) followed by strain TA7006 (C.G-->G.C transversion). 2- And 3-nitrofluoren-9-one isomers, 2-NPy and 2,7-dinitrophenanthrene were also markedly mutagenic in strain TA7005 but not in strain TA7006. For 2-, 3- and 9-nitrophenanthrene isomers, 2-nitrofluoranthene (2-NFT) and 4-NPy, TA7004 (G.C-->A.T transition) was the most responsive strain. 3-NFT was unique, showing the highest mutagenicity in strain TA7002 (T.A-->A.T transversion). All nitro-PAHs tested induced C.G-->A.T transversion, which is observed as the most frequent base-substitution mutation of p53 tumor suppressor gene in human lung cancer.
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PMID:Comparison of the mutational specificity induced by environmental genotoxin nitrated polycyclic aromatic hydrocarbons in Salmonella typhimurium his genes. 943 49

The binding of p53 protein to DNA is stimulated by its interaction with covalent as well as noncovalent modifiers. We report the identification of a factor from HeLa nuclear extracts that activates p53 DNA binding. This factor was purified to homogeneity and identified as the high mobility group protein, HMG-1. HMG-1 belongs to a family of highly conserved chromatin-associated nucleoproteins that bend DNA and facilitate the binding of various transcription factors to their cognate DNA sequences. We demonstrate that recombinant His-tagged HMG-1 enhances p53 DNA binding in vitro and also that HMG-1 and p53 can interact directly in vitro. Unexpectedly, HMG-1 also stimulates DNA binding by p53Delta30, a carboxy-terminally deleted form of the protein that is considered to be constitutively active, suggesting that HMG-1 stimulates p53 by a mechanism that is distinct from other known activators of p53. Finally, using transient transfection assays we show that HMG-1 can increase p53 and p53Delta30-mediated transactivation in vivo. HMG-1 promotes the assembly of higher order p53 nucleoprotein structures, and these data, along with the fact that HMG-1 is capable of bending DNA, suggest that HMG-1 may activate p53 DNA binding by a novel mechanism involving a structural change in the target DNA.
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PMID:High mobility group protein-1 (HMG-1) is a unique activator of p53. 947 15

Missense mutations in the p53 tumor suppressor occur frequently in human breast cancer and influence both the prognosis and response to chemotherapy. Amino acid 175 (equivalent to murine 172) is the second most common site of missense mutations in p53 in human breast cancer. Over 95% of these mutations are arginine-to-histidine (R-H) substitutions resulting in a gain-of-function, and not merely a dominant-negative phenotype. Transgenic mice expressing a p53 172(R-H) construct targeted to the mammary gland by means of a whey acidic protein (WAP) promoter were characterized as a model system in order to determine the specific effects of this mutation on mammary tumorigenesis. Although transgene expression alone had no apparent effect on normal mammary development, transgenic mice treated with the chemical carcinogen dimethylbenz(a)anthracene developed tumors with much shorter latency than did control littermates and had a greater tumor burden. Tumors arising in transgenic mice did not exhibit either decreased apoptosis or increased cell proliferation relative to tumors arising in nontransgenic littermates, but did display increased genomic instability. Large pleiomorphic nuclei were visible in many tumors from transgenic mice, and DNA flow analysis confirmed the presence of significant aneuploid cell populations. Since these transgenic mice develop very few spontaneous tumors, while accelerating carcinogen-and oncogene-mediated tumorigenesis, this mouse model will, therefore, be useful in the investigation of early events in mammary tumorigenesis. It may also be used as a preclinical model to test newly developed chemotherapeutic strategies.
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PMID:A transgenic mouse model for mammary carcinogenesis. 951 74

We recently reported that murine MethA mutant but not wild-type p53 specifically binds to MAR-DNA elements (MARs) with high affinity. Here we show that this DNA binding activity is exerted not only by MethA mutant p53 but also by other murine mutant p53 proteins isolated from the transformed murine BALB/c cell lines 3T3tx and T3T3 and differing in their conformational status. High affinity MAR-DNA binding was not restricted to the Xbal-IgE-MAR-DNA fragment from the murine immunoglobulin heavy chain gene enhancer locus [Cockerill et al. (1987): J Biol Chem 262:5394-5397] used in previous studies, as MethA p53 also specifically interacted with other A/T-rich bona fide MARs. Not only murine but also human mutant p53 proteins carrying the mutational hot spot amino acid exchanges 175Arg-->His, 273Arg-->Pro, or 273Arg-->His bound to the Xbal-IgE-MAR-DNA fragment. We therefore conclude that high affinity MAR-DNA binding is a property common to a variety of mutant p53 proteins.
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PMID:High affinity MAR-DNA binding is a common property of murine and human mutant p53. 958 65

p53-interacting proteins from mouse epidermal cells and human myelogenous leukemia cells were isolated by affinity chromatography using glutathione S-transferase (GST)-p53 fusion proteins. One of these proteins was topoisomerase I, whose interaction with p53 was recently reported. A carboxyl-terminal fragment containing the last 92 amino acids of p53 (GST-299-390) was sufficient for binding to topoisomerase I. Nanomolar concentrations of either GST-p53 or GST-299-390 enhanced the catalytic activity of purified human topoisomerase I. Purified wild-type human p53 and point mutants Ser-239, Ser-245, and His-273 were equivalent in their enhancement of human topoisomerase I activity. Because topoisomerase I is thought to promote genetic recombination, competence to enhance topoisomerase I catalytic activity coupled with a deficiency in transcriptional activity may be a mechanism for gain of function in mutant p53 proteins.
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PMID:Wild-type and mutant forms of p53 activate human topoisomerase I: a possible mechanism for gain of function in mutants. 960 49

The p53 and PAX3 genes were examined by PCR, SSCP and DNA sequencing methods in 50 and 58 paraffinembedded medullablastoma tissues, respectively. Four novel mutations were identified among these samples in exon 5 of the p53 gene. Two tumours showed a G to A transition. One heterozygous mutation was located on codon 158 which changed the encoded amino acid from Arg (CGC) to His (CAC). Another was located on codon 174 and replaced AGG (Arg) with AAG (Lys). There was a single base deletion of guanine located on codon 160 in another two samples, causing a frameshift. This is the first study of mutation status of PAX gene in medulloblastoma wherein only one polymorphism was identified in the gene. The polymorphism changed codon 43 from GGC to GGT but both encoded glycine.
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PMID:The mutation status of PAX3 and p53 genes in medulloblastoma. 961 31

An 18-year old male was admitted to our hospital complaining of back pain. His chest computed tomography showed a tumor in the posterior mediastinum. Open biopsy was performed, and a diagnosis of peripheral neuroepithelioma was made. No genetic abnormalities were detected in the DNA obtained from the biopsy specimen. He received chemotherapy and radiation several times. These treatment regimens were effective, but he relapsed 14 months later and died of respiratory failure due to tumor growth. Autopsy examination revealed a large tumor which occupied almost the entire right thoracic cavity, but there was no evidence of metastasis to other organs. Chromosomal translocation t(14;17) (q24;p12.2) and point mutation of exon 5 of the p53 gene were detected.
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PMID:An autopsy case of peripheral neuroepithelioma in posterior mediastinum with p53 point mutation. 961 73

Mutations of the p53 tumor suppressor gene have been used as molecular genetic markers of disease and serve as a prognostic indicator in various malignancies including non-Hodgkin's lymphoma (NHL). Alterations in the p53 gene were investigated in a bone marrow sample from a NHL patient admitted for autologous bone marrow transplantation. Diffuse mixed small and large cell NHL, was initially diagnosed which eventually progressed to large cell lymphoma at relapse following poly-chemotherapy. A sequential technique of polymerase chain reaction-mediated single-strand conformational polymorphism (PCR-SSCP) of the p53 gene revealed a shift in one band of exon 6 in the bone marrow, collected at the time of initial diagnosis. No mutations were detected in exons 5, 7, 8 and 9. Direct sequencing of exon 6 detected a single base change from G to C resulting in an amino acid substitution from glycine to histidine. Results of this study and data reviewed from other publications suggest that the missense p53 mutation seen in this patient at the time of diagnosis may perhaps have been used to predict the eventual outcome of the disease. This could, therefore, serve as an important genetic disease marker particularly in bone marrow or peripheral blood samples initially collected and cryopreserved for future possible autologous transplantation.
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PMID:p53 gene mutation in the bone-marrow of a patient with diffuse mixed cell type lymphoma at diagnosis predicting eventual progression to large cell lymphoma. 968 39


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