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)

Critical determinants of DNA recognition by p53 have been identified by a molecular genetic approach. The wild-type human p53 fragment containing amino acids 71 to 330 (p53(71-330)) was used for in vitro DNA binding assays, and full-length human p53 was used for transactivation assays with Saccharomyces cerevisiae. First, we defined the DNA binding specificity of the wild-type p53 fragment by using systematically altered forms of a known consensus DNA site. This refinement indicates that p53 binds with high affinity to two repeats of PuGPuCA.TGPyCPy, a further refinement of an earlier defined consensus half site PuPuPuC(A/T).(T/A) GPyPyPy. These results were further confirmed by transactivation assays of yeast by using full-length human p53 and systematically altered DNA sites. Dimers of the pentamer AGGCA oriented either head-to-head or tail-to-tail bound efficiently, but transactivation was facilitated only through head-to-head dimers. To determine the origins of specificity in DNA binding by p53, we identified mutations that lead to altered specificities of DNA binding. Single-amino-acid substitutions were made at several positions within the DNA binding domain of p53, and this set of p53 point mutants were tested with DNA site variants for DNA binding. DNA binding analyses showed that the mutants Lys-120 to Asn, Cys-277 to Gln or Arg, and Arg-283 to Gln bind to sites with noncanonical base pair changes at positions 2, 3, and 1 in the pentamer (PuGPuCA), respectively. Thus, we implicate these residues in amino acid-base pair contacts. Interestingly, mutant Cys-277 to Gln bound a consensus site as two and four monomers, as opposed to the wild-type p53 fragment, which invariably binds this site as four monomers.
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PMID:Discrimination of DNA binding sites by mutant p53 proteins. 765 37

A patient with Philadelphia-positive chronic myelogenous leukemia (CML) evolved in extramedullary blast crisis, was studied for the presence of alterations of the P53 tumor suppressor gene in the different stages of disease progression. No P53 gene aberrations were detected during the chronic and accelerated phases. Two identical missense point mutations, involving codons 249 and 281 and leading to the amino acid substitutions Arg-Ser and Thy-Asp, were identified in cells of an extramedullary mass and then in peripheral blood blast crisis cells. The data indicate that the medullary and extramedullary blast cells belong to the same cellular clone. They also strongly suggest that in this case, the alteration of P53 gene is strictly related to the progression of the disease, although this mechanism is certainly neither the only nor the most frequent molecular event leading to the acute phase.
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PMID:Double P53 point mutation in extramedullary blast crisis of chronic myelogenous leukemia. 769 24

Endogenously generated or exogenously applied nitric oxide (NO) redox species induce apoptotic cell death in murine RAW 264.7 macrophages. Activation of the inducible NO synthase by incubation of cells with a combination of lipopolysaccharide and interferon-gamma produced internucleosomal DNA fragmentation and morphological alterations, i.e., chromatin condensation, indicative of apoptotic cell death. These alterations, reflecting the production of NO, were prevented by an inhibitor of NO synthase, NG-monomethyl-L-arginine. Moreover, NO derived from endogenous or exogenous sources caused accumulation of the tumor suppressor gene p53. Proposing a link between NO generation and DNA fragmentation, we investigated interfering biochemical signaling pathways. Therefore, we tested the ability of four NO-releasing compounds [sodium nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), and S-nitrosoglutathione (GSNO)] to cause specific DNA fragmentation. All NO donors induced DNA fragmentation in a time- and concentration-dependent manner. However, substance-specific differences became obvious. After an 8-hr incubation period, GSNO proved to be the strongest apoptotic inducer, whereas SIN-1 was much less active. Apoptosis was rapid with GSNO and SNP, yielding specific DNA fragments after 4 hr and 5 hr, respectively. In contrast, SNAP and SIN-1 produced DNA fragmentation after considerable lag times of 9 hr and 14 hr, respectively. Furthermore, an inhibitory effect of protein kinase C (PKC) and cAMP-dependent protein kinase became apparent. 12-O-Tetradecanoylphorbol-13-acetate, an activator of PKC, inhibited DNA fragmentation by all four NO donors, whereas PKC inhibitors such as staurosporine and calphostin C sensitized macrophages to apoptosis induced by SNP and GSNO. Lipophilic cAMP analogues suppressed SNP-, SIN-1, and SNAP-induced DNA fragmentation. Thus, our study suggests the existence of specific down-modulatory mechanisms related to NO-induced apoptotic DNA fragmentation.
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PMID:Nitric oxide-induced apoptosis in RAW 264.7 macrophages is antagonized by protein kinase C- and protein kinase A-activating compounds. 772 36

In order to assess similarities between the atherogenic and the carcinogenic processes, we investigated whether the p53 tumor suppressor gene, the most commonly altered gene in human cancer, may be also involved in human atherosclerotic lesions. The medium layers of abdominal aorta fragments taken at surgery from 32 patients were subjected to immunohistochemical analysis, using either monoclonal (Pab 1801) or polyclonal (CM-1) antibodies, and to molecular analysis by the PCR-based denaturing gradient gel electrophoresis approach. The results obtained indicated that p53 mutations are not involved in the pathogenesis of atherosclerotic lesions, and that no accumulation of the wild-type protein occurs in smooth muscle cells of these lesions. A polymorphism characterized by an AT to GC transition at codon 213 (CGA --> CGG) causing no aminoacid substitution (Arg --> Arg) was detected in the 10.5% of the examined patients. Our negative findings do not support the hypothesis that the atherosclerotic plaques may be pathogenetically akin to benign tumors yet they are not in contrast with this theory, since in most cases p53 is involved in advanced stages of the carcinogenesis process.
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PMID:Cancer biomarkers in human atherosclerotic lesions: no evidence of p53 involvement. 774 17

The tumor suppressor gene p53 plays a critical role in the cellular response to genetic damage caused by radiation. In addition, mutations in this gene are often encountered in cells in lung tumors resected from uranium miners whose exposure to radon daughters exceeded 450 working level months. However, most of these miners also smoked tobacco products. Thus whether this gene is of specific importance in lung cancer is unclear. In this study, aberrations in the p53 gene were investigated using an immunohistochemical assay on 38 lung tumors (26 squamous cell carcinomas, 9 adenocarcinomas and 3 adenosquamous carcinomas) from rats that had inhaled 239PuO2 aerosols. Only 2 tumors exhibited detectable levels of staining of p53 products; both were large, well-differentiated squamous cell carcinomas that had invaded the pleural cavity or mediastinum. Direct DNA sequence analysis was used to characterize the mutations in these two tumors, and both exhibited G-->A transition mutations. One tumor was mutated in the first position of codon 283, resulting in a lysine for glutamine substitution; the other tumor was mutated at the second position of codon 280, resulting in a histidine to arginine substitution. No alterations in exons 5-7 of the p53 gene were found in a representative sample of tumors that did not exhibit elevated levels of the protein by immunohistochemistry. Further, no detectable polymorphisms or deletions were observed within the rat p53 gene after Southern blot analysis of 18 randomly selected 239Pu-induced tumors. These results suggest that p53 mutations are relatively unimportant in the development of lung tumors induced in the rat by high-linear energy transfer radiation.
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PMID:p53 alterations in plutonium-induced F344 rat lung tumors. 776 75

Human tobacco-related cancers show a high frequency of G-to-T transversions in several mutation hot-spot regions of the p53 tumor suppressor gene, probably the result of specific mutagens in tobacco smoke, most notably benzo[a]pyrene. To gain insight into the mechanism of formation of these G-to-T transversions in tobacco-associated carcinogenesis, we studied the mutagenesis of p53 codons 247-250 by benzo[a]pyrene in human hepatocellular carcinoma cells by restriction fragment length polymorphism-polymerase chain reaction genotypic analysis. Benzo[a]pyrene preferentially induced G-to-T transversion in the second and third positions of codon 248 and C-to-A transversion in the first position of codon 248. However, benzo[a]pyrene did not induce base-pair changes in codon 249, which is a mutational hot-spot in aflatoxin-related hepatocarcinogenesis, in which predominantly G-to-T transversion in the third position of codon 249 is observed. The benzo[a]pyrene-induced G-to-T transversion in the middle position of codon 248, in which arginine is changed into leucine, is frequently observed in tumors of the lung. The other two benzo[a]pyrene-induced base-pair changes in codon 248, namely the C-to-A transversion in the first position and G-to-T transversion in the third position, do not lead to a change in the amino-acid composition of the p53 protein. These mutations are silent and therefore are not selected in tumors. It follows that benzo[a]pyrene-induced mutability on the DNA level in p53 codons 247-250 correlates well with the type of mutation found in tumors of the lung. Therefore, our results support the hypothesis that benzo[a]pyrene is the etiological agent in tobacco-related cancers.
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PMID:Benzo[a]pyrene-induced mutagenesis of p53 hot-spot codons 248 and 249 in human hepatocytes. 776 6

p53 expression was studied immunohistochemically to identify a precursor lesion of basal cell carcinoma (BCC) in the epidermis adjacent to BCC. With two different anti-p53 antibodies of CM1 and DO7, p53 expression was frequently detected in the epidermis adjacent to BCCs arising on the face and in the normal epidermis with usual sun exposure. In the epidermis adjacent to BCC, stained cells were occasionally clustered in a small area, but no cluster was found in the normal epidermis with usual sun exposure. The expression was less frequent in the normal epidermis with rare sun exposure. Ten cases of normal skin with usual sun exposure, showing CM1 staining in the epidermis, were screened for p53 gene mutations with polymerase chain reaction-single-strand conformation polymorphism analysis using DNAs obtained from the epidermis. No mutation was detected in exons 2 to 10 of the p53 gene in these 10 cases. The epidermis flanking three BCCs that was stained with CM1, on the other hand, carried a missense mutation of C to G transversion at a dipyrimidine site of codon 249. This alteration replaced arginine with threonine. The mutation of codon 249 was not detected in the three BCCs. Our results first suggest that ultraviolet light irradiating the skin in a daily life induces p53 accumulation in the epidermis and secondly that the frequent clonal expansion of p53 mutant cells occurs in the epidermis adjacent to BCCs. This clonal expansion of mutant p53 may provide a molecular basis for high risk of developing subsequent new skin cancers in patients with BCC.
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PMID:Frequent p53 accumulation in the chronically sun-exposed epidermis and clonal expansion of p53 mutant cells in the epidermis adjacent to basal cell carcinoma. 776 52

A group of 20 CLL patients selected for advanced clinical stage p53 mutations were analysed by single-strand conformational polymorphism (SSCP) following PCR amplification of exons 5-9. In two patients abnormal SSCP of either exon 5 or exon 8 was found and PCR products were analysed by direct sequencing. A hemizygous or homozygous 12bp deletion at codon 135 and 3bp heterozygous deletion at codon 264 were detected; also, in the latter sample a heterozygous mutation at codon 282 (Arg to Gln) was found. To our knowledge, this is the first report of p53 deletions in B-CLL. The two patients were elderly, and both had a rapidly progressive disease in the absence of unfavourable cytogenic abnormalities. These findings support a role for p53 alterations in the clinical course of some B-CLL patients.
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PMID:Novel small deletions of the p53 gene in late-stage B-cell chronic lymphocytic leukaemia. 781 13

WAF1/CIP1, a gene up-regulated by p53 encodes an inhibitor of cyclin-dependent kinases. Induction of WAF1/CIP1 in cells with intact p53 is believed to be instrumental in cell cycle arrest and apoptosis caused by DNA damage. In a model system, WAF1/CIP1 has been shown to have tumor suppressive activity. It is not known however whether WAF1/CIP1 is mutated in human primary tumors. Cells from colorectal cancer have been shown to acquire a series of genetic alterations, including frequent p53 mutations. Thus colorectal tumors, particularly those without identified p53 mutations, are good candidate to search for putative WAF1/CIP1 mutations. DNA extracted from 45 tumors, (including 28 tumors for which p53 mutations had previously been searched for and not found) were PCR amplified for exon 2 of WAF1/CIP1. A search for point mutations was performed in each amplified product using a denaturing gradient gel electrophoresis (DGGE) technique which enables the efficient screening of codons 9 to 139 (i.e. 80% of the WAF1/CIP1 coding sequence). Two different DNA variants were identified and shown to be present in constitutional DNAs of the corresponding patients. The first variant, a C to A transversion at codon 31, changes a serine for an arginine and was detected in eight tumors (18% of the cases). The second variant, detected in a single case (2%) is a silent A to T transversion at the third base of codon 91. DNA extracted from 70 unrelated members from the Centre d'Etude du Polymorphisme Humain (CEPH) was screened for these polymorphisms. The ser/arg polymorphism of codon 31 was detected in seven cases (10%) thus suggesting that it is not associated with a marked colorectal cancer predisposition. The polymorphism on codon 91 was not detected. Two additional variants (arginine to histidine at position 67 and threonine to methionine at position 80) were observed once each in the CEPH family members. Somatic mutation of the WAF1/CIP1 gene was not observed, indicating that, unless there are hot spots for mutations outside the screened region, this gene is not a frequent site of point mutation in colorectal cancer.
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PMID:Polymorphisms and probable lack of mutation in the WAF1-CIP1 gene in colorectal cancer. 784 85

The p53 encodes a cellular phosphoprotein that has been association with both neoplastic transformation and the control of cellular growth. Recent studies have reported that p53 also acts as a transcriptional regulator. We have studied transactivational properties of human wild-type and mutant p53 proteins representing 4 major mutational hotspots (codons 141, 175, 248, 273) as well as a double mutant Tyr141/His273 and a p53 with the transcriptional activating region removed (pcDC2). Transactivation by p53 was shown with a p53 concensus binding sequence controlled CAT reporter gene, and activity was assayed after co-transfection of the reporter with either wild-type or mutant p53 expression constructs. Wild-type p53 as well as one mutant p53 [(mutation of arginine to histidine at codon 273 (His 273)], had strong transactivating activity, but all other mutant p53s were inactive in transcriptional activation, including the double mutant Tyr141/His273 suggesting that the Tyr141 mutation was dominant over the His273 mutation in the same protein. Moreover, when mutant p53 (Tyr141, His175, Trp248, or Tyr141/His273) was cotransfected with either wild-type p53 or mutant His273 p53, these mutants inhibited the transactivation of coexpressed wild-type p53. The p53 vector (pcDC2), which contains p53 oligomerization sequences, but not the transactivational domain, markedly inhibited wild-type p53 transactivational activity. Each of the mutant p53s similarly inhibited the transactivation of His273 p53. Therefore, with the exception of His273, each of the other mutant p53 were unable to transactivate and each behaved in a dominant negative fashion.
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PMID:Mutant p53 proteins behave in a dominant, negative fashion in vivo. 784 18


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