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)

Recent studies have shown that inactivation of tumor suppressor p53 gene is a key point in the development of human carcinomas and that normal p53 protein acts as a "molecular policeman" monitoring the integrity of the genome. In the present study, a series of 22 primary human salivary gland carcinomas were examined for alterations and expression of the p53 gene by a combined molecular and immunohistochemical approach, polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP), direct gene sequencing and p53 protein immunostaining. In addition, in order to identify correlations between p53 abnormalities and genetic instability, DNA aneuploidy and tumor growth characteristics were analyzed by cytofluorometry and the AgNOR technique. Seven of the 22 cases displayed nuclear p53 overexpression as revealed by immunostaining with p53 monoclonal antibody (Do-7), and 2 of these 7 cases were associated with the presence of point mutations [codon 140: ACC (Thr)-->ATC (Ile), codon 175: CGC (Arg)-->CAC (His)] of the p53 gene. Twelve of the 22 cases were aneuploid on the DNA histogram, and this phenomenon was statistically correlated with the 7 cases exhibiting p53 nuclear accumulation. AgNOR staining, on the other hand, was not statistically correlated with p53 abnormalities. These findings support the view that abnormal nuclear accumulation of the p53 protein is correlated with genetic instability of human salivary gland carcinoma cells.
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PMID:[p53 abnormality in salivary gland carcinoma and its relation to tumor DNA aneuploidy and AgNOR]. 786

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. A considerable number of environmentally induced, cancer-related p53 mutations in human tumors have been found in a highly conserved proline-rich sequence of the p53 protein encompassed by amino acid residues 147-158. Using conformational energy analysis based on ECEPP (Empirical Conformational Energy for Peptides Program), we have determined the low-energy three-dimensional structures for this dodecapeptide sequence for the human wild-type p53 protein and three environmentally induced, cancer-related mutant p53 proteins with His-151, Ser-152, and Val-154, respectively. The results suggest that the wild-type sequence adopts a well-defined low-energy conformation and that the mutant peptides adopt well-defined conformations that are distinctly different from the conformation of the wild-type peptide. These results are consistent with experimental conformational studies demonstrating altered detectability of antigenic epitopes in wild-type and mutant p53 proteins. These results suggest that the oncogenic effects of these environmentally induced, cancer-related, mutant p53 proteins may be mediated by distinct local conformational changes in the protein.
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PMID:Conformational effects of environmentally induced, cancer-related mutations in the p53 protein. 793 52

Relatively little progress has been made in understanding the nature of the Reed-Sternberg (RS) cell and its morphologic variants in Hodgkin disease (HD). This is primarily due to the fact that RS cells represent a minute subpopulation within HD lesions. To investigate the clonal origin of RS cells and variants, we studied 27 HD lesions obtained from 11 patients. Using an image analyzer (CAS 200) we were able to demonstrate that CD30-positive RS cells are clonal elements with unique and individualized DNA profiles and that the DNA content of any given patient RS cell population is constant over time and in different pathologic sites. Using 1, 9, 11, and X alpha satellite chromosome probes and interphase cytogenetics, we also demonstrated that RS cells obtained from different tissue samples of the same patient have a unique and often abnormal chromosomal pattern. To definitively prove the hypothesis that CD30-positive RS cells are clonal elements, we investigated the presence of point mutations within p53 gene exons 5 through 9 and found that only a single patient possessed a nonsense p53 somatic point mutation (Arg to His). This same mutation could be identified in all of his available biopsies. Altogether, these findings demonstrate that RS cells and variants in HD are clonal and represent the neoplastic elements of this entity.
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PMID:The Reed-Sternberg cells of Hodgkin disease are clonal. 793 2

We studied the occurrence of a p53 mutation along passages stored as frozen vials during establishment of a nontumorigenic human mammary epithelial cell line HMT-3522. Mutations were identified by a PCR-SSCP approach using DNA as a template. The mutation, a nonconservative nucleotide substitution at codon 179 changing a histidine into an asparagine, appeared between passages 51 and 63 and was concommitant to a change in growth conditions. Cells were no longer grown on collagen coat and cell growth was not responsive to insulin, transferrin, or hydrocortisone anymore. To assess if the mutation was an early or a late event during cell line evolution we put a vial of cells frozen at passage 30 back into culture and tested for the appearance of a p53 mutation along newly produced passages. The same mutation (His to Asp at codon 179), as previously identified, reemerged between passages 48 and 52, thus indicating that the mutation was preexisting in passage 30 and gradually selected out because of the growth advantage it conferred. In order to gain in sensitivity we used a RFLP approach on PCR fragments which allowed us to detect the mutation as early as passage 44. Hence it took 14 passages (approx 50 cell doublings) for the mutated cells to become detectable and another 9 passages (33 generations) to overgrow the wild-type component of the population. We calculated that the mutated cells acquired a growth advantage which allowed them to cycle 1.2 +/- 0.05 faster than wild type. Computer simulations were consistent with the mutation appearing at passage 20.
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PMID:Gradual selection of a cellular clone presenting a mutation at codon 179 of the p53 gene during establishment of the immortalized human breast epithelial cell line HMT-3522. 798 76

Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women. In rats, TAM is a strong liver carcinogen which induces the formation of liver DNA adducts. The DNA of 24 hepatocarcinomas (HCCs) collected at necropsy from individual female Sprague-Dawley rats that were given 22.6 mg/kg TAM daily for 12 months was studied for the presence of mutations in exons 5-9 of the p53 gene by single-strand conformation polymorphism and DNA sequencing analysis. The sequences of introns 5-8 of the rat p53 gene were determined in order to design primers homologous to regions located in these introns. p53 mutations were found in 50% (12 of 24) of the HCCs. These mutations were all specifically clustered in two sites, codons 231 (exon 6-7) and 294 (exon 8). Nine HCCs contained a transition from adenine to guanine in the second base of codon 231 (CAC to CGC), which resulted in a histidine to arginine amino acid substitution; 4 HCCs contained a nonmiscoding transition from cytosine to thymidine in the third base of codon 294 (TGC to TGT; cysteine to cysteine). One HCC contained both mutations. The present report supports previous observations on the genotoxicity of TAM in rodents and raises concerns about its use as a chemopreventive agent against breast cancer in women.
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PMID:Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen. 803 8

We have analysed the p53 status in non-progressive and progressive chronic B-cell leukemia (B-CLL) by ELISA, immunoprecipitation, FACS and cDNA sequencing in relation to in vitro proliferation in response to Staphylococcus aureus strain Cowan I (SAC) and IL-2. In FACS, cells from progressive leukaemia were found to over-express p53 with a conformation recognized by PAB240. In a PAb240-based ELISA, 60% of progressive B-CLL were positive. DNA sequencing of p53 exons 5 to 9 revealed a codon 179 His to Gln change in one of the ELISA-positive, progressive B-CLL but failed to reveal any mutations in 4 other ELISA-positive, progressive B-CLL. Among progressive B-CLL populations, 10/14 responded by proliferation in vitro to SAC/IL-2. In non-progressive cells, low levels of p53 were found by FACS, none was positive in the PAb240 ELISA and only one case showed a weak proliferative response to SAC/IL-2. Low p53 expression was also seen in different types of normal B cells, resting and activated, and in EBV-transformed B-cell lines, in contrast to the high expression observed in Burkitt lymphoma cell lines with verified p53 mutations. We conclude that progressive B-CLL is characterized by aberrant p53 expression which may be a significant prognostic factor.
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PMID:Progressive B-cell chronic lymphocytic leukaemia frequently exhibits aberrant p53 expression. 805 42

To clarify gene alterations in functional human adrenal tumors, we performed molecular analysis for p53 abnormalities in 23 cases with adrenal neoplasms. The immunohistochemical study with anti-p53 monoclonal antibody pAb1801 demonstrated that 10 of 23 (43.5%) cases overexpressed p53 protein in the tumor cells. Using a polymerase chain reaction-single strand conformation polymorphism study, 5 of 6 (83.3%) pheochromocytoma tissues (1 malignant and 5 benign) and 11 of 15 (73.3%) adrenocortical adenomas (2 with Cushing's syndrome and 13 with primary aldosteronism, all benign) showed an apparent electrophoretic mobility shift between the tumor and its paired adjacent normal adrenal tissue. Such differences were detected in exon 4 (12 cases), exon 5 (2 cases), and exon 7 (3 cases). The types of these mutations in exon 4 were a substitution from threonine (ACC) to isoleucine (ATC) at codon 102 in 5 cases, from glutamine (CAG) to histidine (CAC) at codon 104 in 1 case, from glycine (GGG) to alanine (CGG) at codon 117 in 1 case, from glutamate (GAG) to glutamine (CAG) at codon 68 in 1 case, and single base changes resulting in a premature stop codon at codon 100 in 2 cases. A 2-basepair deletion at codon 175 in exon 5 resulting in a frame shift was identified in 1 case. A single point mutation was identified, resulting in the substitution of glutamine (CAG) for arginine (CGG) at codon 248 of exon 7 in 1 case. A single basepair deletion at codon 249 resulted in a frame shift in 2 cases. There was 1 case with malignant pheochromocytoma that combined a single point mutation in exon 4 and a single base deletion in exon 7. Only 2 of 23 cases showed a loss of a normal allele encoding in the p53 gene. Northern blot analysis with 1.8-kilobase p53 cDNA revealed that p53 mRNA was overexpressed in 6 cases. Our results indicate that high frequencies of p53 gene mutation, especially in exon 4, exist in functional adrenal tumors. As p53 protein is a regulator of guanine nucleotide synthesis, the loss of normal inhibitory regulation by the p53 mutation would serve to increase the availability of GTP for the transduction of signals essential for increased cell growth and hormone expression in the adrenal tumors. These findings suggest that the p53 gene mutation may play a role in the tumorigenesis of benign and functional human adrenal tumors.
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PMID:Mutations of the p53 gene in human functional adrenal neoplasms. 810 38

Overexpression and point mutation of the p53 protein/gene was investigated in a series of chondrosarcoma by an immunohistochemical approach, and direct sequencing of the genomic DNA, respectively. In 2 of the 16 cases studied, both of which were high grade chondrosarcomas (grade III), immunodetectable p53 was identified. Histologically, one was ordinary type and the other a clear cell variant. However, no positivity was observed in the other cases including nine of low grade, ordinary type, three of low grade, clear cell type, and two of extraskeletal myxoid chondrosarcoma. Direct sequencing, following polymerase chain reaction amplification of exons 5-9 of the p53 gene in 14 cases, in which fresh materials were available, successfully demonstrated base substitution mutations in only two cases with detectable p53 overexpression on immunohistochemistry. Their details were GTC (valine) to TTC (phenylalanine) at codon 157 in exon 5, and CGT (arginine) to CAT (histidine) at codon 273 in exon 8. No mutation was detected in the other 12 cases which were negative for p53 immunostaining. These findings strongly suggest that p53 mutation plays a crucial role in the biologically aggressive subtype, and possibly in the process of tumor progression in human chondrosarcoma.
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PMID:Possible association of p53 overexpression and mutation with high-grade chondrosarcoma. 811 3

p53 tumour suppressor gene mutations were studied in 118 renal cell carcinomas using paraffin-embedded surgical material. Optimal results were obtained with analysis of exon lengths between 150 and 200 base pairs for polymerase chain reaction. Single strand conformation polymorphism and sequencing analysis revealed only two point mutations (2/118, 2%): one involving codon 135; TGC-->TTC (cysteine-->phenylalanine) and the other codon 175; CGC-->CAC (arginine-->histidine). Both of these cases were classified as granular cell subtype on microscopic observation. The data suggest that the p53 tumour suppressor gene is not related to tumour initiation, promotion, or progression of renal cell carcinomas. However, there is the possibility that granular cell type carcinomas may have a different genetic background from clear cell type renal neoplasms.
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PMID:Polymerase chain reaction-single strand conformation polymorphism analysis of the p53 gene in paraffin-embedded surgical material from human renal cell carcinomas. 818 88

DNA from tumor tissue and peripheral blood lymphocytes of primary breast cancer patients was screened for the presence of p53 mutations. In DNA from one tumor we found that the histidine codon 193 (CAT) was somatically converted to arginine (CGT). This amino acid residue is highly conserved in many species, thus suggesting that such mutation plays an important role in the loss of wt-p53 function.
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PMID:A novel p53 mutant in human breast cancer revealed by multiple SSCP analysis. 818 56


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