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)

Genomic DNA was extracted from archival pathology specimens comprising 10 squamous and 14 adenocarcinomas, including 7 with Barrett's epithelium adjacent to tumor, and corresponding normal esophagus from the resection margin. The polymerase chain reaction was used to amplify selected exons of p53 which were analyzed for mutations using single-strand conformation polymorphism analysis. Mutations were localized to exon 8 for 1 adenocarcinoma and to exon 5 for 1 squamous tumor and 4 of 7 Barrett's specimens. Sequencing confirmed mutations at codons 273 (CGT----CAT; adenocarcinoma) and 176 (TGC----TTC; squamous) and in Barrett's epithelium at codons 152 (CCG----CTG), 155 (ACC----GCC) and 175 (CGC----CAC). Specimens of Barrett's epithelium from separate sites had identical p53 mutations suggesting a clonal origin. Cancers arising in mutant epithelium did not have mutations corresponding to those found in the Barrett's specimens suggesting that other events are required for tumorigenesis.
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PMID:p53 gene mutations in Barrett's epithelium and esophageal cancer. 186 73

Using PCR-SSCP and immunohistochemical analyses, mutations of the p53 tumor suppressor gene were examined in 5 cases of primary malignant lymphoma of the brain (diffuse large cell type). By PCR-SSCP and nucleotide analyses, p53 gene mutations were seen in 2 of the 5 cases. The mutation in one case was a missense G: C-T:A transversion at codon 176 (TGC-TTC; Cys-Phe) which was located in the highly conserved domains and adjoined a previously proposed hot spot codon (codon 175) in various tumors. p53 immunoreactivity was also shown in this case. The mutation in another case was a nonsense G:C-A:T transition at codon 52 (TGG-TGA; Trp-stop codon) leading to a truncated p53 peptide. Thus, these mutations may have actually given rise to serious structural and functional alterations of the p53 protein. These findings suggested that the p53 gene mutation was related with oncogenesis in the primary malignant lymphoma of the brain.
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PMID:Primary malignant lymphoma of the brain: demonstration of the p53 gene mutations by PCR-SSCP analysis and immunohistochemistry. 789 17

We have mutagenized human p53 expressed in yeast and selected two mutants, 121F and 123A, which activate transcription from one, rather than the normal two, copies of the consensus p53 DNA binding sequence. Both mutants have a 6-fold increase in affinity for a single copy of the sequence GGG CATG CCC. The 121F mutant has a decrease, and the 123A mutant an increase, in the affinity for the sequence GAA CATG TTC. This genetic and biochemical evidence supports the crystallographic finding that amino acid 120 contacts guanine in the major groove at the second position in the consensus. The major p53 binding site in the p21WAF1/CIP1 promoter resembles the GAA CATG TTC form of the consensus. Compared with wild type p53, the 121F mutant has a 7-fold lower affinity for the p21WAF1/CIP1 site in vitro, and the 121F mutant is defective in p21 induction in vivo. Mutants with subtly altered sequence specificity may facilitate dissection of downstream pathways activated by p53.
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PMID:Mutation of conserved domain II alters the sequence specificity of DNA binding by the p53 protein. 795 5

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

We have investigated the frequency of p53 gene mutations in Ewing's sarcoma (ES) and neuroblastoma (NB) by using polymerase chain reaction-single strand conformation polymorphism analysis for genomic DNA or complementary DNA generated from total RNA. Mutations of the p53 gene were found in six of seven ES cell lines: a missense mutation of TGC (Cys)-->TAC (Try) at codon 141 in one, a missense mutation of CGT (Arg)-->TGT (Cys) at codon 273 in one, a missense mutation of TGC (Cys)-->TTC (Phe) at codon 176 in three, and one base deletion of CGC-->CG at codon 283 in one. Further analysis of 14 ES and related primary tumors showed mutations of the p53 gene in only two: one base insertion of CCG-->CCCG at codon 152 in one and a missense mutation of GGC (Gly)-->GTC (Val) at codon 154 in the other. Both of the two tumors were obtained from patients with an advanced stage disease. Three of the eight ESs with mutations of the p53 gene showed the same missense mutation at codon 176, suggesting the mutational hot spot of the p53 gene in ESs. In contrast to ES, none of 6 NB cell lines or 48 NB tumors including advanced-stage ones with or without N-myc amplification showed any aberration of the p53 gene. Our findings suggest that mutations of the p53 gene in ES might represent late genetic events related to tumor progression, and that aberrations of the p53 gene might not be involved in the development or the progression of NB.
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PMID:Mutations of the p53 gene are involved in Ewing's sarcomas but not in neuroblastomas. 822 63

Non-familial human adrenocortical adenomas and carcinomas were screened for mutations in exons 5-8 of the p53 tumor suppressor gene by single-strand-conformation-polymorphism (SSCP) analysis, followed by direct sequencing of PCR-amplified DNA. Point mutations in codons 12, 13 and 61 in H-ras, K-ras and N-ras proto-oncogenes were similarly assessed by direct DNA sequencing. Three out of 15 primary adrenocortical carcinomas (20%) contained a mis-sense point mutation in the conserved regions (exons 5 and 8) of the p53 gene. Mutations were located in codon 157 (GTC-->TTC; Val-->Phe), codon 163 (TAC-->AAC; Tyr-->Asn), and codon 273 (CGT-->TGT; Arg-->Cys). The mutation in codon 157 was detected in the primary tumor as well as in brain and lymph-node metastases. Among 18 adrenocortical adenomas, there was only a single non-miscoding mutation in codon 295 (CCT-->CCC; Pro-->Pro). These data suggest that mutational inactivation of the p53 gene occurs in a minority (20%) of sporadic adrenocortical carcinomas and that these mutations constitute a late event in the multi-step process of malignant transformation. No ras mutations were detected in any of these tumors, suggesting that these genes are not involved in the development of tumors originating from the adrenal cortex.
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PMID:p53 mutations in sporadic adrenocortical tumors. 850 16

Management of Transitional Cell Carcinoma (TCC) of the bladder depends on clinicopathological parameters at initial presentation. These criteria are insufficient predictors because of tumor heteterogeneity. Progress in tumor biology suggest that molecular markers may be used to dismember bladder cancer according to their biological behavior. Evidences have accumulated that cancer result from accumulation of molecular defect specially on tumor suppressor genes. In this respect we studied by mean of immunohistochemistry the prognostic value of p53 nuclear overexpression using monoclonal antibody P1801. The study was performed on 114 TTC and 13 normal bladders. Nuclear straining was quantified using an eye piece reticule at magnification 400x. Scoring was determined counting 500 nuclei in 3 to 5 arbitrary fields. Results between stage, grade and percentage of stained nuclei are as follow: TA 0,92-T1 0,144-T2 0,354-T4 0,622-G1 0,105-G2 0,212-G3 0,406. Comparison of mean nuclear straining between group with and without progression indicates a threshold of 16% for p53 nuclear overexpression. Using this limit there is a significant progression free survival rate for the all group (p < 0,0001) and for the group of superficial tumors (p = 0,0007). Multivariate analysis using stepvise logistic regression indicate a p53 prognostic value independent from stage and grade (OR 23,4). This result indicates that p53 overexpression which can be determined on routine preparation has a strong prognostic value and a certain clinical utility.
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PMID:[Evaluations of protein p53 overexpression in cancer of the bladder: prognostic value]. 897 42

Alterations in the p53 gene are frequently observed in a wide variety of human cancers. To elucidate the role of p53 in tumorigenesis of the dog, we analyzed nine mammary tumor cell lines, and the primary or metastatic tumors used for their establishment, for the presence of genomic p53 abnormalities. Possible genomic rearrangements were analyzed by Southern blotting using a canine cDNA probe. More subtle alterations were identified by single strand conformation polymorphism (SSCP) analysis for which we partially characterized the canine p53 gene (codon 109-388 as compared to the human gene). The presence of mutations in SSCP fragments with altered mobility was confirmed by DNA sequencing. Three of the nine cell lines showed a mutated p53 gene. All were missense mutations accompanied by loss of the wild type allele. The point mutations, at codon 176 (TGC * TTC), 236 (TAC * AAC) and 245 (GGC * GCC), were all located in one of the four regions that are frequently affected in human cancers. Analysis of the DNA extracted from the tumors of origin demonstrated the presence of two of these point mutations. These findings indicate the involvement of the p53 gene in the genesis of canine tumors in a way comparable to that of human tumors.
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PMID:P53 mutations in mammary tumor cell lines and corresponding tumor tissues in the dog. 904 50

Topotecan, a camptothecin analogue, is a specific inhibitor of topoisomerase I approved for use in the treatment of patients with refractory ovarian carcinoma. The drug's mechanism of action suggests a potential efficacy of drug combinations incorporating DNA-damaging agents. In an attempt better to define a rational basis for drug combination we examined the effect of topotecan on the cytotoxicity and antitumor activity of cisplatin in an ovarian carcinoma system growing in vitro and in vivo as a tumor xenograft. The in vitro cell system included a cisplatin-sensitive cell line, IGROV-1, and a cisplatin-resistant subline, IGROV-1/Pt0.5, which is characterized by p53 mutation and loss of normal function of the wild-type gene of the parental cell line. This cell system was chosen since the cell sensitivity to DNA-damaging agents appears to be dependent on p53 gene status. Cytotoxicity was assessed by the growth inhibition assay using different schedules: (a) a 1-h period of cisplatin exposure followed by a 24-h topotecan treatment and (b) a 1-h period of simultaneous exposure to cisplatin and topotecan. In the case of the sequential schedule, an additive interaction was observed in IGROV-1 and IGROV-1/Pt0.5 cells. When the simultaneous schedule was used, a synergistic interaction, more evident for the cisplatin-sensitive cells, was found. On the basis of these observations at a cellular level, the effect of concomitant administration of the two drugs (i.e., the most favorable schedule) was studied in the IGROV-1 tumor xenograft, which is moderately responsive to cisplatin and topotecan. Suboptimal doses of each drug (with a low dose of topotecan, 5.1 mg/kg) achieved an antitumor effect comparable with or superior to that of the optimal dose of a single treatment (tumor weight inhibition, 60%), thus indicating a pharmacological advantage of the combination over the single treatment. However, an increase in the topotecan dose (7.1 mg/kg) was associated with an evident increase in the toxicity of the combination, thereby suggesting that the drug interaction was not tumor-specific. Although the molecular basis of the drug interaction is not clear, it is likely that inhibition of topoisomerase I affects the ability of cells to repair cisplatin adducts. Such findings may have pharmacological implications since they suggest the potential clinical interest of topoisomerase I inhibitors in combination with cisplatin.
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PMID:In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. 952 34


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