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

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.
 ...
PMID:Primary malignant lymphoma of the brain: demonstration of the p53 gene mutations by PCR-SSCP analysis and immunohistochemistry. 789 17

A family with an aggregation of adrenocortical carcinoma, rhabdomyosarcoma, osteosarcoma, and early onset breast cancer was referred to our laboratory. Because this aggregation was reminiscent of Li-Fraumeni syndrome, germ-line mutation of the p53 tumor suppressor gene was sought in the DNA of two affected members. The highly conserved regions spanning exons 5 to 8 of the p53 gene were screened by a previously validated denaturing gradient gel electrophoresis method. A single base pair deletion at codon 215 was detected in constitutional DNA of the two patients, and in the DNA extracted from an adrenocortical carcinoma tumor specimen of the propositus. This deletion is predicted to lead to the formation of a truncated p53 protein, a relatively rare event in Li-Fraumeni families. The spectrum of tumors observed in this family does not differ markedly from the spectrum observed in families with missense p53 mutations.
 ...
PMID:Single base pair germ-line deletion in the p53 gene in a cancer predisposed family. 803 1

The wild type p53 protein has a short half-life and cannot be detected by immunohistochemistry on tissue sections. Mutated p53, on the other hand, has a prolonged half-life and becomes detectable by this method, so that its detection by immunohistochemistry in solid tumors is almost synonymous with mutation. We assessed the value of immunocytochemical analysis of p53 protein on blood or bone marrow slides in the detection of p53 mutation in hematological malignancies, by comparison with single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene. One hundred and twenty eight patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), myelodysplastic syndromes (MDS), or chronic lymphocytic leukemia (CLL) were studied by both methods. Immunocytochemistry showed detectable levels of intracellular p53 in 19 cases (including 2/19 AML, 2/21 ALL, 11/48 MDS, 4/40 CLL). Staining by p53 antibodies was restricted to the nucleus of blasts in AML, ALL, and MDS, and of lymphocytes in CLL. In 16 of the 19 cases, SSCP analysis, followed by direct sequencing, showed a p53 missense mutation in exons 4 to 8 of the gene. In the remaining three cases, where the number of cells stained by p53 antibodies was small, no p53 mutation could be detected. On the other hand, SSCP and sequence analysis identified a p53 mutation in two patients who had negative immunocytochemical findings. Both cases had a nonsense mutation, presumably leading to reduced levels of truncated p53. Thus, overall, immunocytochemistry and SSCP gave concordant results in 123 of the 128 (96%) patients analyzed. Our findings show that immunocytochemistry on blood and bone marrow smears is a sensitive method of p53 mutation detection in hematological malignancies, except in the rare patients with chain-terminating mutations. Positive immunocytochemistry is found in some patients with normal SSCP findings, and could correspond to overexpression of a non-mutated p53, but also to p53 mutation in a minor proportion of the malignant cells, undetectable by SSCP.
 ...
PMID:Detection of p53 mutations in hematological malignancies: comparison between immunocytochemistry and DNA analysis. 805 71

Using a set of overlapping peptides of the human p53 protein, we analysed the epitopes recognized by 18 monoclonal antibodies specific for human p53. We showed that most of these epitopes correspond to linear antigenic determinants which lie predominantly in the amino- or carboxy-terminus of the p53 protein. Using either truncated p53 or the set of human p53 peptides, we directly analysed the sera of animals immunized with human p53. These sera contained antibodies which also recognized the regions corresponding to the extremity of the p53 protein. These p53 regions were similar to those recognized by p53-specific antibodies present in sera of patients with cancer. Preferential recognition of these regions by antibodies specific for non conformational epitopes suggested that these regions are localized at the surface of the p53 protein as unfolded structures.
 ...
PMID:Linear antigenic sites defined by the B-cell response to human p53 are localized predominantly in the amino and carboxy-termini of the protein. 820 53

The expression of the p53 tumor suppressor gene in ten human cell lines (nine cancers and one normal) was studied using reverse transcription, polymerase chain reaction (PCR) and direct sequencing. Using P53U and P53D primers for amplifying a 371-base pair (bp) target fragment spanning exons 7-10 of p53 cDNA, normal-sized PCR products were amplified from 9 cell lines but not from the Hep3B hepatocellular carcinoma (HCC) cell line. An additional larger band (504 bp) was observed for the Molt-4 T-lymphoblastic leukemia cell line. Employing P531 and P53D primers which flank a 76-bp p53 cDNA fragment, 76 bp as well as 209 bp products were generated by PCR of Molt-4 cDNA. Direct sequencing of the 504 bp and 209 bp bands confirmed the presence of a 133 bp insertion between exons 9 and 10 in the aberrant transcript. This insertion was homologous to a 130-bp sequence within the wild-type p53 intron 9, except for 2 point mutations and 3 base insertions. Sequencing of P53U/P53D PCR products of Molt-4 genomic DNA revealed an 8 bp deletion just downstream to the 133 bp insertion, creating a novel donor splicing site within intron 9. This site, coupled with an inherent acceptor splicing site just upstream to the 133 bp insertion, suggests that the 133 bp stretch represents an alternative exon. The occurrence of a termination signal within this alternative transcript is predicted to culminate in a truncated p53 translational product. The sequences of the 371 bp PCR products of Molt-4, HT-1080, SiHa, CaSki, HeLa and MRC-5 cell lines corresponded with the wild-type p53 cDNA. G-->T transversions at the third base of codon 249 of p53 were detected in Mahlavu and PLC/PRF/5 HCC lines, while a TAC to CAC mutation at codon 234 was observed in an allele of the Raji Burkitt lymphoma line.
 ...
PMID:Alternative splicing of the p53 tumor suppressor gene in the Molt-4 T-lymphoblastic leukemia cell line. 822 26

Inactivation of the tumor suppressor function of the p53 gene is found in association with 20-40% cases of chronic myeloid leukemia (CML) in blast crisis. A common mechanism of p53 inactivation in CML is by complete deletion of one p53 allele in association with a point mutation which produces a mutant p53 protein on the remaining allele. Whether the mutant p53 protein, which is generally expressed at an elevated level, plays any role in the pathogenesis of blastic transformation or in maintaining the neoplastic proliferation, as it does in some solid tumors, is unknown. By using an antisense oligonucleotide approach, we investigated the cellular function of known abnormal forms of p53 protein, both mutant and truncated, expressed in CML cell lines. We found that the introduction of p53 antisense oligonucleotides can specifically inhibit the translation of the p53 mRNA. However, inhibiting p53 expression had no effect on cell proliferation, cell viability, and colony formation. There was no change in cell doubling time when the cells were maintained in serum-free medium (SFM) in the presence of antisense oligonucleotides compared with cells maintained in SFM alone. We conclude that the mutant or truncated p53 proteins expressed in the blast cells of CML have no growth-promoting effect and are not required for cell survival and proliferation. We further speculate that the loss of the tumor suppressor function of p53 might be the only mechanism by which p53 is involved in the transition from chronic phase to blast crisis.
 ...
PMID:The abnormal p53 proteins expressed in CML cell lines are non-functional. 823 Dec 51

p53 mutation is most likely an integral early step in the formation of a subset of human diffuse, fibrillary astrocytomas, but is not a frequent event in other studied brain tumors. In astrocytomas, p53 mutations are clustered in the conserved regions of the gene and are predominantly single base pair transitions, frequently at CpG dinucleotides. These mutations result in mutant or truncated p53 proteins that lack the transcriptional activating ability to induce G1 arrest, DNA repair, apoptosis or differentiation. On the other hand, some astrocytomas without p53 mutations may accumulate wild-type protein, perhaps as a physiological response to DNA damage or deregulated proliferation in the tumor cells. Finally, while data on the p53 gene and protein studies in human brain tumors are accumulating rapidly, the clinical significance of such data remains unclear.
 ...
PMID:The p53 gene and protein in human brain tumors. 830 15

Chromosome 17p has been shown to be an early and frequent target for loss of heterozygosity through mitotic recombination in astrocytomas. These losses are frequently accompanied by point mutations in the p53 gene of the remaining allele, resulting in loss of wild type p53 function. However, a fraction of astrocytomas retain constitutional heterozygosity and do not have p53 mutations; some of these lose wild type p53 activity through binding to the protein product of amplified mdm2 genes. To test whether loss of wild type p53 biological function is a necessary step in astrocytoma progression we analyzed p53 expression and biological function in 13 glioma cell lines. All the cell lines expressed a 2.8-kilobase p53 transcript and showed various amounts of p53 protein by immunoprecipitation, except for cell line LN-Z308 which had only a small truncated p53 mRNA and no protein expression. To test whether the p53 expressed in these cell lines was functionally wild type or mutant we transfected them with a plasmid construct harboring a chloramphenicol acetyltransferase (CAT) reporter gene under the control of transcriptional elements that are induced by wild type but not mutant p53. Four lines were shown to retain wild type p53 function. Sequencing of the p53 gene in two of these cell lines confirmed the wild type genotype. These results show that inactivation of the p53 gene is not an obligatory step in glioblastoma genesis. This suggests either that two pathways (p53 inactivation dependent or independent) may lead to a tumor group classified histologically as glioblastoma or that in some cases p53 mutations are bypassed due to the presence of mutations in downstream effector genes.
 ...
PMID:Analysis of the p53 gene and its expression in human glioblastoma cells. 830 26

We studied the structure and expression of Rb and p53 genes in six myeloid leukemia cell lines (HL-60, KBM3, K562, KBM5, EM2, KBM7) in the light of the published reports that structural abnormalities of these genes are rarely seen in leukemic cells and also a recent finding that Rb gene expression can be regulated by the p53 protein. Except for HL-60 cells which have a truncated p53 gene, none of the other cell lines revealed any gross structural abnormalities in the Rb and p53 genes. KBM3, KBM5 and EM-2 expressed lower levels of Rb mRNA than HL-60, K562 and KBM7. The amount of Rb protein was lowest in KBM3 cells and in this and two other cell lines (KBM5, KBM7) Rb was markedly hypophosphorylated compared to the other three cell lines. HL-60 and K562 did not express p53 m-RNA, while the other four cell lines all expressed high levels of mutant p53 protein. Thus even in the absence of gross structural alterations, subtle abnormalities in the expression pattern of Rb and p53 genes occur in myeloid leukemia cells.
 ...
PMID:Expression of differentially phosphorylated Rb and mutant p53 proteins in myeloid leukemia cell lines. 835 7

Loss of wild-type p53, either through deletion or mutation, has been demonstrated in most squamous cell carcinomas of the head and neck (HNSCC). Whether these mutant molecules contribute to tumor progression purely through loss of wild-type functions or by growth-promoting mechanisms, however, remains unclear. To begin to address these issues, we isolated a series of p53 cDNAs from HNSCC cell lines that contain missense or nonsense point mutations, insertions, or deletions. The ability of each of these molecules to transform NIH/3T3 cells to a malignant phenotype was assessed by stable transfection and expression under the control of a strong heterologous promoter. NIH/3T3 cells transfected with pLTR6p53, which harbors an H179L missense mutation, formed large tumors rapidly (in less than 4 wk) when transplanted to athymic mice, as did cells expressing pLTR13p53, which had undergone a V173F missense mutation and an in-frame deletion of 48 bp between codons 208 and 223. Cells transfected with pLTR17p53, predicted from the nucleotide sequence to encode a severely truncated p53 corresponding to the N-terminal 56 amino acids, also formed tumors. Cells transfected with pLTR15p53, which was predicted to encode a less severely truncated molecule, formed much smaller tumors and at lower frequencies. NIH/3T3 cells transfected with pLTR12p53 (exon 7 splice donor mutant), pLTRwtp53 (wild-type p53), or vector alone failed to form tumors for up to 2 mo after transplantation. pLTR6p53-transfected cells exhibited a highly malignant phenotype with invasion of regional lymph nodes, mediastinal and lung metastases, invasion of the abdominal wall, and dissemination throughout the peritoneal cavity. Histological assessment of the tumors revealed intensely vascularized fibrosarcomas with numerous cellular atypia, including frequent and aberrant mitoses. Tumor explants were recultured, and northern blot analysis of cellular RNA confirmed that the expression of exogenous p53 was maintained in each case. These data indicate that different p53 mutants contribute to tumorigenesis by specific mechanisms. Furthermore, the results obtained by using the pLTR17p53 transfectants imply that some truncated molecules may overcome the effects of wild-type p53 to contribute to malignancy.
 ...
PMID:Functional characterization in vivo of mutant p53 molecules derived from squamous cell carcinomas of the head and neck. 904 83


<< Previous 1 2 3 4 5 6 7 8 Next >>