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)

Germline mutations in the p53 tumor suppressor gene are associated with the Li-Fraumeni syndrome, characterized by childhood sarcoma, leukemia and early onset breast cancer and has occasionally been found also in familial breast-ovarian cancer. Most mutations found are of missense type and located in the central region of the gene (exons 5 to 8). In the present study, a germline p53 alteration was identified in a late onset breast cancer family (kindred Lund 5; mean age 58 years) using single stranded conformation polymorphism and sequence analysis. The mutation (a CCG to CTG transition) at codon 82 in exon 4, resulting in a proline to leucine substitution, has not previously been reported and was not present in a control set of 60 healthy individuals. Three of five woman with breast cancer (45, 57 and 65 years) were carriers of the alteration. Loss of heterozygosity at the p53 locus was not seen in the primary tumors of these women, but appeared as a partial loss of the wildtype allele in subsequent recurrent lesions of two gene carriers. The family manifested no linkage to the p53 gene (a two-point LOD-score of -0.41), and has previously also been excluded for linkage to the BRCA1 and BRCA2 loci, as well as being carrier of a BRCA1 germline mutation. Although it seems unlikely that the p53 germline mutation is the major cause of disease predisposition in Lund 5, the data suggest that some p53 alteration may confer a subtle influence on breast cancer development and progression.
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PMID:A novel p53 germline alteration identified in a late onset breast cancer kindred. 871 Mar 80

The p53 gene regulates the G1 cell cycle checkpoint in response to DNA damage. A primary murine mesothelial cell line (D9) spontaneously acquired a point mutation at codon 135 in exon 5 of the p53 gene, resulting in substitution of alanine for proline; early passage D9 cells expressed wild-type p53. The growth rate of late passage D9 cells that acquired the p53 mutation was increased compared to that of early passage cells; however, this mutation was not sufficient to confer tumorigenicity to this cell line. Mammalian cells that express wild-type p53 show a transient arrest in G1 after exposure to ionizing radiation. Early passage D9 cells showed a G1 arrest following ionizing radiation, while late passage D9 cells arrested in G2 or mitosis. The clastogenic effects of ionizing radiation can be demonstrated by the cytokinesis-arrested micronucleus assay. Following treatment with cytochalasin B to arrest cytokinesis, ionizing radiation induced micronuclei in 50% of late passage D9 cells compared to 15% of early passage cells. After exposure to 15 micrograms/cm2 of crocidolite asbestos fibers, 18% of late passage cells had micronuclei compared to 4% of early passage cells. It is hypothesized that loss of the G1 cell cycle checkpoint contributes to genetic instability in murine mesothelial cells.
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PMID:Spontaneous p53 mutation in murine mesothelial cells: increased sensitivity to DNA damage induced by asbestos and ionizing radiation. 891 99

Activation of the p53 tumor suppressor protein has been demonstrated to block cell growth by inducing either a transient cell cycle arrest or programmed cell death (apoptosis). Although evidence exists linking p53's function as an activator of transcription to its ability to effect cell cycle arrest, the role of this activity in the induction of apoptosis remains unclear. To gain insight into the molecular mechanisms underlying p53-mediated antiproliferative pathways, a study was initiated to explore the functions of a putative p53 signaling domain. This region of the human p53 protein is localized between amino acids 61 and 94 (out of 393) and is noteworthy in that it contains five repeats of the sequence PXXP (where P represents proline and X any amino acid). This motif has been shown to play a role in signal transduction via its SH3 domain binding activity. A p53 cDNA deletion mutant (delta pro AE), which lacks this entire proline-rich domain (deleted for amino acids 62-91), was created and characterized for a variety of p53 functions. The entire domain has been shown to be completely dispensable for transcriptional activation. On the other hand, this deletion of the p53 proline-rich domain impairs p53's ability to suppress tumor cell growth in culture. Amino acid substitution mutations at residues 22 and 23 of p53 (eliminates transcriptional activity) also impair p53-mediated inhibition of cell growth in culture. Unlike wild-type p53, the delta proAE mutant cDNA can be stably expressed in tumor derived cell lines with few immediate detrimental effects. These cells express physiologic levels of p53 protein that are induced normally in response to DNA damage, indicating that removal of the proline-rich domain does not disrupt p53's upstream regulation by DNA damage. These data indicate that, in addition to the transcriptional activation domain, the p53 proline-rich domain plays a critical role in the transmission of antiproliferative signals down-stream of the p53 protein and may link p53 to a direct signal transduction pathway.
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PMID:Identification of a novel p53 functional domain that is necessary for efficient growth suppression. 898 12

Paraffin embedded tissue of 84 oligodendrogliomas (63 primary tumours, 21 recurrences), 21 glioblastomas with oligodendroglial growth pattern (15 primaries, 6 recurrences) and 17 mixed gliomas was investigated for the presence of mutations in exons 5-9 by means of single stranded conformation polymorphism (SCCP), temperature gradient gel electrophoresis (TGGE) and direct DNA sequencing. In parallel, p53 protein accumulation was determined by means of immunohistochemistry. The percentage of mutations was found to be higher than previously reported (6 of 44 grade II oligodendrogliomas, 4 of 19 grade III oligodendrogliomas, 4 of 15 glioblastomas). In 4 cases, the mutations lead to distinct changes in the primary or secondary structure of the protein (cysteine-->tyrosine, proline-->leucine) and were associated with marked accumulation of p53 protein. A significant correlation between p53 protein accumulation and TP53 gene aberrations was found (P < 0.001), although p53 protein accumulation was detected more often than TP53 gene anomalies, indicating that factors other than TP53 gene mutation may also lead to a p53 protein accumulation in the tumour cells. A significant correlation was found for p53 protein accumulation and tumour grade but not TP53 gene mutations. In conclusion, evaluation of p53 protein accumulation reflected the clinical course of oligodendrogliomas better than the mere presence of TP53 gene mutations.
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PMID:Demonstration of p53 protein and TP53 gene mutations in oligodendrogliomas. 903 5

Multidrug resistance in MCF-7/Adr human breast cancer cells is mediated by several mechanisms including overexpression of the MDR1 gene product, P-glycoprotein and glutathione-related detoxifying enzymes. Mutations in the p53 tumor suppressor protein have been reported to play a role in the development of resistance to DNA damaging agents in several human cancer cells. In the present study we have assessed the mutational status of the p53 protein and its expression levels, degree of stability and cellular localization to investigate whether it is involved in modulating multidrug resistance in MCF-7/Adr cells compared to sensitive MCF-7 cells. As revealed by immunofluorescence microscopy using the anti-p53 mouse monoclonal antibody DO-1, wild-type p53 is sequestered in the cytoplasm of MCF-7 cells, whereas in MCF-7/Adr cells, the protein is localized in the nucleus. The sequencing of full-length p53 cDNA revealed a 21 bp deletion in its one of the four conserved regions within the conformational domain, spanning codons 126-133 at exon five, in MCF-7/Adr cells. Moreover, detection of ThaI polymorphism of codon 72 showed that MCF-7 cells predominantly express wild-type p53 with proline, while mutated p53 in MCF-7/Adr cells contains an arginine residue at codon 72. In addition, we demonstrate that the half-life of p53 in MCF-7 cells is less than 30 min while the mutated protein is more stable; its half-life is about 4 h in MCF-7/Adr cells. Thus, this study demonstrates that the deletion of codons 126-133 in p53 causes increased stability, overexpression and nuclear localization of the protein in multidrug resistant MCF-7/Adr cells, and further suggests that mutated p53 might be involved in the development of multidrug resistance in this cell line.
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PMID:Expression of the mutated p53 tumor suppressor protein and its molecular and biochemical characterization in multidrug resistant MCF-7/Adr human breast cancer cells. 905 47

Several polymorphic genes have been reported to be possibly involved in modifying lung cancer risk in smokers. The gene GSTM1 is frequently deleted in human populations, and the null genotype has been reported to be a risk factor for developing lung carcinoma. A germline polymorphism of p53 with a single-base change at codon 72 that causes an amino acid replacement of arginine (Arg; CGC) by proline (PRO; CCC) has also been reported to be associated with cancer susceptibility in a Japanese population. Both polymorphisms were genotyped by PCR in a northwestern Mediterranean healthy population (n = 147) and in a group of lung cancer patients (n = 139). The results showed that the frequency of the GSTM1 null genotype was higher in the lung cancer patients compared to the controls [odds ratio (OR), 1.57; 95% confidence interval (CI), 0.99-2.51]. The histological subtypes most clearly modified were small cell carcinoma (OR, 1.89; CI, 0.97-3.65) and adenocarcinoma (OR, 1.93; CI, 0.90-4.14). The null GSTM1 genotype was more frequent among those cancer patients who were medium/ light smokers (< or = 50 pack-years) and in those who showed an onset of the disease at a more advanced age. The study of the p53 polymorphism in the healthy population showed allele frequencies of 0.79 (Arg) and 0.21 (Pro). The frequencies found in the lung cancer patients were statistically similar. Both polymorphisms were studied together, and the relative risk of the combination null GSTM1 and Pro/Pro or Arg/Pro genotypes was calculated taking the combination of GTSM1 + together with Arq/Arg as a baseline. The OR found (1.97; CI, 1.03-3.73) suggests that the Pro allele of the p53 germline polymorphism may slightly increase the risk fo the GSTM1 null genotype among smokers.
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PMID:Glutathione-S-Transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility. 916 98

Leukemia in the soft-shell clam, Mya arenaria, is characterized by tumor cells which are detected initially in the hemolymph. This disease is much more common in clams inhabiting polluted waters, suggesting an environmental component to its pathogenesis. In this study, leukemia cells were identified using a murine monoclonal antibody, 1E10, which recognizes a leukemia-specific protein expressed by tumor cells. Mutant p53 protein was detected using a murine monoclonal antibody (PAb 240) which reacts with mutant p53. Using immunofluorescence, the reactivity of clam cells to the 1E10 antibody was evaluated along with mutant p53 protein reactivity. Reverse transcriptase-polymerase chain reactions followed by sequence analyses were utilized to examine clams with hemocytes reacting with the p53 antibody for possible p53 gene mutations. Mutant p53 protein was expressed by tumor cells from five animals with advanced disease (in which greater than 90% of cells reacted with 1E10). A C-->G transversion was detected at the end of exon 6 from two of the five animals that reacted with both the mutant p53 antibody and 1E10. This substitution changes the amino acid of this codon from proline to alanine. Overall, our results suggest that environmentally induced alterations in p53 can contribute to the pathogenesis of leukemia in soft-shell clams inhabiting polluted water and/or sediment.
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PMID:Detection of mutant p53 in clam leukemia cells. 916 98

The WW domain is a globular protein domain that is involved in mediating protein-protein interaction and that ultimately participates in various intracellular signaling events. The domain binds to polyproline ligands containing the xPPxY consensus (where x signifies any amino acid, P is proline and Y is tyrosine). One of the first WW domain-ligand links that was characterized in vitro was the WW domain of Yes-Associated Protein (YAP) and its WBP-1 ligand. To further characterize this molecular interaction, we used two independent approaches, both of which focused on the mutational analysis of the WBP-1 ligand. We screened repertoires of synthetic decamer peptides containing the xPPxY core of WBP-1 in which all ten positions were sequentially replaced with the remaining amino acids. In addition, we screened decamer repertoires with all permutations of the amino acids which individually increased the binding to the WW domain of YAP, as compared to the wild type. In a parallel approach, we used a phage-displayed combinatorial peptide library biased for the presence of two consecutive prolines to study ligand preferences for the WW domain of YAP. Interestingly, these two lines of investigation converged and yielded the core sequence PPPPYP, which is preferred by the YAP-WW domain. This sequence was found within the p53 (tumor suppressor) binding protein-2, a probable cognate or alternative ligand interacting with YAP.
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PMID:Using molecular repertoires to identify high-affinity peptide ligands of the WW domain of human and mouse YAP. 922 34

The frequency of dysfunction of the p53 tumor suppressor gene in cancer has made the concept of gene replacement therapy with wild-type p53 an attractive strategy. Codon 72 of the p53 gene is highly polymorphic with a reported arginine/proline allelotype frequency of 0.65/0.35 for Caucasians and a reversal of this ratio in African-Americans. Ovarian cancer is more common and less aggressive in Caucasians. The arginine and proline alleles have different biochemical properties. Thus, we have hypothesized that these alleles may also have different biologic properties that could make one superior to the other for gene replacement therapy. To test this hypothesis in vivo, we investigated the prevalence of each allelotype in a population of 190 Midwestern American women with ovarian cancer and 52 healthy controls without a family history of cancer. We have found that: (1) the heterozygous arginine/proline allelotype is more common in probands with borderline cancers than in probands with invasive cancers (P = .0001) or healthy controls (P = .005); (2) despite a survival advantage (P = .006), probands homozygous for the arginine allele developed ovarian cancer at an earlier age (P = .01); (3) the frequency of tumor p53 mutations was independent of the germline p53 allelotype, but (4) when a loss of heterozygosity occurred in probands with invasive disease, the proline allele was lost preferentially (P = .002), and (5) any tumor which retained a proline allele was more prone to mutation (P = .04) than a tumor without a proline allele. Our results suggest that variation in the p53 codon 72 allelotype is an example of an intermediate risk polymorphism which interacts with epigenetic factors to play a role in ovarian carcinogenesis and may differentially influence cellular DNA repair and apoptotic pathways. These findings may have important ramifications in the choice of wild-type p53 genotype for gene replacement therapy of ovarian cancer.
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PMID:The influence of the p53 codon 72 polymorphism on ovarian carcinogenesis and prognosis. 925 9

Certain polymorphic variants of H-ras-1 and p53 have been investigated for an association between inheritance and cancer risk. The results of a metaanalysis, which reviews studies of H-ras-1 rare alleles and p53 codon 72 allelic variants in breast and lung cancer, are presented. The data constituted evidence for elevated risk of both breast and lung cancer with inheritance of rare H-ras-1 alleles. Calculated population attributable risks are 0.092 and 0.037 for breast and lung cancer, respectively. The frequency of the rare H-ras-1 alleles was observed to be greater in African Americans than in Caucasians, and a specific allele (A3.5) that is common in African Americans was found only at low frequency in Caucasians. For p53 a consensus has yet to be reached. Lung cancer studies conducted in Caucasian and African-American populations have found no evidence of risk associated with the proline variant of codon 72. Two similar studies conducted in Japanese populations suggested an association between p53 genotype distribution and lung cancer risk. However, one implicates the proline allele but the other implicates the arginine allele. The frequency of the proline variant is significantly dependent on race. Frequencies have been reported for control populations of Japanese (0.347 and 0.401), Caucasian (0.295, 0.284, and 0.214), African American (0.628 and 0.527), and Mexican American (0.263).
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PMID:Polymorphisms of H-ras-1 and p53 in breast cancer and lung cancer: a meta-analysis. 925 81


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