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)

The prevalence and type of mutations in the p53 tumour-suppressor gene have been determined in 15 hepatocellular carcinomas (HCC) originating from Thailand. Direct sequencing of exons 5-8 revealed 2 mutations, an AGG to AGT (Arg-->Ser) transversion at codon 249, and an ATC-->AAC (Ile-->Asn) transversion at codon 254. Samples from the Thai patients were analyzed for the presence of aflatoxin-liver DNA and aflatoxin-serum albumin adducts, and all but one were found negative. All the patients were genotyped for glutathione-S-transferase (GST) mu, an enzyme possibly involved in the detoxification of AFB1, and 12 out of 15 had the null genotype. In general, the level of aflatoxin-albumin adducts in sera and the prevalence of p53 mutation at codon 249 in HCC were lower than in other areas at high risk of HCC, including southern China and parts of Africa.
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PMID:p53 mutations and aflatoxin B1 exposure in hepatocellular carcinoma patients from Thailand. 838 58

A temperature-sensitive mutant of murine p53 (p53Val-135) was transfected by electroporation into murine erythroleukemia cells (DP16-1) lacking endogenous expression of p53. While the transfected cells grew normally in the presence of mutant p53 (37.5 degrees C), wild-type p53 (32.5 degrees C) was associated with a rapid loss of cell viability. Genomic DNA extracted at 32.5 degrees C was seen to be fragmented into a characteristic ladder consistent with cell death due to apoptosis. Following synchronization by density arrest, transfected cells released into G1 at 32.5 degrees C were found to lose viability more rapidly than did randomly growing cultures. Following release into G1, cells became irreversibly committed to cell death after 4 h at 32.5 degrees C. Commitment to cell death correlated with the first appearance of fragmented DNA. Synchronized cells allowed to pass out of G1 prior to being placed at 32.5 degrees C continued to cycle until subsequently arrested in G1; loss of viability occurred following G1 arrest. In contrast to cells in G1, cells cultured at 32.5 degrees C for prolonged periods during S phase and G2/M, and then returned to 37.5 degrees C, did not become committed to cell death. G1 arrest at 37.5 degrees C, utilizing either mimosine or isoleucine deprivation, does not lead to rapid cell death. Upon transfer to 32.5 degrees C, these G1 synchronized cell populations quickly lost viability. Cells that were kept density arrested at 32.5 degrees C (G0) lost viability at a much slower rate than did cells released into G1. Taken together, these results indicate that wild-type p53 induces cell death in murine erythroleukemia cells and that this effect occurs predominantly in the G1 phase of actively cycling cells.
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PMID:Cell cycle analysis of p53-induced cell death in murine erythroleukemia cells. 841 61

We reported an association of smoking-induced lung cancer susceptibility with the human cytochrome P450 1A1 (CYP1A1) polymorphisms in our previous studies. To investigate a relationship between genetically determined individual predispositions and mutations of target genes in the early stage of lung carcinogenesis, we examined p53 mutations in relation to germ line polymorphisms of the CYP1A1 and GSTM1 genes, using surgical specimens of 148 non-small cell lung cancer patients who were smokers. The frequency of p53 mutations among heavy smokers was higher than in patients who had never smoked [P < 0.01; odds ratio (OR), 3.74; 95% confidence interval (CI), 1.46-9.56]. By single-strand conformational polymorphism, aberrant migration bands of p53 gene fragments were detected in 56 cases (38%). Smokers with susceptible rare homozygous alleles of either the MspI or Ile-Val polymorphism of the CYP1A1 gene have a 4.5-fold (P < 0.005; OR, 4.48; 95% CI, 1.64-12.26) or 5.5-fold (P < 0.01; OR, 5.52; 95% CI, 1.55-19.64) higher risk of having a mutation of the p53 gene than those with nonsusceptible predominant homozygous alleles of the gene. Non-small cell lung cancer patients with a susceptible CYP1A1 genotype were at remarkably high risk of having a mutation of the p53 gene when the genotype was combined with a deficient genotype, GSTM1(-). However, there was no difference between the types of p53 mutation and genotypes of the drug-metabolizing enzymes. These results showed that CYP1A1 germ line polymorphisms, which were associated with the genetic predisposition for lung cancer, were related to cigarette smoking-associated p53 mutations.
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PMID:Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer. 854 78

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. Vinyl chloride, a known human carcinogen that induces the rare sentinel neoplasm angiosarcoma of the liver, has been associated with specific A-->T transversions at the first base of codons 249 and 255 of the p53 gene. These mutations result in an Arg-->Trp amino acid substitution at residue 249 and an Ile-->Phe amino acid substitution at residue 255 in a highly conserved region in the DNA-binding core domain of the p53 protein. To determine the effects of these substitutions on the three-dimensional structure of the p53 protein, we have performed molecular dynamics calculations on this core domain of the wild-type and the Trp-249 and Phe-255 mutants to compute the average structures of each of the three forms. Comparisons of the computed average structures show that both mutants differ substantially from the wild-type structure in certain common, discrete regions. One of these regions (residues 204-217) contains the epitope for the monoclonal antibody PAb240, which is concealed in the wild-type structure but accessible in both mutant structures. In order to confirm this conformational shift, tumor tissue and serum from vinyl chloride-exposed individuals with angiosarcomas of the liver were examined by immunohistochemistry and enzyme-linked immunosorbent assay. Individuals with tumors that contained the p53 mutations were found to have detectable mutant p53 protein in their tumor tissue and serum, whereas individuals with tumors without mutations and normal controls did not.
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PMID:Conformational effects in the p53 protein of mutations induced during chemical carcinogenesis: molecular dynamic and immunologic analyses. 881 13

Generalized glucocorticoid resistance is associated with chronic hyperactivation of the hypothalamic-pituitary-adrenal axis, compensating for impaired glucocorticoid receptor function. We report a unique patient with sporadic generalized glucocorticoid resistance who, at age 33, presented with infertility and hypertension and, at 38, developed pituitary Cushing's disease. Leukocyte-binding studies revealed normal affinity of the glucocorticoid receptor but a reduction of binding sites by 50%. [3H]thymidine incorporation by this patient's lymphocytes was not suppressible by dexamethasone. He had a novel heterozygous missense mutation in the glucocorticoid receptor gene (isoleucine 559 to asparagine 559). The mutant receptor exhibited a strong dominant-negative effect on the ability of the wild-type receptor to induce gene transcription in vitro. The mutation was present in all of the patient's cultured lymphoblasts and fibroblasts as well as in 50% of his sperm, as demonstrated by single-cell polymerase chain reaction; it was not present in his parents and seven siblings. This novel mutation was thus both de novo and present in the germ line. Immunohistochemical staining of this patient's pituitary corticotropinoma revealed accumulation of p53 protein, indicating the presence of a putative somatic oncogenic mutation in the p53 gene in the tumor cells. Investigation of the lymphoblast and skin fibroblast cultures for p53 abnormalities did not show any aberration. Thus, a novel de novo germ line mutation of the glucocorticoid receptor with strong dominant-negative activity caused severe sporadic generalized glucocorticoid resistance, which preceded corticotroph adenoma formation. The latter probably was due to the combined effects of chronic corticotroph hyperstimulation, decreased glucocorticoid negative feedback, and at least one subsequent somatic defect in the control of the cell cycle.
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PMID:Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. 886 43

Although numerous studies have demonstrated increased expression of p53 protein in the Reed-Sternberg cells of Hodgkin's disease, little data exist as to whether mutations of the p53 gene is a common occurrence in this neoplasm. Using a microdissection technique coupled with PCR, single-strand conformation analysis, and DNA sequencing, we studied 23 cases of Hodgkin's disease for mutations within exons 5 to 8 of the p53 gene. We found seven mutations within six cases; six were missense mutations. An identical missense mutation was found in three cases (codon 243, methionine to isoleucine), and another identical missense mutation was found in an additional two cases (codon 204, glutamic acid to lysine). Verification of the mutations was accomplished either by direct Southern blotting of PCR-amplified p53 exon products from re-extracted DNA or by hybridization of cloned PCR-amplified p53 exon products from re-extracted DNA with a mutant-specific oligonucleotide. There was no good correlation between the presence of p53 mutations and the level of p53 protein expression, which was found to be overexpressed in all cases, the level of MDM2 protein expression, or the proliferation rate as determined by K-67 antibody. None of the cases with p53 mutation had evidence of Epstein-Barr virus within the Reed-Sternberg cells, as compared with 7 of 17 of the other cases (p < 0.06). These results suggest that p53 mutation may represent an important mechanism in the pathogenesis of Hodgkin's disease, and this mechanism may be independent of Epstein-Barr virus.
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PMID:p53 mutations in Hodgkin's disease. 887 83

The MDM-2 (murine double minute 2) gene codes for a cellular protein that can bind to the p53 tumor suppressor gene product, thereby functioning as a negative regulator of p53. In order to define the role of the MDM-2 gene in the pathogenesis of human acute myeloid leukemia, the expression and the sequence of the MDM-2 gene were examined in samples of bone marrow and/or peripheral mononuclear cells of 38 patients by using immunostaining, polymerase chain reaction (PCR), single strand conformation polymorphism, and sequencing. Immunohistochemical staining detected a weak accumulation of the MDM-2 protein in AML patients of FAB classification M4 and M5. RT-PCR analysis revealed a heterogeneous expression pattern of MDM-2 mRNA in AML samples of different FAB classification. An increased level of MDM-2 mRNA expression was observed in 17 of 38 AML patients when compared to normal controls. No structural changes in a 488 bp region extending from nucleotide 890 to 1378 of the MDM-2 cDNA were detected using RT-SSCP and sequence analysis. In addition, heterogeneous expression of p53 transcripts was found with the highest p53 mRNA levels in AML M4 and M5. Interestingly, there seems to be a correlation between the relative ratios of p53 and MDM-2 mRNA levels in AML M4 and M5: in 15 of 23 cases high p53 mRNA expression was directly associated with high levels of MDM-2 transcripts. An exclusively intranuclear p53 immunostaining pattern was found in 10 of 16 (58%) AML FAB M4 and M5, whereas the remaining AML samples tested were negative for p53 (0/10). Using RT-SSCP analysis and direct sequencing of the RT-PCR amplification products of p53 exon 5-8, we observed that only 1 of 38 AML patients showed a point mutation in the p53 gene. This missense mutation occurred in the evolutionary highly conserved region of p53 at codon 255 (Ile to Phe). These data indicated that structural alterations of the p53 gene do not play an important role in the initiation and progression of AML. However, abrogation of p53 tumor suppressor function due to MDM-2 overexpression may be an alternative molecular mechanism by which a subset of AMLs may escape from p53-regulated growth control.
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PMID:Analysis of the p53 and MDM-2 gene in acute myeloid leukemia. 889 28

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.
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PMID:CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein. 938 68

The mammalian target of rapamycin (mTOR) has been shown to link growth factor signaling and posttranscriptional control of translation of proteins that are frequently involved in cell cycle progression. However, the role of this pathway in cell survival has not been demonstrated. Here, we report that rapamycin, a specific inhibitor of mTOR kinase, induces G1 cell cycle arrest and apoptosis in two rhabdomyosarcoma cell lines (Rh1 and Rh30) under conditions of autocrine cell growth. To examine the kinetics of rapamycin action, we next determined the rapamycin sensitivity of rhabdomyosarcoma cells exposed briefly (1 h) or continuously (6 days). Results demonstrate that Rh1 and Rh30 cells were equally sensitive to rapamycin-induced growth arrest and apoptosis under either condition. Apoptosis was detected between 24 and 144 h of exposure to rapamycin. Both cell lines have mutant p53; hence, rapamycin-induced apoptosis appears to be a p53-independent process. To determine whether induction of apoptosis by rapamycin was specifically due to inhibition of mTOR signaling, we engineered Rh1 and Rh30 clones to stably express a mutant form of mTOR that was resistant to rapamycin (Ser2035-->Ile; designated mTOR-rr). Rh1 and Rh30 mTOR-rr clones were highly resistant (>3000-fold) to both growth inhibition and apoptosis induced by rapamycin. These results are the first to indicate that rapamycin-induced apoptosis is mediated by inhibition of mTOR. Exogenous insulin-like growth factor (IGF)-I protected both Rh1 and Rh30 from apoptosis, without reactivating ribosomal p70 S6 kinase (p70S6K) downstream of mTOR. However, in rapamycin-treated cultures, the response to IGF-I differed between the cell lines: Rh1 cells proliferated normally, whereas Rh30 cells remained arrested in G1 phase but viable. Rapamycin is known to inhibit synthesis of specific proteins but did not inhibit synthesis or alter the levels of mTOR. To examine the rate at which the mTOR pathway recovered, the ability of IGF-I to stimulate p70S6K activity was followed in cells treated for 1 h with rapamycin and then allowed to recover in medium containing > or =100-fold excess of FK506 (to prevent rapamycin from rebinding to its cytosolic receptor FKBP-12). Our results indicate that, in Rh1 cells, rapamycin dissociates relatively slowly from FKBP-12, with a t1/2 of approximately 17.5 h. in the presence of FK506, whereas there was no recovery of p70S6K activity in the absence of this competitor. This was of interest because rapamycin was relatively unstable under conditions of cell culture having a biological t1/2 of approximately 9.9 h. These results help to explain why cells are sensitive following short exposures to rapamycin and may be useful in guiding the use of rapamycin analogues that are entering clinical trials as novel antitumor agents.
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PMID:Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. 1002 80

Cystosarcoma phyllodes (CSP) is a rare breast neoplasm composed of stromal and epithelial elements. It usually runs a benign course but it may metastasize. In a 31-year-old patient with recurring CSP, a mesenchymal tumor in the leg developed. The question arose whether the latter tumor could be a metastasis from the CSP, which would have major treatment consequences. The problem was addressed using molecular methods, i.e., comparison of the pattern of polymorphic repeat markers on chromosome 17p as well as single strand conformation polymorphism analysis and sequencing of exons 5 to 8 of the TP53 gene in both tumor and normal tissue. An identical pattern of loss of heterozygosity in both breast tumors was demonstrated, but a different pattern was shown in the tumor in the leg. This led to the conclusion that the latter tumor had to be a new primary tumor. A mutation in codon 162 of the TP53 gene was found in the tumor tissue as well as in the normal tissue of this patient. This germ line mutation leads to the replacement of isoleucine by asparagine and most likely has functional consequences. In all four examined tumors of this patient, the normal TP53 allele was lost. This is strong evidence that this germ line TP53 mutation causes the genesis of these two rare primary mesenchymal tumors in this young patient. The current study exemplifies the power of molecular diagnostic methods in investigating the specific clinical problem of clonal relation between two separate tumors. The germ line mutation found in codon 162 of the TP53 gene and the association with cystosarcoma phyllodes have not been described previously.
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PMID:Molecular assessment of clonality leads to the identification of a new germ line TP53 mutation associated with malignant cystosarcoma phyllodes and soft tissue sarcoma. 1020 67


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