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 purpose of this study was to evaluate the effects of the loss of a p53 allele and phenethyl isothiocyanate (PEITC) pre-treatment on the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and K-ras mutation frequency in a hybrid mouse model. Male TSG-p53 'knock-out' mice were bred with A/J female mice to produce (A/J x TSG-p53) F1 mice either homozygous (p53+/+) or heterozygous (p53+/-) for p53 alleles. These mice, together with female A/J mice, were treated at 6-8 weeks of age with NNK or dosed with PEITC prior to administration of NNK. The A/J mice treated with NNK had a 100% incidence of lung tumors, with 9.7 +/- 3.4 tumors/mouse. A/J mice pre-treated with PEITC prior to NNK administration had 3.5 +/- 2.1 lung tumors/animal, although the incidence remained at 100%. In (A/J x TSG-p53) F1 mice with either the p53(+/-) or p53(+/+) genotype PEITC pre-treatment significantly decreased tumor incidence (100 to 40 and 36%, respectively) and multiplicity (2.0 +/- 0.5 to 0.5 +/- 0.4 and 2.1 +/- 0.5 to 0.5 +/- 0.4, respectively), indicating that PEITC is an effective chemopreventive agent in both A/J mice and (A/J x TSG-p53) F1 mice. Analysis of lung tumor DNA from A/J mice treated with NNK or NNK/PEITC indicated that 15 of 17 (88%) and 20 of 23 (87%) of the tumors, respectively, contained G-->A transitions at the second base of codon 12 in the K-ras gene. Similarly, in lung tumors from (A/J x TSG-p53) F1 mice treated with NNK or NNK/PEITC 29 of 30 (96%) and 9 of 10 (90%), respectively contained G-->A transitions at the second base of codon 12 of the K-ras gene. No mutations of the p53 gene were found in any of the tumors analyzed, suggesting minimal involvement of this gene in the development of lung adenomas. These data indicate that absence of a p53 allele in (A/J x TSG-p53) F1 mice does not alter the incidence or multiplicity of NNK-induced lung tumors and that PEITC inhibition of NNK tumorigenesis does not affect the frequency or spectrum of K-ras gene mutations found consistently with NNK carcinogenesis.
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PMID:K-ras mutations in lung tumors from A/J and A/J x TSG-p53 F1 mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and phenethyl isothiocyanate. 758 56

Cell proliferation and cell death in mouse epidermis are altered by topical application of benzo[a]pyrene (BaP), a procarcinogen, which yields metabolites that can form DNA adducts. The mitotic rate, nuclear abnormalities, labelling index, grain density, necrosis and apoptosis were compared in the epidermis of TSG-p53 null (p53-/-) and C57BL wild-type (wt) mice after weekly treatments with BaP to determine whether the absence of the p53 gene altered cytokinetic responses to DNA damaging agents in vivo. Acetone alone or 64 micrograms BaP in 50 microliters acetone was applied to the clipped dorsum of mice once, or in four consecutive weekly treatments. Indices of cell proliferation and cell death were the same in both wt and p53-/- mice treated only with acetone. One application of BaP depressed mitosis and slowed the rate of DNA synthesis in both genotypes. After four applications of BaP the number of keratinocytes in S phase increased substantially, while there was no further slowing in the rate of S phase in the wt and p53-/- mice. Cell proliferation rates and numbers of cells with nuclear abnormalities were higher and there were fewer apoptotic cells and apoptotic bodies in the p53-/- mice than in the wt mice. Numbers of 'sunburn' cells were similar in both types.
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PMID:Cell proliferation and nuclear abnormalities are increased and apoptosis is decreased in the epidermis of the p53 null mouse after topical application of benzo[a]pyrene. 905 Nov 19

Tissue-specific expression of parental K-ras allele(s) was investigated by single-strand conformation polymorphism analysis of the 3' untranslated region of the K-ras gene in normal lung, spleen, liver and kidney from (A/J x TSG-p53) F1 mice. The expression of A/J K-ras allele was equal to that of C57BL/6J allele in normal spleen, liver and kidney. However, transcripts from A/J K-ras allele were found to be 2-12-times greater than those from C57BL/6J allele in lung tissues harvested over a 20-week period. Similar to our previous observation with dimethylnitrosamine- and benzo[a] pyrene-induced lung tumors, K-ras mRNA transcribed from A/J allele was 10-40-times more abundant than those from C57BL/6J allele in all of 40 (A/J x TSG-p53) F1 mouse lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. In addition, K-ras mutations (G to A transitions at the second base of codon 12) were detected in 38 of 40 (95%) lung tumors and all of the mutations were found on the allele inherited from the A/J parent. These data demonstrate tissue-specific allele-specific transcription of the K-ras gene and provide further support to the thesis that K-ras allele itself is a primary mouse lung tumor susceptibility gene.
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PMID:Tissue-specific expression of the K-ras allele from the A/J parent in (A/J x TSG-p53) F1 mice. 913 1

TSG-p53/Big Blue double transgenic mice offer a powerful tool for examining the effect of a p53 germline mutation on spontaneous somatic mutation in vivo. After sequencing the DNA-binding domain of the lacI gene, we previously reported no differences in mutant frequency between p53 nullizygous (-/-) and p53 wild-type (+/+) mice in liver, spleen and brain. However, jackpot mutations elsewhere in the gene may have obscured a real difference in mutation frequency and the small sample size of mutations not at CpG dinucleotides (n = 23) may have been insufficient to reveal differences in mutation spectra. Herein we have sequenced the entire lacI gene, including the promoter and lacZ operator regions. 123 additional independent mutations have been found including 70 mutations not at CpG sites. The mutation frequency was determined by correcting for jackpot mutations. There were no statistically significant differences in mutation frequency or spectrum between the p53 (+/+) and p53 (-/-) genotypes in any of the three tissues.
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PMID:Spontaneous mutation frequencies and spectra in p53 (+/+) and p53 (-/-) mice: a test of the 'guardian of the genome' hypothesis in the Big Blue transgenic mouse mutation detection system. 933 Jun 18

The genes involved in negative cell cycle regulation and familial tumour susceptibility including APC, BRCA, p53, RB, WT1 are unique and have no homologies with other genes. Our hypothesis suggests they originated from mating factor genes, which halted cell division in response to stress to generate genetic diversity by sexual mechanisms. Some have evolved principally by vertical transmission (mismatch repair), others by horizontal transmission via mobile elements, predominantly in oocytes. We demonstrate amplification in human extra-embryonic tissues in fetus and mother in implantation; in the developing fetus, differing tissue-specific patterns are seen, especially between testis and ovary. We suggest that the fetus is susceptible to maternal transmission of infections including CMV, malaria, trypanosomes, whose sequences occur within these genes. In head and neck cancers, we demonstrate specific patterns of loss or instability involving up to seven different TSG. We suggest mechanisms of tumourigenesis involve transposable elements and episome formation, leading to loss of negative cell cycle regulation and exit from G0.
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PMID:The Knights of the Round Table hypothesis of tumour suppressor gene function--noble sacrifice or sexual dalliance: genes, including p53, BRCA1/2 and RB have evolved by horizontal and vertical transmission of mating factor genes and are involved in gametogenesis, implantation, development and tumourigenesis. 945 83

Phenolphthalein, a common ingredient in nonprescription laxatives and a multisex, multispecies rodent carcinogen, was evaluated under chronic exposure conditions for genotoxicity in transgenic female mice heterozygous for the p53 gene (heterozygous TSG-p53 mice). Phenolphthalein was administered in the diet at 200, 375, 750, 3,000, and 12,000 ppm (corresponding to a time-weighted average of 37, 71, 146, 569, and 2,074 mg/kg/day, respectively) for 6 months (183 days). On days 39, 92, 137, and 183 of treatment, peripheral blood samples were collected and evaluated for the frequency of micronucleated polychromatic and normochromatic erythrocytes (MN-PCE and MN-NCE, respectively), the percentage of PCE (%PCE) among total erythrocytes, and the extent of DNA damage (single strand breaks, alkali labile sites, DNA crosslinking) in leukocytes. In addition, the extent of DNA damage was evaluated in liver parenchymal cells sampled from mice at the end of the 6-month treatment period. DNA damage was evaluated using the alkaline (pH > 13) Single Cell Gel (SCG) assay. In addition, using a modified SCG technique, the frequencies of leukocytes and liver parenchymal cells with extremely low molecular weight DNA (indicative of apoptosis and/or necrosis) were determined. At each sample time, phenolphthalein induced a highly significant, dose-dependent increase in the frequency of MN-PCE and MN-NCE and in %PCE. Maximal induction of MN-PCE and %PCE decreased with increasing treatment duration, most likely due to a treatment duration-dependent decrease in the relative amount of ingested phenolphthalein. A comparative analysis of the kinetochore status of MN in erythrocytes sampled from control mice and mice ingesting phenolphthalein at 12,000 ppm for 183 days indicates that the induced MN resulted predominantly but not exclusively from numerical chromosomal damage. The analysis for increased levels of DNA damage in blood leukocytes was inconclusive, with a small but statistically significant increase in DNA migration on days 39 and 137 but not on days 92 and 183. The extent of DNA migration in liver parenchymal cells sampled from mice at the end of treatment was not altered significantly. The frequencies of apoptotic and/or necrotic leukocytes and liver parenchymal cells were not increased among mice ingesting phenolphthalein. The lowest effective dose at which a significant genotoxic response (i.e., the induction of MN-NCE) was detected was 200 ppm, the lowest dose tested in this study. This dose in mice is comparable to doses (on a mg/m2 basis) experienced by humans.
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PMID:Measurement of micronucleated erythrocytes and DNA damage during chronic ingestion of phenolphthalein in transgenic female mice heterozygous for the p53 gene. 954 89

The results of a number of epidemiology studies suggest that exposure to power frequency (50 and 60 Hz) magnetic fields may be a risk factor for hematopoietic neoplasia. To generate experimental data to test this hypothesis, the influence of magnetic field exposure on lymphoma induction was determined in two strains of mice that are genetically predisposed to the disease. PIM mice, which carry the pim-1 oncogene, are highly sensitive to lymphoma induction by N-ethyl-N-nitrosourea (ENU); ENU-treated PIM mice were studied as a 'high incidence' lymphoma model. TSG-p53 (p53 knockout) mice, in which the p53 tumor suppressor gene has been deleted from the germ line, develop lymphoma as an age-related change; hemizygous TSG-p53 mice were studied as a 'low incidence' lymphoma model. Beginning 1 day after a single i.p. injection of 25 mg ENU/kg body wt, groups of 30 PIM mice/sex were exposed for 18.5 h/day to pure, linearly polarized, transient-free 60 Hz magnetic fields at field strengths of 0 (sham control), 0.02, 2.0 or 10.0 Gauss (G). An additional group of 30 PIM mice/sex was exposed intermittently (1 h on, 1 h off) to 10.0 G fields. Groups of 30 TSG-p53 mice/sex were exposed continuously to magnetic field strengths of 0 (sham control) or 10.0 G; TSG-p53 mice received no ENU. Studies were terminated after 23 weeks of magnetic field exposure. Lymphoma incidence in male PIM mice exposed continuously to 10.0 G magnetic fields was significantly reduced from that seen in sex-matched sham controls; survival, lymphoma incidence and lymphoma latency in other groups of PIM mice did not differ from sham controls. Survival and lymphoma incidence in all groups of TSG-p53 mice was 7% or less, regardless of magnetic field exposure regimen. These data do not support the hypothesis that exposure to magnetic fields is a significant risk factor for lymphoid neoplasia in mice with a genetic predisposition to the disease.
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PMID:Exposure to 60 Hz magnetic fields and risk of lymphoma in PIM transgenic and TSG-p53 (p53 knockout) mice. 977 37

This study was performed to determine the frequency of inactivation and clinical correlates in non-small cell lung cancer (NSCLC) of three known tumor suppressor genes [TSGs; RB, MTS1/CDKN2 (p16), and p53] and various regions of 3p loss of heterozygosity (LOH) as other major potential TSG sites. Paraffin sections from 103 resected NSCLCs were analyzed for expression of pRB, p16, and p53 by immunohistochemistry, whereas DNA from tumor and normal tissue were tested for LOH at 3p25-26, 3p21, and 3p14. Previously published LOH data for 5q, 11p, 17q, and 18q were also available. Loss of pRB or p16 expression and overexpression of p53 were considered abnormal. The immunohistochemical and LOH data were correlated with a variety of clinical parameters including stage, age, sex, smoking history, and survival. With respect to pRB, p16, and p53, the tumors could be grouped into four categories: normal for all three proteins (21%); abnormal for pRB or p16 and normal for p53 (30%); normal for pRB and p16 and abnormal for p53 (20%); and abnormal in both pathways (28%). Aberrant expression of pRB, p16, p53, and 3p LOH, either individually or in combination, was not associated with survival differences or any other clinical parameters, with the exception that pRB/pl6 abnormalities were more common in older patients (P = 0.0005). pRB and p16 expression showed a strong inverse correlation (P = 0.002), whereas there was no correlation between expression of pRB, p16, and p53. Abnormal expression of any of the three genes inversely correlated with K-ras codon 12 mutations (P = 0.004), but not with 3p LOH or LOH at other TSG loci. We conclude that resectable NSCLCs show distinct patterns of TSG inactivation, but that no clear clinical correlates exist either alone or in combination for pRB, p16, p53, and 3p abnormalities.
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PMID:Correlation of abnormal RB, p16ink4a, and p53 expression with 3p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. 1021 14

Recent evidence indicates that individuals with a p53 germ-line mutation (Li-Fraumeni syndrome) have a 50% risk of developing lung cancer by age 60. In this study, p53 heterozygous knockout mice and p53 transgenic mice carrying a dominant negative mutant were crossed with the A/J mouse, which is highly susceptible to lung tumor induction, to investigate whether a p53 germ-line mutation is a predisposing gene for carcinogen-induced pulmonary adenomas in mice. The number of lung tumors was not significantly increased in (TSG-p53 x A/J)F1 p53 heterozygous knockout mice as compared with that in (TSG-p53 x A/J)F1 wt mice 16 weeks after exposure to N-nitrosomethylurea (MNU). In contrast, an average of 22 lung tumors were observed in (UL53-3 x A/J)F1 mice carrying a mutant p53 transgene (135Valp53) compared with an average of 7 lung tumors seen in (UL53-3 x A/J)F1 wt mice after treatment with N-nitrosomethylurea. Similar enhancement of lung tumor multiplicity (approximately 3-fold) was seen when mutant versus wt mice were treated with the tobacco-related carcinogens benzo[a]pyrene or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that the mutant p53 transgene may have a dominant negative effect on the wt p53. The potential usefulness of this new mouse model in lung cancer chemoprevention and chemotherapy was examined. The chemopreventive efficacy of the green tea or a combination of dietary dexamethasone and myoinositol and the chemotherapeutic efficacy of Taxol or Adriamycin was examined in wt mice or mice with a mutation in the p53 gene. Mice treated with dexamethasone/myo-inositol and green tea displayed an average of 70 and 50% inhibition of lung tumors, respectively, regardless of p53 status. Similarly, when mice bearing established lung adenomas were treated with Taxol or Adriamycin, a decrease in tumor volume of approximately 70% was observed independent of p53 mutation status. Thus, the (UL53-3 x A/J)F1 p53 transgenic mouse seems to be an excellent model for human carriers of p53 germ-line mutations (Li-Fraumeni syndrome). Furthermore, the lung adenomas generated in this model possess mutations in both the K-ras proto-oncogene and the p53 tumor suppressor gene. This model should prove directly useful for chemoprevention and chemotherapy studies.
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PMID:A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents taxol or adriamycin. 1070 3

Deletions in the 5q14 region have been described in a variety of neoplasms, such as testicular germ cell tumors, ovarian, gastric and lung cancer. The high frequency of allelic losses observed in this region implies the presence of putative tumor suppressor gene(s) (TSGs). In the present study, we investigated in a series of 56 non-small cell lung carcinomas (NSCLCs) the allelic imbalance (Alm) within the 5q14 region, employing the D5S644 marker, and its relationship with p53 abnormalities, the kinetic parameters [proliferation index (PI) and apoptotic index (AI)] and the ploidy status of the carcinomas. AI at D5S644 was found at a frequency of 51.2%. The rather high percentage of Alm in stage I tumors suggests an early involvement in NSCLC development. LOH at 5q14 was associated with decreased AR in lung tumors insinuating the presence of a putative TSG(s) (P=0.008). Simultaneous alterations of both p53 and D5S644 locus were the most frequent pattern observed (37.5%). Cases demonstrating this profile also exhibited a marked decrease in AI (P=0.001). These findings imply a synergistic mechanism of co-operation between different TSGs. However, proliferation activity was dependent only on p53 status, leading to the assumption that the putative TSG(s) present at 5q14 may probably be involved in normal apoptotic procedures. Further studies are needed to identify the candidate gene(s).
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PMID:Allelic imbalance at the 5q14 locus is associated with decreased apoptotic rate in non-small cell lung carcinomas (NSCLCs). Possible synergistic effect with p53 gene alterations on apoptosis. 1081 90


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