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)

Twenty-one chemicals were evaluated by standardized protocols in 6 mouse models that have been sugggested as alternatives to the 2-year mouse bioassay. Included were genotoxic and nongenotoxic chemicals, carcinogens and noncarcinogens, immunosuppressive and estrogenic agents, peroxisome proliferators, and chemicals producing cancer in rodents by other mechanisms. Mice were sacrificed at the end of 6 to 12 months, depending on the model. Standardized histopathology, biostatistical analyses, and criteria for overall evaluation of the results were employed. The TgAC transgenic (dermal and oral administration), the Tg-rasH2 transgenic, the heterozygous p53 gene knockout, the homozygous XPA and homozygous XPA-heterozygous p53 gene knockout, and the neonatal mouse models were evaluated. The chemicals were also evaluated in the in vitro SHE assay. Comparison of the results between the various in vivo models suggest that they might have usefulness as screening bioassays for hazard identification for potential human carcinogens. They have the benefits of being quicker, less expensive, and involve fewer animals than the traditional 2-year mouse bioassay. They do not appear to be overly sensitive. However, they do not definitively distinguish between genotoxic and nongenotoxic carcinogens, and they do not have 100% specificity for identifying human carcinogens. Like the 2-year bioassay, the results from these models need to be evaluated in conjunction with other information on a chemical in an overall weight-of-evidence, integrated analytical approach to assess risk for human exposures.
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PMID:Alternative models for carcinogenicity testing: weight of evidence evaluations across models. 1195 Jan 74

A Drug Information Association (DIA) workshop was held in May 2001 to discuss the outcome of the International Life Sciences Institute-Health and Environmental Sciences Institute (ILSI-HESI) project on alternative models for carcinogenicity assessment such as the P53(+/-) and XPA(+/-) knockout mouse models, the RasH2 and Tg.AC transgenic mouse models, and the neonatal mouse model. The "ICH Guideline S1B on Testing for Carcinogenicity of Pharmaceuticals" advocates that carcinogenicity testing of pharmaceuticals, when needed, might be carried out choosing one 2-year rodent carcinogenicity study (rat) plus one other study that supplements the 2-year study and providing additional information that is not readily available from the 2-year study: either (1) a short- or medium-term in vivo rodent test system or (2) a 2-year carcinogenicity study in a second rodent species (mouse). Another topic of discussion was pros and cons of the short- and medium-term models being evaluated by the ILSI-HESI project, in particular the usefulness of the models in relation to results of genotoxicity assays. Further discussions were advised following publication of the ILSI-HESI database, which is expected before the end of 2001. The use of the short- and medium-term rodent test systems were not considered appropriate for the assessment of carcinogenic potential of biotechnology-derived medicinal products.
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PMID:The in vivo rodent test systems for assessment of carcinogenic potential. 1184 41

Age-related decline in DNA repair capacity (DRC) is associated with decreased constitutive levels of p53 and other nucleotide excision repair proteins. To determine whether pretreatment of cells with small DNA oligonucleotides compensates for decreased DRC in the elderly, fibroblasts from donors of different ages were pretreated with thymidine dinucleotide (pTT), a 5' phosphorylated 9 base oligonucleotide (p9mer) or diluent alone for 48 h, then UV-irradiated with solar-simulated light. Western blot analysis revealed age-associated decreases of 40%-80% between newborn and old adult donor cells in the constitutive protein levels of p53, p21, XPA, RPA, ERCC1, and PCNA. Treatment with pTT or p9mer up-regulated these proteins by 200%-650% at 24, 48, and 72 h. Moreover, pretreatment with oligonucleotides significantly increased the removal rate of photoproducts as determined by reacting DNA with thymine dimer-specific antibodies: 40+/-5% vs. 20+/-9% and 15+/-11% remained after 24 h in diluent, pTT and p9mer treated cells, respectively. Oligonucleotide-treated adult cells removed thymine dimers at least as rapidly as diluent treated newborn cells, demonstrating that pTT and p9mer completely corrected the age-associated decrease in DRC. Our studies suggest that topical oligonucleotide treatment may enhance DRC in older adults and thus reduce the carcinogenic risk from solar UV irradiation in this age group.
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PMID:DNA oligonucleotide treatment corrects the age-associated decline in DNA repair capacity. 1192 22

The potential of Xpa-/- and Xpa-/-/p53+/- mice for short-term carcinogenicity assays was evaluated with di(2-ethylhexyl)phthalate (DEHP). Groups of 15 male and female Xpa-/- mice, received diets containing 0, 1, 500, 3,000, or 6,000 ppm DEHP, and wild-type (WT) and Xpa-/-p53+/-mice 0 or 6,000 ppm DEHP for 39 weeks. Xpa-/-, Xpa-/-/p53+/-, and WT males, fed 2,500 ppm p-cresidine, served as a positive control. In all models, the survival was not altered by DEHP. Increased incidences of nonneoplastic lesions were recorded in testes and kidneys with no apparent difference between the models. The only liver tumors in all models were adenomas in males with no statistically significantly increased incidence. For p-cresidine. the survival was decreased (p < 0.05) only in transgenic models. Statistically significantly increased incidences of nonneoplastic lesions were recorded in the liver, urinary bladder, and nasal cavity in all models, and in kidneys in transgenic models. The only tumors with statistically significantly increased incidence were liver adenomas in transgenic models (XPA: I vs 7: 'XPA/p53': 0 vs 12; WT: 0 vs 5, p = 0.053) and urinary bladder carcinomas in XPA/p53 model (0 vs 7). The negative carcinogenic response to DEHP and the positive response to p-cresidine support the expected sensitivity to genotoxic carcinogens in these transgenic models.
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PMID:Assessment of carcinogenicity of di(2-ethylhexyl)phthalate in a short-term assay using Xpa-/- and Xpa-/-/p53+/- mice. 1195 Jan 62

Metal ions are essential components of biological systems; nevertheless, even essential elements may have toxic or carcinogenic properties. Thus, besides As(III) and Cd(II), also Ni(II) and Co(II) have been shown previously to disturb different types of DNA repair systems at low, non-cytotoxic concentrations. Since some metals exert high affinities for SH groups, we investigated whether zinc finger structures in DNA-binding motifs of DNA repair proteins are potential targets for toxic metal ions. The bacterial formamidopyrimidine-DNA glycosylase (Fpg protein) involved in base excision repair was inhibited by Cd(II), Cu(II) and Hg(II) with increasing efficiencies, whereas Co(II), As(III), Pb(II) and Ni(II) had no effect. Furthermore, Cd(II) still disturbed enzyme function when bound to metallothionein. Strong inhibition was also observed in the presence of phenylselenyl chloride, followed by selenocystine, while selenomethionine was not inhibitory. Regarding the mammalian XPA protein involved in the recognition of DNA lesions during nucleotide excision repair, its DNA-binding capacity was diminished by Cd(II), Cu(II), Ni(II) and Co(II), while Hg(II), Pb(II) and As(III) were ineffective. Finally, the H(2)O(2)-induced activation of the poly(ADP-ribose)polymerase (PARP) involved in DNA strand break detection and apoptosis was greatly reduced by Cd(II), Co(II), Ni(II) and As(III). Similarly, the disruption of correct p53 folding and DNA binding by Cd(II), Ni(II) and Co(II) has been shown by other authors. Therefore, zinc-dependent proteins involved in DNA repair and cell-cycle control may represent sensitive targets for some toxic metals such as Cd(II), Ni(II), Co(II) and Cu(II), as well as for some selenium compounds. Relevant mechanisms of inhibition appear to be the displacement of zinc by other transition metals as well as redox reactions leading to thiol/disulfide interchange.
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PMID:Interference by toxic metal ions with zinc-dependent proteins involved in maintaining genomic stability. 1206 81

Since new guidelines on ICH carcinogenicity testing of pharmaceuticals have been adopted, evaluation on carcinogenicity of newly-developed pharmaceuticals using genetically modified animals has been conducted. Validation studies have suggested that rasH2 mice carrying human prototype c-Ha-ras gene, heterozygous p53 deficient [p53 (+/-)] mice and homozygous XPA deficient [XPA (-/-)] mice are very susceptible to genotoxic carcinogens. In addition, many experimental studies using rasH2 and p53 (+/-) mice in our laboratory suggest that these mouse models are very useful for clarifying the mechanism of organ-specific carcinogenesis. On the other hands, there are unsolved mechanisms and points that need to be clarified in these models, as described below. (1) The mechanism of the enhanced carcinogenesis is not completely understood; point mutations of human prototype c-Ha-ras gene are not always related to the tumor induction in rasH2 mice, but recent studies demonstrated that overexpression of the transgene is responsible for the enhanced carcinogenesis. (2) Malignant lymphomas are induced by the treatment of phenolphthalein in p53 (+/-) C57Bl/6 mice, in which exon 5 of the lateral p53 allele was inactivated, but not in p53 (+/-) CBA and C57Bl/6 mice, in which exon 2 of the p53 allele was inactivated. In this respect, such a strain difference and different genetically engineering procedure should be taken into account when p53 (+/-) mice are planned to be used for the evaluation of carcinogenic potential of newly-developed chemicals.
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PMID:Evaluation on carcinogenicity of chemicals using transgenic mice. 1250 18

UV light provokes DNA lesions that interfere with replication and transcription. These lesions may compromise cell viability and usually are removed by nucleotide excision repair (NER). In humans, inactivation of NER is associated with three rare autosomal recessive inherited disorders: xeroderma pigmentosum (XP), Cockayne syndrome, and trichothiodystrophy. The NER earliest step is lesion recognition by a complex formed by XPC and HHR23B proteins. In a subsequent step, XPA protein becomes associated to the repair complex. Here we investigate whether XPA and XPC proteins, involved in global genome repair, may contribute to a signal transduction pathway regulating the response to UVC-induced lesions. We monitored the expression of several UVC-induced genes in cells deficient in either a transduction pathway or mutated on an NER gene. Expression of the KIN17 gene is induced after UVC irradiation independently of p53 and of activating transcription factor 2. However, in human cells derived from XPA or XPC patients the UVC-induced accumulation of KIN17 RNA and protein is abolished. Our results indicate that the presence of functional XPA and XPC proteins is essential for the up-regulation of the KIN17 gene after UVC irradiation. They also show that the integrity of global genome repair is required to trigger KIN17 gene expression and probably other UVC-responsive genes.
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PMID:Global genome repair is required to activate KIN17, a UVC-responsive gene involved in DNA replication. 1252 3

Functional tumor suppressor p53 is mainly required for efficient global genomic repair (GGR), a subpathway of nucleotide excisions repair (NER). In this study, the regulatory effect of p53, on the spaciotemporal recruitment of XPC and TFIIH to DNA damage sites, was investigated in repair-proficient and -deficient human cells in situ. Photoproducts were induced through micropore UV irradiation of discrete subnuclear areas of intact cells and the specific lesions, as well as recruited repair factors, were detected by immunofluorescent intensity and density of the damaged DNA subnuclear spots (SNS). Both cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4PP) were visualized in situ at SNS within irradiated nuclear foci. The in situ repair kinetics revealed that p53-WT normal fibroblasts are proficient for the repair of both CPD and 6-4PP, whereas, p53-Null Li-Fraumeni syndrome (LFS) fibroblasts fail to efficiently repair CPD but not 6-4PP. Colocalization experiments of the NER factors showed that in normal human cells, XPC and TFIIH are rapidly and efficiently recruited to DNA damage within SNS. By contrast, recruitment of both XPC and TFIIH to DNA damage in SNS occurred much less efficiently in p53-Null or p53-compromised cells. The total cellular levels of XPC and XPB were similar in both p53-WT and -Null cells and remained unchanged up to 24h following UV irradiation. The results also showed that dispersal of recruited XPC and TFIIH from DNA damage SNS occurs within a short period after DNA damage. Such dispersal requires functional XPA, XPF and XPG proteins. Taken together, the results demonstrated that p53 plays a pronounced role in the damage recognition and subsequent assembly of repair machinery during GGR and the recruitment of XPC and TFIIH to CPD is p53-dependent. Most likely mechanism of this p53 action is through its downstream effector protein, DDB2.
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PMID:Tumor suppressor p53 dependent recruitment of nucleotide excision repair factors XPC and TFIIH to DNA damage. 1271 9

The p53 tumor suppressor gene is an important mediator of the cellular response to ultraviolet (UV)-irradiation-induced DNA damage and affects the efficiency of the nucleotide excision repair (NER) pathway. The mechanism by which p53 regulates NER may be through its ability to act as a transcription factor, and/or through direct interactions with damaged DNA or the repair machinery. p53 has been shown to regulate the expression of the DDB2 gene (encoding the p48 protein) and the XPC gene, two important components of the NER pathway involved in DNA damage recognition. In this study, a localized UV-irradiation technique was used to examine the localization of p53, p48 and XPC proteins in relation to sites of UV photoproducts, in vivo. We did not observe any specific co-localization of p53 with sites of UV-induced DNA damage, but did observe rapid co-localization of both p48 and XPC to these sites. p48 bound to UV photoproducts in cells mutant or deficient for either p53, XPC or XPA, and p48 enhanced XPC binding to lesions, suggesting that p48 is a very early recognition factor of DNA damage. We propose that p53 functions to transcriptionally regulate the DDB2 and XPC NER genes, but does not activate the NER pathway through direct interactions with UV-induced damaged DNA or other repair factors.
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PMID:p53 responsive nucleotide excision repair gene products p48 and XPC, but not p53, localize to sites of UV-irradiation-induced DNA damage, in vivo. 1277 Oct 27

Mice lacking the xeroderma pigmentosum group A gene (XPA-/- mice), which have a complete deficiency in nucleotide excision repair (NER), are highly predisposed to tongue squamous cell carcinoma (SCC) when exposed to 4-nitroquinoline 1-oxide (4NQO). To explore the effects of the interaction of the NER machinery with p53 in oral tumorigenesis, we generated an XPA-/- mouse strain carrying mutant alleles for p53. This mouse model of 4NQO carcinogenesis demonstrated that despite the same tumor frequency, XPA-/-p53+/- mice reached 100% SCC incidence at 25 weeks compared with 50 weeks for XPA-/-p53+/+ littermates. XPA-/-p53-/- mice succumbed to spontaneous thymic lymphomas before the development of tongue tumors (before 13 weeks of age). SCC originated in XPA-/-p53+/- mice maintained the p53+/- genotype and the retained wild-type p53 allele appeared to be structurally intact. Only one of 20 XPA-/-p53+/+ SCC showed a missense mutation of p53. Collectively, the accelerated tongue tumor growth may be a consequence of haploinsufficiency but not of mutation of p53 in the context of NER deficiency.
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PMID:p53 haploinsufficiency profoundly accelerates the onset of tongue tumors in mice lacking the xeroderma pigmentosum group A gene. 1457 72


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