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)

To determine whether a constitutive p53 deficiency would enhance the rate of development of chemically induced hepatocellular carcinoma, we treated groups of wild-type, p53-heterozygous (+/-), and null (-/-) male mice with a single dose of diethylnitrosamine at 12 d of age. Although the null mice had to be killed very early, at 15 wk of age because of the development of nonliver tumors, hemangiosarcoma of the liver had already developed in two of seven mice. More detailed analysis of the wild-type and heterozygous mice showed no difference in the number, size, or growth rate of early microscopic lesions or in the number or apparent malignancy of hepatocellular adenomas or carcinomas at later time points. Thus, germline p53 deficiency does not enhance the rate of development of diethylnitrosamine-induced hepatocellular adenoma or carcinoma but may instead favor development of hepatic hemangiosarcoma.
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PMID:Hepatocarcinogenesis in p53-deficient mice. 789 66

We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during carcinogenesis remains unclear. In the present study, heterozygous and nullizygous p53-deficient mice and their littermates were treated with the urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary bladder carcinogenesis but not development of other tumors in the nullizygous p53-deficient mice. Thus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational inactivation of the wild-type allele was not apparent in either the single transitional cell carcinoma observed in a wild-type mouse and a hemangiosarcoma in a heterozygote. Overall, it can be concluded that the number of normal p53 alleles is a significant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urinary bladder carcinogenesis may thus be to diminish the threshold for occurrence of additional genetic alterations.
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PMID:Enhancement of urinary bladder carcinogenesis in nullizygous p53-deficient mice by N-butyl-N-(4-hydroxybutyl)nitrosamine. 1009 21

A cell line (ISO-HAS) has been established from tumor tissue of a human hemangiosarcoma arising on the scalp by the use of conditioned medium from a murine-phenotypic angiosarcoma cell line (ISOS-1). Cells have been cultured for more than 2 years with up to 100 passages. The cells retained endothelial-cell properties, such as a characteristic cobblestone appearance at confluency, contact-inhibited growth, active uptake of acetylated low-density lipoprotein labeled with 1,1-dioctadecyl 1,3,3,3,3-tetramethyl-indocarbocyanine perchlorate (DiI-Ac-LDL) and CD31 expression. However, they were weakly positive for von-Willebrand-factor (vWf) antigen and for binding of Ulex europaeus agglutinin-I (UEA-I) lectin, and lacked tube-formation activity. These findings indicate that ISO-HAS is a poorly differentiated endothelial cell line. ISO-HAS cells showed accumulation of p53 protein in the nuclei, and a new-typed p53-gene point mutation was found in exon 7 at codon 240. When inoculated s.c. into severe-combined-immunodeficiency (SCID) mice, the cells showed solid-tumor growth that caused death. These properties suggest that ISO-HAS is a malignant endothelial cell line with high tumorigenicity.
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PMID:Establishment of a human hemangiosarcoma cell line (ISO-HAS). 1018 35

Hemangiomas and hemangiosarcomas are uncommon in rodents and humans and, as such, the mechanisms giving rise to these tumors are poorly understood. Inactivating mutations in the p53 gene have been detected in sporadic and chemically induced human and rodent hemangiosarcomas. Additionally, experimental ablation of p53 function in mice by targeted gene disruption increases the incidence of both spontaneous and carcinogen-induced vascular tumors. These findings implicate p53 disruption in vascular tumor development. In this study, we characterized p53 inactivation immunocytochemically and by gene sequencing in a large number of vascular tumors that developed in B6C3F1 mice during a long-term (2-year) study of the thiazolidinedione troglitazone. For comparative purposes, a murine hemangiosarcoma induced by polyoma middle-T antigen, which transforms endothelial cells via a p53-independent mechanism, five spontaneous human hemangiosarcoma specimens, and species-specific positive control tissues were also evaluated by immunocytochemistry for p53 inactivation. While 20% of the human hemangiosarcomas and all positive control tissues expressed significant levels of nuclear p53, indicating functional inactivation of the protein, none of the 161 mouse vascular tumors studied expressed detectable p53 protein. The absence of inactivating mutations was confirmed in eight of the histologically most malignant mouse hemangiosarcomas by sequencing exons 5 to 8 of the p53 gene. These results demonstrate that p53 inactivation did not play a role in development of the vascular tumors seen in the long-term study of troglitazone, and they indicate that loss of p53 function is not essential for vascular tumor development in mice.
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PMID:p53 is not inactivated in B6C3F1 mouse vascular tumors arising spontaneously or associated with long-term administration of the thiazolidinedione troglitazone. 1019 75

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a very potent mutagen which induces tumors in the liver, lung and hematopoietic system of CDF1 mice and the liver, Zymbal gland and skin in F344 rats. The recent development of transgenic knockout mice allows their introduction for sensitive screening of environmental carcinogens due to the rapid development of tumors. P53 gene deficient mice (p53-/-) were found to spontaneously develop malignant lymphoma and hemangiosarcoma, whereas heterozygotes (p53+/-) mice display a high incidence of tumors of the urinary bladder when treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. In the present study, to determine whether p53 gene knockout mice can be utilized in a short-term assay model for the screening of heterocyclic amines (HCAs), the effects of MeIQx, as a representative compound, at low doses were examined. Male and female p53+/- mice and wild type littermates (p53+/+) were continuously given diets containing 0, 0.1, 1, 10 and 100 ppm MeIQx for 1 year. No significant difference in tumor induction was observed other than an increase in liver adenomas in males receiving 10 ppm MeIQx treatment. The results indicate that p53+/- mice have no practical advantages for use in short-term carcinogenicity tests of HCAs.
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PMID:Heterozygous p53-deficient mice are not susceptible to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) carcinogenicity. 1039 76

p19(ARF) is a key regulator of the p53-mediated apoptotic and tumor suppressor pathway. The proapoptotic Bax gene is a transcription target of p53, yet genetic studies in some animal models have suggested that Bax and p53 loss may cooperate in tumorigenesis. ARF-deficient mice are tumor prone, and to determine whether Bax loss could cooperate in the development of these tumors, we generated mice null for both ARF and Bax. The tumor latency of Bax+/+ARF-/-, Bax+/-ARF-/- and Bax-/-ARF-/- mice was similar with a mean survival of 48.9, 48.1, and 47.6 weeks, respectively. In Bax+/+ARF-/- mice, the predominant tumor type was B- and T-cell lymphoma followed by sarcomas and a lack of carcinomas. However, the frequency of lymphoma development dramatically decreased, whereas that of sarcomas and carcinomas increased, in a gene dosage-dependent manner in Bax+/-ARF-/- and Bax-/-ARF-/- mice. Furthermore, uncommon tumors of ARF-/- mice (osteosarcoma and hemangiosarcoma) were observed in Bax/ARF-double null mice, and tumor types not described previously in ARF-null mice (mixed germ cell tumor, Triton tumor, and histiocytic sarcoma) also developed in Bax-/-ARF-/- animals. Importantly, multiple primary malignant tumors of different lineage arose in 25% of the Bax-/-ARF-/- mice, whereas only one tumor type per animal was observed in Bax+/+ARF-null littermates. Finally, the wild-type Bax allele was retained in tumors arising in Bax+/-ARF-/- mice. Thus, Bax appears to function as a tumor modifier rather than as a classic tumor suppressor, and the combined loss of Bax and the ARF allows for the emergence of multiple malignant tumor types, an alteration of the tumor spectrum, and tumors not observed previously in ARF-null mice.
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PMID:Loss of Bax alters tumor spectrum and tumor numbers in ARF-deficient mice. 1192 42

Riddelliineis a naturally occurring pyrrolizidine alkaloid found in certain poisonous rangeland plants of the western United States. In National Toxicology Program 2-year studies, riddelliine induced high incidences of hemangiosarcoma in the liver of F344/N rats (both sexes) and B6C3F1 mice (males). To understand this pathogenesis, we tested short-term effects of riddelliine. Three groups (control; 1.0 mg/kg/day, high dose used in the 2-year study; and 2.5 mg/kg/day) of seven male F344/N rats per group were terminated after 8 consecutive doses and 30 doses (6 weeks, excluding weekends). Serum vascular endothelial growth factor (VEGF), histological, immunohistochemical [factor VIII-related antigen/von Willebrand factor (fVIII-ra/vWf)], VEGF, VEGF receptor-2 (VEGFR2), glutathione S-transferase-pi, S-phase (BrdU), p53, apoptosis, and ultrastructural evaluations were performed on the liver. Following 8 doses of 1.0 and 2.5 mg/kg/day, increased numbers of apoptotic and S-phase nuclei appeared in hepatocytes and endothelial cells. Following 30 doses of 1.0 and 2.5 mg/kg/day, hepatocytes exhibited reduced mitosis, fewer S-phase nuclei, increased hypertrophy, and fatty degeneration, while endothelial cells showed karyomegaly, cytomegaly, decreased apoptosis, more S-phase nuclei, and p53 positivity. Hepatocytes of treated animals expressed higher VEGF immunopositivity. That altered endothelial cells were fVIII-ra/vWf and VEGFR2 positive confirmed their identity. These changes may have promoted hemangiosarcoma development upon long-term exposure through endothelial adduct formation, apoptosis, proliferation of endothelial cells having undamaged and/or damaged DNA, and mutation. Endothelial proliferation may also have been promoted through endothelial arrest at S phase, which was associated with endothelial karyo- and cytomegaly, resulting in hepatocytic hypoxia, triggering VEGF induction.
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PMID:The hepatic endothelial carcinogen riddelliine induces endothelial apoptosis, mitosis, S phase, and p53 and hepatocytic vascular endothelial growth factor expression after short-term exposure. 1246 Jul 43

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.
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PMID:Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways. 1558 24

The prophylactic use of zidovudine (3'-azido-3'-deoxythymidine, AZT) during pregnancy greatly reduces transmission of HIV-1 from infected mothers to their infants; however, the affinity of host cell DNA polymerases for AZT also allows for its incorporation into host cell DNA, predisposing to cancer development. To expand upon previous transplacental carcinogenesis assays performed in CD-1 mice, the transplacental carcinogenicity of AZT was evaluated in a second mouse strain and a second rodent species. Date-mated female mice and rats were gavaged daily with 0, 80, 240, or 480 mg AZT/kg bw during the last 7 days of gestation. At 2 years postpartum, male and female B6C3F1 mouse and F344 rat offspring (n = 44-46 of each sex and species/treatment group) were necropsied for gross and microscopic tissue examinations. Under the conditions of these two-year studies, there was clear evidence of carcinogenic activity based upon significant dose-related trends and increases in the incidences of hemangiosarcoma in male mice and mononuclear cell leukemia in female rats. There was some evidence of carcinogenic activity in the livers of male mice based upon a positive trend and an increased incidence of hepatic carcinoma in the high-dose AZT group. The incidence of gliomas in female rats exceeded the historical background rates for gliomas in F344 rats. P53 overexpression was detected in some AZT-treated mouse neoplasms. These and other cancer-related findings confirm and extend those of previous transplacental carcinogenicity studies of AZT in mice, support the need for long-term follow-up of nucleoside reverse transcriptase inhibitor (NRTI)-exposed children, and indicate the necessity for effective protective strategies against NRTI-induced side effects.
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PMID:Transplacental carcinogenicity of 3'-azido-3'-deoxythymidine in B6C3F1 mice and F344 rats. 1735 26

To investigate whether inactivation of the p53 and retinoblastoma (Rb) protein pathways contributes to the development of canine hemangiosarcoma (HSA), we examined immunohistochemically the expression of p53, Rb, phosphorylated Rb (phospho-Rb), p16, and cyclin D1 in 39 spontaneous canine HSAs and 10 hemangiomas. In addition, mutations in the p53 gene were analyzed by polymerase chain reaction (PCR)-single-stranded conformation polymorphism and PCR direct sequencing; furthermore, we quantified cyclin D1 mRNA by semiquantitative real-time reverse transcription-PCR. Positive immunoreactivity for p53 was observed in 17.9% of HSAs. However, mutations were not detected in these cases. The labeling indices for Rb, phospho-Rb, and cyclin D1 were markedly higher in all HSAs than in hemangiomas. Of the 7 cases with cyclin D1-positive immunoreactivity, 4 overexpressed cyclin D1 mRNA (to a level more than 10-fold higher than that of GAPDH mRNA). The p16 protein was clearly detected in all hemangiomas; however, 82% of the neoplastic cells in HSA showed a loss of or low immunoreactivity. These results suggest that alteration of the p16-cyclin D1-Rb pathway, rather than the p53 pathway, may be associated with the pathogenesis of canine HSA.
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PMID:The significance of p53 and retinoblastoma pathways in canine hemangiosarcoma. 1740 43


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