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)

A novel mutation of the p53 gene has been found in a rat hepatoma cell line, FAA-HTC1. This cell line carried two kinds of abnormal p53 transcripts; one lacked the exon 8 sequence, and the other had a single base substitution G to T which resulted in a new stop codon in exon 8. In the genomic DNA, this base substitution in exon 8 was present, indicating that both transcripts were transcribed from the mutated gene. No mutation was detected in its two flanking introns. In this cell line, the exon-deleted transcript seems to be generated by exon skipping due to an unknown mechanism other than splice site mutations.
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PMID:Alternatively-spliced p53 mRNA in the FAA-HTC1 rat hepatoma cell line without the splice site mutations. 129 97

p53 and c-myc are both known to be involved in apoptotic cell death as well as positive or negative regulation of cell proliferation, but it is not well established whether their functions are mechanistically correlated. We found that FAA-HTC1 cells, a rat hepatocellular carcinoma cell line, expressed c-myc independently of cell cycle and no detectable p53. To investigate possible co-operation between p53 and c-myc, the dexamethasone (Dex)-inducible wild type rat p53 was stably transfected into this cell line and c-myc expression was suppressed by treatment with c-myc antisense oligonucleotide (AS). p53 expression in the p53-introduced derivative resulted in apoptotic cell death, but it did not inhibit proliferative growth of the viable cells. On the other hand, when c-myc was suppressed in the p53-expressing cells, both apoptosis and cell growth were inhibited. These results indicate that p53 can act in the same cells either as a growth-inhibitor or apoptosis-inducer depending on the status of c-myc expression.
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PMID:Wild type p53 and c-myc co-operation in generating apoptosis of a rat hepatocellular carcinoma cell line (FAA-HTC1). 756 58

2-Acetylaminofluorene (2-AAF) is a complete carcinogen in rat liver. To investigate the specific properties, that distinguish 2-AAF from incomplete carcinogens, rats were fed 0.02% AAF in the diet for 6, 12, 16 weeks and some indicators of genotoxic and chronic toxic effects were studied immunohistochemically. GST-P, a marker for single initiated cells and preneoplastic foci, was induced in response to 2-AAF exposure. The effects were slight after 6 weeks of feeding, after 12 weeks GST-P-positive preneoplastic foci were present. The proto-oncogenes c-fos and c-jun are induced by several tumor promoters. In the present study c-FOS protein levels were increased in all 2-AAF treated animals at early stages not only in preneoplastic foci. However, all GST-P-positive foci were also c-FOS-positive. Surprisingly c-JUN was not enhanced in GST-P positive foci. It was comparatively expressed in hepatocytes and bile duct cells in all animals. We did not observe any immunolabeling for p53, either in preneoplastic foci or in hepatocytes from treated animals. A significant increase of apoptoses was noted in the whole liver lobule but also gathered in groups in the periportal area. The results support our proposal that oxidative stress and energy impairment in the mitochondria of periportal hepatocytes trigger morphological alterations in the rat liver.
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PMID:Early initiating and promoting effects in 2-AAF-induced rat liver carcinogenesis: an immunohistochemical study. 852 4

DNA damage is recognized widely as a cause of programmed cell death (apoptosis), aimed at eliminating cells bearing genotoxic lesions. Therefore, inhibition of DNA damage-induced apoptosis may play an important role in carcinogenesis and has been suggested as a mechanism of action of tumor-promoting agents. In the present study, the effects of treatment with UV light or the carcinogenic aromatic amine 2-acetylaminofluorene (2-AAF) on apoptosis were studied in rat hepatocytes in primary culture. A significantly increased incidence of apoptotic nuclei, showing condensed or fragmented chromatin visualized with the fluorescent dye Hoechst 33258, was found after each type of treatment. After 48 h, the incidence of apoptosis had returned to the control level. When the liver tumor promoters 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and phenobarbital were added to the medium, apoptosis did not increase in UV- or 2-AAF-treated compared with untreated cultures. Furthermore, TCDD and phenobarbital suppressed internucleosomal DNA fragmentation elicited by UV irradiation. In contrast, the promoters did not suppress apoptosis induced by transforming growth factor beta 1. Immunoprecipitation of the tumor suppressor gene product p53 demonstrated that the increase in p53 observed after UV irradiation was abrogated almost completely by TCDD. Apoptosis induced in rat hepatocytes by DNA-damaging agents such as UV light or 2-AAF is suppressed by TCDD and phenobarbital. Inhibition of apoptosis allowing survival of hepatocytes bearing genotoxic lesions may be crucial for the tumor-promoting action of TCDD and phenobarbital in the liver.
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PMID:Influence of liver tumor promoters on apoptosis in rat hepatocytes induced by 2-acetylaminofluorene, ultraviolet light, or transforming growth factor beta 1. 864 Aug 13

The effects of dietary 2-acetylaminofluorene (2-AAF) on cell cycle-related proteins was studied in regenerating livers from male Wistar rats. The levels of cyclins, cyclin dependent kinases (cdks), and related proteins were studied at different times during the first cell cycle after partial hepatectomy (PH). The frequency of proliferation cell nuclear antigen (PCNA)-positive nuclei, a marker of S phase progression, was almost zero during the first 27 hours after PH in the mitoinhibited 2-AAF-treated rats, while about 50% of the nuclei were labeled 24 hours after PH in control animals. Accordingly, Western blot tests showed markedly elevated PCNA protein levels from 18 hours to the end of S phase in untreated animals but no upregulation in response to 2-AAF. Compared with control animals, animals treated with 2-AAF showed increased levels of cdk 4 and cyclin D3 from 12 and 15 hours after PH, respectively, and altered cyclicity in cyclin D3 expression. No effects on cyclin E were observed, while the increase in cdk 2 levels in control animals during late G1/S (15-27 hours) was abolished by 2-AAF. p53 was induced by 2-AAF treatment during the same period, with a peak at 24 hours. The protein detected with p21 antibodies was highly expressed in unstimulated hepatocytes in control animals, and further increased by 2-AAF. The expression was sustained until 15 hours after PH in control rats while 2-AAF-treated animals lacked detectable protein during this period; however, a transient increase was observed at 21 hours. Thus, 2-AAF affects several parameters of cell cycle regulation of possible relevance for its inhibitory effects on hepatocyte proliferation in vivo.
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PMID:Inhibition of in vivo rat liver regeneration by 2-acetylaminofluorene affects the regulation of cell cycle-related proteins. 950 Jun 96

Most available data on the involvement of p53 in rodent carcinogenesis are based on results of the end point of chemically or virally induced carcinogenesis, i.e., tumors. To investigate the role of altered p53 expression in early stages of rodent hepatocarcinogenesis in a systematic way, we treated male Wistar rats for 6 wk, for 13 wk, and for 6 wk followed by a 7-wk recovery period with chemicals classified as genotoxic (200 ppm acetylaminofluorene [AAF], 100 ppm N-nitrosomorpholine [MMN], 200 ppm benzo(a)pyrene), as tumor promoters and carcinogenic in experimental animals (5 ppm ethinylestradiol, 500 ppm phenobarbitone, 3,000 ppm clofibric acid), as carcinogenic in animal experiments (600 ppm thioacetamide), as noncarcinogenic (200 ppm thyroxine), and as tumor promoters in experimental animals (20,000 ppm tryptophan, 120,000 ppm fructose). Immunohistochemical assessment of altered p53 expression on liver sections with polyclonal serum (CM5) resulted in positive staining in 17/21 benzo(a)pyrene-, 1/18 thioacetamide-, 2/21 clofibric acid-, 2/21 phenobarbitone-, 7/19 ethinylestradiol-, 1/21 tryptophan-, 3/19 thyroxine-, and 1/21 fructose-treated rats and in 2/19 controls. These data support earlier results obtained from analogous investigations with a high incidence of altered p53 expression after NNM and AAF treatment. Thus, altered p53 expression appears to be an early and frequent event in rodent carcinogenesis induced by genotoxic chemicals in contrast to most epigenetically acting chemicals.
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PMID:Altered p53 expression in early stages of chemically induced rodent hepatocarcinogenesis. 978 50

2-Acetylaminofluorene (AAF) is a potent tumor promoter in rat liver carcinogenesis models. In the resistant hepatocyte model, AAF is combined with a growth stimulus for efficient promotion of preneoplastic lesions. The promoting property of AAF in this model is closely associated with mito-inhibition of normal hepatocytes, an effect to which initiated cells are resistant. How AAF induces growth arrest is not known, but genotoxic as well as non-genotoxic effects have been implicated. To elucidate the mechanisms of AAF-induced mito-inhibition, we studied the expression of the tumor suppressor protein p53 and the cyclin-dependent kinase (cdk) complexes mediating G1 progression and S-phase entry. Hepatocytes were isolated from male Fisher 344 rats fed either a control diet or a diet supplemented with 0.02% AAF for 1 wk and cultured in a defined serum-free medium containing epidermal growth factor, insulin, and dexamethasone. Thymidine labeling revealed a profound inhibition of DNA synthesis in AAF-exposed cells compared with control cells. The retinoblastoma protein did not become hyperphosphorylated in AAF-exposed cells. Thus, inhibition of G1 cyclin-cdk activity was implied as a cause of growth arrest. Indeed, G1 cell-cycle arrest was accompanied by reduced induction and nuclear accumulation of the cyclin D1-cdk4 complex and inhibited nuclear translocation of cdk2. Furthermore, the growth arrest was not mediated through p21/waf1 upregulation, although nuclear levels of p53 were increased. Thus, carcinogen-induced mito-inhibition may be effected by altered levels and localization of G1 cyclin-cdk complexes, independent of the upregulation of cdk inhibitory proteins.
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PMID:Alteration of G1 cell-cycle protein expression and induction of p53 but not p21/waf1 by the DNA-modifying carcinogen 2-acetylaminofluorene in growth-stimulated hepatocytes in vitro. 1002 9

In the Solt-Faber model DENA and 2-Acetaminofluorene (AAF) treatment combined with hepatectomy induces hepatocellular carcinoma in rats. In this model AAF blocks proliferation of hepatocytes, while oval cells restore liver mass. Here we studied the molecular mechanism involved in blocking AAF-dependent cell cycle progression of hepatocytes. AAF inhibits cell proliferation of hepatocytes shown by the lack of Cyclin E expression before the G1/S phase restriction point. Immunfluorescence studies revealed that Cyclin E positive signals were restricted to oval cells, while hepatocytes remained negative. Additionally, AAF treatment induces strong nuclear p53 expression which is associated with increased p21 mRNA levels. Inhibition of active Cyclin/CdK (cyclin dependent kinase) complexes is reflected in AAF-treated animals by decreased RB expression and phosphorylation. The decrease in RB expression and phosphorylation, which is essential in triggering DNA synthesis and Cyclin A expression, leads to a deficiency in transcriptionally active E2F complex formation after hepatectomy. Thus, two molecular explanations are evident to account for AAF-dependent cell cycle progression of hepatocytes in vivo: first, induction of p53 expression which leads to higher p21 mRNA levels, and second, a lack of Cyclin E expression at the G1/S phase restriction point after hepatectomy.
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PMID:2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21 induction and lack of cyclin E expression. 1059 46

We report here the successful application of the restriction site mutation (RSM) assay in detecting 2-acetylaminofluorene (2-AAF)-induced mouse liver mutations. A total of seven 2-AAF-induced liver mutations were detected out of a total of 304 analyses performed on 2-AAF-treated liver tissue. No mutations were detected in the 190 RSM analyses performed on untreated liver tissue. The 2-AAF-induced point mutations comprised 60% GC-->TA transversions, 30% GC-->AT transitions, 10% GC-->CG transversions, and 1 insertional event was also detected. All seven mutations were detected in intron 6 of the mouse p53 gene, with no mutations detectable in exons 4 or 5, supporting our previous data on the greater mutability of intron regions. In addition to the RSM analysis, we also report the application of the in vivo bone marrow micronucleus assay in detecting the clastogenicity of 2-AAF. We detected a small, but statistically significant, increase in the number of micronuclei induced by 2-AAF, but only after 2,000 cells were scored. This also confirms previous data showing that 2-AAF is a weak clastogen. Finally, we attempted to compare the sensitivity of the two assays to 2-AAF-induced genotoxicity, as had been previously undertaken with ENU. Both assays detected genotoxicity in their respective tissues; however, different endpoints were analysed. The RSM assay appears to be more adaptable than the micronucleus assay, due to its tissue and organism independence and has the potential to provide more molecular information on genotoxicity. Teratogenesis Carcinog. Mutagen. 20:107-117, 2000.
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PMID:Restriction site mutation (RSM) analysis of 2-acetylaminofluorene (2-AAF)-induced mouse liver mutations and comparison with the measurement of in vivo micronucleus induction in the bone marrows of (2-AAF)-treated mice. 1082 Apr 21

Previous studies have indicated that isolated preneoplastic rat hepatocytes in vitro fail to induce nuclear p53 protein and fail to block replication in response to genotoxic compounds. This suggests that defects in the protection of genomic integrity are part of their premalignant character. In the present study, we have investigated if similar defects occur in vivo. Preneoplastic glutathione-S-transferase (GST) 7-7-positive foci were induced in male Wistar rats by diethylnitrosamine (DEN) initiation and promotion with 2-acetylaminofluorene (2-AAF)/partial hepatectomy (PH). The response to genotoxic damage was studied by X-irradiation. p53 protein was moderately expressed in nuclei in surrounding hepatocytes. This nuclear p53 staining had decreased 2 weeks after 2-AAF treatment. In foci, the protein was detected in the cytoplasm whereas the nuclei were negative. Levels of p21(waf1/cip1) protein were high in nuclei and cytoplasm of surrounding hepatocytes, whereas the expression in foci was low. A low level of Mdm2 in nuclei was observed in surrounding liver, while both Mdm2 and Bcl-2 protein were strongly expressed in the cytoplasm in foci. X-ray exposure further induced nuclear expression of p53, p21(waf1/cip1), and Mdm2 in surrounding hepatocytes, but focal nuclei were still negative. DNA replication was strongly reduced by X-irradiation in surrounding hepatocytes, but only partially reduced in the foci. These results indicate that the p53 pathway of response to genomic stress is impaired in preneoplastic cells in vivo. This may support their clonal expansion and their further malignant transformation because protection against genetic damage is diminished.
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PMID:Loss of nuclear p53 protein in preneoplastic rat hepatocytes is accompanied by Mdm2 and Bcl-2 overexpression and by defective response to DNA damage in vivo. 1117 56


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