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)

DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life Sciences Institute (ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair deficient models respond to genotoxic carcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.
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PMID:Xpa and Xpa/p53+/- knockout mice: overview of available data. 1169 47

To determine whether interferon alfa (IFN-alpha) prevents in vivo oncogenesis in very-early-stage cancer cells, we evaluated the action of IFN-alpha2b over preneoplastic foci in rats. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine [DEN] plus 2-acetylaminofluorene [2-AAF]) of preneoplasia development (group 1), treated with IFN-alpha2b during the 2 phases (group 2), only during initiation with DEN (group 3), only during administration of 2-AAF (group 4), subjected only to an initiation stage (group 5), and treated with IFN-alpha2b during this period (group 6). The numbers of placental form of rat glutathione S-transferase (rGST-P)-positive foci per liver and the foci as percentage of liver were significantly reduced in groups 2, 3, and 6 but not in group 4. Rats treated with IFN-alpha2b showed a higher apoptotic index (AI) in altered hepatic foci (AHF). Levels of p53 and Bax protein in liver lysates were significantly increased in those animals. Similarly, levels of antiapoptotic proteins Bcl-2 and Bcl-x(L) in mitochondrial fraction were decreased. Finally, increased levels of Bax protein were localized in the mitochondria of rats that received IFN-alpha2b, at least during the DEN phase (groups 2, 3, and 6), whereas mitochondrial Bax expression was not increased in group 4. In conclusion, the preneoplastic hepatocytes in rats that received IFN-alpha2b during the initiation stage undergo programmed cell death as a primary result of a significant increase in the amount and translocation to the mitochondria of Bax protein.
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PMID:The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein. 1191 28

Both carcinogenic NF and AAF are metabolized to a common N-hydroxy metabolite, N-OH-AF. We investigated oxidative DNA damage by N-OH-AF, using (32)P-labeled human DNA fragments from the human p53 and p16 tumor-suppressor genes and the c-Ha-ras-1 protooncogene. N-OH-AF caused Cu(II)-mediated DNA damage, and endogenous reductant NADH markedly enhanced this process. Catalase and bathocuproine, a Cu(I)-specific chelator, decreased the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). N-OH-AF induced piperidine-labile lesions frequently at thymine and cytosine residues. With formamidopyrimidine-DNA glycosylase treatment, N-OH-AF induced cleavage at guanine residues, especially of the ACG sequence complementary to codon 273, a well-known hot spot of the p53 gene. N-OH-AF dose-dependently induced 8-oxodG formation in the presence of Cu(II) and NADH. Treatment with N-OH-AF increased amounts of 8-oxodG in HL-60 cells compared to the H(2)O(2)-resistant clone HP100, supporting the involvement of H(2)O(2). The present study demonstrates that the N-hydroxy metabolite of NF and AAF induces oxidative DNA damage through H(2)O(2) in both a cell-free system and cultured human cells. We conclude that oxidative DNA damage may play an important role in the carcinogenic process of NF and AAF in addition to previously reported DNA adduct formation.
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PMID:Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N-acetylaminofluorene. 1240 98

The hepatocarcinogen 2-acetylaminofluorene is one of the most studied experimental carcinogens. We have shown previously that normal rat hepatocytes accumulate the tumour suppressor p53 after exposure to this compound while preneoplastic rat hepatocytes do not. We suggested that the lack of p53 response may confer a growth advantage on preneoplastic hepatocytes and may be an important factor in hepatic tumor promotion by 2-acetylaminofluorene and other genotoxic compounds. Inhibition of RNA polymerase II driven transcription by DNA lesions may constitute one of the mechanisms leading to accumulation of the tumour suppressor p53. We have investigated the accumulation of p53 by structurally different DNA lesions of 2-acetylaminofluorene for which the rate of nucleotide excision repair (NER) and inhibition of transcription are known. Experiments were performed with NER proficient human fibroblasts as well as repair deficient xeroderma pigmentosum group A (XPA) cells, XPC cells [only transcription coupled repair (TCR)] and Cockayne syndrome (CS)B cells [only global genome repair (GGR)]. The cells were exposed to N-acetoxy-acetylaminofluorene (NAAAF) in the presence or absence of paraoxon inducing dG-C8-AAF or dG-C8-AF adducts respectively. Both treatments led to accumulation of p53 in all cells. However, dG-C8-AAF adducts produced greater p53 induction than dG-C8-AF adducts. The percentage p53-positive cells was highest and the threshold for p53 accumulation was lowest in XPA and CSB cells. Our results further demonstrate that both the potency of a lesion to inhibit transcription as well as the restoration of RNA synthesis determines the magnitude of p53 induction.
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PMID:Blockage of transcription as a trigger for p53 accumulation by 2-acetylaminofluorene DNA-adducts. 1288 15

To investigate effects that distinguish AAF from incomplete carcinogens, the rate of cell death (apoptosis) and cell proliferation was studied at early stages of AAF induced rat liver carcinogenesis. Male Wistar rats were fed 0.04% AAF in the diet for 2, 6 and 16 weeks and immunohistochemical markers were measured in the liver. The formation of initiated cells and preneoplastic foci was followed by staining for GST-P (glutathione-S-transferase). GST-P-positive foci were present from 6 weeks on. Apoptosis was increased in the periportal area and in preneoplastic foci at all time points. Cell proliferation was enhanced in the periportal area in oval cells and in bile duct-like cells particularly at 2 and 6 weeks and mainly in GST-P positive foci at 16 weeks. Notably, more cells always proliferated than were eliminated. Other apoptosis-related markers like p53 and FAS/Apo-1 could not be demonstrated in either normal hepatocytes, preneoplastic foci or in hepatocytes from treated animals. Scattered bcl-2 positive cells were present in livers at 16 weeks of treatment. The two cell growth and differentiation related proto-oncogenes c-FOS and c-JUN were increased in all treated animals at early stages. If feeding was stopped after 6 weeks, livers did not recover significantly within the following 10 weeks. The results support the complex effects of AAF in rat liver carcinogenesis. Chronic toxicity locally impairs the balance between cell proliferation and cell death and induces morphological alterations that promote the growth of initiated cells.
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PMID:Early effects in chemical-induced rat liver carcinogenesis: an immunohistochemical study following exposure to 0.04% AAF. 1464 69

Both nucleotide excision repair (NER) and the p53 tumor suppressor protein play crucial roles in the prevention of cells becoming cancerous. This is clearly demonstrated by the fact that NER-deficient xeroderma pigmentosum patients and Li-Fraumeni patients who carry a germ-line p53 mutation are highly tumor prone. The NER-deficient Xpa and the p53(+/-) mouse models clearly mimic their human counterparts, because they are both tumor prone as well. The aim of the study presented here was to analyze the relative contribution of these two pathways in tumor suppression and to analyze a possible link between NER and p53 activation in vivo. For this, we exposed Xpa, p53(+/-), and Xpa/p53(+/-) mice to 2-acetylaminofluorene (2-AAF). We show that 2-AAF-induced urinary bladder tumor suppression is dependent on p53 status, because p53(+/-) mice were highly tumor prone. Xpa/p53(+/-) mice were even more tumor prone, whereas no increased tumor response was found in Xpa mice. Short-term assays revealed a decreased apoptotic response in Xpa/p53(+/-) mice, pointing in vivo toward a link between NER and p53-mediated apoptosis. In contrast, liver tumor response was primarily dependent on appropriate DNA repair, because Xpa-deficient mice were liver tumor prone. p53 heterozygosity had no influence on liver tumor incidences, in line with the results obtained from the short-term 2-AAF studies revealing no altered cellular response in p53(+/-) or Xpa/p53(+/-) mice. Interestingly, however, mice completely deficient in both NER and p53 (Xpa/p53(-/-) mice) showed a dramatic increase of hepatocellular proliferation accompanied by lacZ reporter gene mutations.
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PMID:p53 heterozygosity results in an increased 2-acetylaminofluorene-induced urinary bladder but not liver tumor response in DNA repair-deficient Xpa mice. 1528 14

Cellular activity of the tumor suppressor protein p53 is primarily regulated by posttranslational modifications. Phosphorylation of the COOH terminus, including Ser389, is thought to result in a conformational change of the p53 protein, enhancing DNA binding and transcriptional activity. In vitro studies presented here show that, in addition to UV radiation, Ser389 is phosphorylated upon exposure to 2-acetylaminofluorene (2-AAF). Both agents induce bulky DNA adducts repaired by nucleotide excision repair (NER). In contrast, ionizing radiation, known to induce DNA damage not repaired by NER, does not result in Ser389 phosphorylation. Previously, we have shown that p53.S389A mutant mice, lacking the Ser389 phosphorylation site, are sensitive to developing UV-induced skin tumors. Here, we show that p53.S389A mice are also prone to developing 2-AAF-induced urinary bladder tumors, whereas no increased tumor response was found upon ionizing irradiation. These results provide evidence for our hypothesis that phosphorylation of Ser389 is important for activation of p53 to exert its function as a tumor suppressor not exclusively upon the presence of UV-induced DNA damage, but also upon exposure to other bulky adduct-inducing agents. Analysis of 2-AAF- and UV-induced tumors from p53.S389A mice revealed the presence of additional p53 mutations, indicating that lack of Ser389 phosphorylation by itself is not sufficient to abrogate p53 function in tumor suppression. In addition, analyses of skin tumors of p53.S389A mice revealed an interesting hotspot mutation previously found exclusively in NER-deficient mice and patients.
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PMID:Lack of p53 Ser389 phosphorylation predisposes mice to develop 2-acetylaminofluorene-induced bladder tumors but not ionizing radiation-induced lymphomas. 1586 55

Mice with non-phosphorylated serine 389 in p53 are susceptible for bladder tumors induced by 2-acetylaminofluorene (2-AAF). Since p53 is a transcription factor, this might well be preceded by differences in the regulation of gene expression. Microarray analysis was used to determine early transcriptional changes that might underlie this cancer-prone phenotype. Interestingly, lack of Ser389 phosphorylation led to endogenously different gene expression levels. The number of genes affected was, however, rather small. Conversely, after short-term exposure to 2-AAF, wild-type and p53.S389A bladders demonstrated a significant number of differentially expressed genes. Differences between wild-type and p53.S389A could mainly be attributed to a delayed, rather than complete absence of, transcriptional response of a group of genes, including well-known p53 target genes involved in apoptosis and cell-cycle control like Bax, Perp and P21. An analysis of differentially expressed genes in non-tumorigenic tissue and bladder tumors of p53.S389A after long-term exposure to 2-AAF revealed 319 genes. Comparison of these with those found after short-term exposure resulted in 23 transcripts. These possible marker genes might be useful for the early prediction of bladder tumor development. In conclusion, our data indicate that lack of Ser389 phosphorylation results in aberrant expression of genes needed to execute vital responses to DNA damage. Post-translational modifications, like Ser389 phosphorylation, seem crucial for fine-tuning the transcription of a specific set of genes and do not appear to give rise to major changes in transcription patterns. As such, Ser389 phosphorylation is needed for some, but certainly not all, p53 functions.
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PMID:Delayed expression of apoptotic and cell-cycle control genes in carcinogen-exposed bladders of mice lacking p53.S389 phosphorylation. 1731 80

The aromatic amine 2-acetylaminofluore (2-AAF) is a powerful complete genotoxic rat liver carcinogen that induces tumors without any additional interventions. While the tumor-initiating genotoxic activity of 2-AAF is well established, its tumor-promotion activity is far less understood. It is believed that the tumor-promoting property of 2-AAF is associated with selective enhancement of cell replication and sustained suppression of apoptosis in initiated cells. In the present study, we investigated the underlying mechanisms of tumor-promoting events induced by 2-AAF-exposure. Male Sprague-Dawley rats were fed NIH-31 diet containing 0.02% of 2-AAF for 12 and 24 weeks, and the expression pattern of genes associated with the p53-signaling pathway and microRNA genes was determined in the livers of control and 2-AAF-fed rats. The results indicate that the tumor-promoting property of 2-AAF during hepatocarcinogenesis is associated predominantly with the up-regulation of anti-apoptotic growth-related genes and down-regulation of expression of pro-apoptotic genes. This disrupts the balance between cell proliferation and apoptosis, which leads to consequential unrestricted cell proliferation, especially of initiated cells. Also, the long-term-administration of 2-AAF resulted in disruption of regulatory miR-34a-p53 feed-back loop that mediates apoptosis. This was evidenced by an increased expression of miR-34a in response to genotoxic effects of 2-AAF in the absence of p53 up-regulation, and loss of regulatory control of mir-34a on SIRT1 function. Additionally, the livers of 2-AAF-exposed rats were characterized by the substantial deregulation of expression of miR-18, miR-21, miR-182, and miR-200 family, microRNAs involved in control of apoptosis/cell proliferation and cell-cell contact pathways, two major pathways disrupted during the promotion stage of hepatocarcinogenesis.
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PMID:The tumor-promoting activity of 2-acetylaminofluorene is associated with disruption of the p53 signaling pathway and the balance between apoptosis and cell proliferation. 1916 16

In this manuscript, an efficient high resolution reversed phase-ion pairing-liquid chromatography electrospray ionization tandem mass spectrometry (RP-IP-LC-MS/MS) method for separation of isomeric modified oligonucleotides using a polymeric (styrene-divinylbenzene) monolithic capillary column is presented. The effects of different ion pairing reagents (IPR), their concentration, mobile phase additives and conditions were evaluated towards achieving the highest possible resolution and chromatographic separation of isomeric oligonucleotides. Ion pairing reagents and mobile phase conditions were evaluated using as model N-acetylaminofluorene [AAF] adducted ss-oligonucleotides (CCC CGA GCA ATC TCA AT). The optimized mobile phase conditions were then applied for the mapping of sites of base modification of AAF adducted 15-base pair oligonucleotide fragments containing codon 135 of the p53 gene and for profiling a complex synthetic oligonucleotide mixture. The optimized method utilizes a monolithic poly(styrene-divinylbenzene) capillary column, triethylammonium bicarbonate as ion pairing reagent and methanol as organic modifier to perform IP-RPLC-ESI-MS/MS separation. The results show that the method is simultaneously applicable not only to oligonucleotide fragments adducted separately by different carcinogens but also to the analysis of multiple adducts in the same oligonucleotide fragment in a single experiment. The method presents itself as a tool for the identification, characterization and mapping of oligonucleotide adducts as biomarkers for DNA damage from carcinogens.
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PMID:Reversed-phase ion-pair liquid chromatography electrospray ionization tandem mass spectrometry for separation, sequencing and mapping of sites of base modification of isomeric oligonucleotide adducts using monolithic column. 2265 52


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