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 elucidate the role of p53 in colon tumorigenesis in mice, we examined allele loss and mutational alteration of the p53 gene in colon tumors induced by 1,2-dimethylhydrazine (DMH) in F1 hybrid mice. Intragenic polymorphism of the p53 gene among parental strains enabled us to assess allele loss of the p53 gene and also to determine parental origin of mutated and/or lost alleles. Allele loss was detected in two of 163 tumors heterozygous for the p53 gene. Polymerase chain reaction-single-strand conformation polymorphism analysis of p53 exons 5-8 revealed 33 mutations in 20 of 182 colon tumors, the incidence being lower than that in human colon cancers. The majority of these mutations were of transition type: G:A transitions at non-CpG sites were most prevalent, while those at CpG sites were less common. Distribution of the mutations along p53 amino acid sequence revealed a difference in the location of 'hot spots' between mice and humans. Incidence of p53 alterations did not differ among alleles of different parental origins, suggesting that genetic changes in DMH-induced mouse colon tumors had occurred independently of parental origin and DMH susceptibility. Detailed analysis of p53 mutations on each allele revealed intratumoral heterogeneity in mouse colon tumors. The low incidence of p53 mutations and rare allele loss suggest that p53 alteration plays only a minor role in colon tumorigenesis in mice.
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PMID:Mutational and LOH analyses of p53 alleles in colon tumors induced by 1,2-dimethylhydrazine in F1 hybrid mice. 758 83

We examined allelic loss in colon tumors induced by 1,2-dimethylhydrazine (DMH) in F1 hybrid mice, using sequence-tagged microsatellite site (STMS) primers derived from the chromosomal region closely linked to the p53 locus. Polymerase chain reaction--single-strand conformation polymorphism (PCR-SSCP) analysis of 155 colonic tumors with two STMS markers revealed that no genetic alterations had occurred in these tumors, except for one case where one of the markers detected an increase of one CA repeat unit in one allele. No allelic loss at the loci closely linked to the p53 locus strongly suggests that allelic loss at the p53 locus is not involved in DMH-induced colon carcinogenesis in mice.
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PMID:No allelic loss at the p53 locus in 1,2-dimethylhydrazine-induced mouse colon tumours: PCR-SSCP analysis with sequence-tagged microsatellite site primers. 833 Mar 70

The predisposition to colon cancer is multigenetically controlled in animals and probably also in humans. We have analyzed the multigenic control of susceptibility to 1,2-dimethylhydrazine-induced colon tumors in mice by using a set of 20 homozygous CcS/Dem recombinant congenic strains, each of which contains a different random subset of approximately 12.5% of genes from the susceptible strain STS/A and 87.5% of genes from the relatively resistant strain BALB/cHeA. Some CcS/Dem strains received the alleles from the susceptible strain STS/A at one or more of the multiple colon tumor susceptibility loci and are susceptible, whereas others are resistant. Linkage analysis shows that these susceptibility genes are different from the mouse homologs of the genes known to be somatically mutated in human colon cancer (KRAS2, TP53, DCC, MCC, APC, MSH2, and probably also MLH1). Different subsets of genes control tumor numbers and size. Two colon cancer susceptibility genes, Scc1 and Scc2, map to mouse chromosome 2. The Scc1 locus has been mapped to a narrow region of 2.4 centimorgans (90% confidence interval).
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PMID:Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. 857 18

We showed the possibility of significant decreasing of the frequency of chemically induced colon cancer in rats by vaccination with polyclonal rabbit IgG generated against purified tumor-associated antigens (TAA). TAA were isolated from benign rat colon tumors by the method developed in our laboratory (Zusman et al 1994) using affinity chromatography columns with gel fiberglass membranes (R. Zusman, 1992) containing anti-tumor IgG. The IgG was isolated from rabbits following their vaccination with TAA. Sprague Dawley rats were vaccinated with anti-TAA IgG (100 micrograms/rat) suspended in Freunds adjuvant by weekly subcutaneous injections for 5 weeks. The induction of colon cancer was caused by weekly injections with 1,2-dimethylhydrazine (DMH) (20 mg/kg) for 7 weeks and was started one week after the end of the vaccination. The results of experiments were evaluated 6 months after the start of cancer induction. IgG protected against the carcinogenic effects of DMH. The number of tumor-bearing rats decreased to 64% as compared with 90% in the control group. In vaccinated rats, the incidence of tumors was almost 3 times less than of control, i.e. 3.6 and 9.3, respectively. The number of malignant tumors was also significantly smaller in vaccinated rats than in controls, being 24% and 58%, respectively. Metastases were found only in controls, 4 of 30 rats. The results of our experiments have shown that anti-TAA IgG not only has anti-tumor effects but also prevents the malignization of benign tumors. As one of the main components of TAA which was isolated from colon cancer rats was soluble p53 antigen (Zusman et al 1994), we suggest that the vaccine which has been generated in our experiments may be regarded as acting mainly against p53 antigen, and its antitumor effects should also be considered as effects of p53 antibodies. The further studies will be performed to clarify this.
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PMID:IgG generated against benign tumor-associated antigens prevented the effects of 1,2-dimethylhydrazine in rats. 870 33

The restriction site mutation (RSM) assay was used to study the mutational sensitivities of three target regions of the murine p53 gene. The non-coding intron 6 target region was compared with the coding regions exon 4 and exon 5 with respect to their relative sensitivity to the induction of mutations by 1,2-dimethylhydrazine (DMH). Our results demonstrated that the majority of induced mutations detected were in the intron 6 gene region. A total of 15 enzyme-resistant restriction sites were detected in DMH treated mice, nine of these in the intron 6 region, four in the exon 4 region and two in the exon 5 region. The elevated sensitivity of the intron 6 region was exemplified by our detection of spontaneous mutations in this region; two resistant restriction sites were detected in untreated animals. No spontaneous mutations were detected in either of the exon sequences studied here, nor have any been detected in exon targets in our previous in vivo RSM analyses. The mutations induced by DMH were mostly GC-->AT transitions, as were the spontaneous mutations identified. The mutation frequencies calculated by the inclusion of a mutant internal standard (MIS) in the RSM method, revealed that the non-coding intron 6 region and the exon 4 region had a 10-fold higher mutation frequency than the exon 5 region. This heterogenous distribution of mutations and their differential mutation frequencies, were probably a consequence of the greater selection in the coding regions in p53 function. However, the actual mechanism of differential mutation induction is, as yet, to be defined.
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PMID:Enhanced restriction site mutation (RSM) analysis of 1,2-dimethylhydrazine induced mutations, using endogenous p53 intron sequences. 917 35

The role of apoptosis, proliferative cell nuclear antigen (PCNA) and p53 protein in the preventive effects of dietary fiber treated with the fungus Pleurotus ostreatus on rat-colon tumorigenesis was studied. Tumors were induced by five subcutaneous injections of 1,2-dimethylhydrazine (DMH), 20 mg/kg rat, once a week. Rats were fed a semi-synthetic fiberfree diet (control) or a high-fiber diet (15%) derived from corncob treated or non-treated with the fungus. The rats we sacrificed 24 weeks after the first carcinogenic injection. The fungus treated corn-cob significantly decreased tumor incidence (to 26%) as compared to 44% and 57% in the other dietary groups. The apoptotic index (AI) significantly decreased in malignant tissue as compared to non-tumorous tissue. PCNA and cytoplasmic content of p53 protein exhibited an increasing trend in malignant tissue as compared to benign tissue (at 15% and 18%, respectively). The fungus-treated corncob significantly increased the content of p53 in the cell cytoplasm (to 33%) and its serum levels in tumor-bearing rats (to 38%). The cellular concentration of PCNA decreased to 61% in tumors obtained from rats fed the fungus-treated corncob as compared to controls. A high positive correlation was found between tumor grade and p53 protein in the serum (r = 0.97) or in the cell cytoplasm (r = 0.77) and between tumor grade and PCNA (r = 0.81). An inverse relationship was found between tumor grade and AI (r = -0.63). We found that 15% of corncob fiber alone seems not to be enough to prevent chemically induced tumorigenesis. The corncob fiber (15%) treated with the fungus had a significant protective effect against DMH-induced rat colon cancer, even at 15% and this effect was accompanied by the activation of some cellular mechanisms such as apoptosis, PCNA and p53 protein activation. Incubation of corncob with the fungus Pleurotus os, increased the dietary fiber content up to 78%. Thus corncob inhibits colon cancer development, and, therefore, may considered of potential use to the public.
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PMID:Role of apoptosis, proliferating cell nuclear antigen and p53 protein in chemically induced colon cancer in rats fed corncob fiber treated with the fungus Pleurotus ostreatus. 921 72

Loss of DNA mismatch repair has been described in a number of tumour types such as colorectal adenocarcinoma and leads to microsatellite instability. This may have clinical relevance due to mismatch repair defects altering chemosensitivity towards certain classes of anti-tumour agent. This study has examined microsatellite instability of eight murine colon adenocarcinoma tumour models induced by 1,2-dimethylhydrazine. Four microsatellite regions were examined suggesting that four of the tumour models exhibit a low level of microsatellite instability. Loss of heterozygosity was found in 5/8 tumours, suggesting that allelic loss may be a relatively common step in the carcinogenesis of these tumour models. Three of the allelic losses involved the D11MIT4 locus which is situated very close to the p53 tumour suppressor locus. Four tumour models are routinely cultured in vitro and these were used to examine whether there was any association between microsatellite instability, mutant frequency and chemo-sensitivity of these tumour models, comparing them with four human adenocarcinoma cell lines of known mismatch repair status. Two cell lines (MAC26 and MAC16) were found to be more chemoresistant towards cisplatin but not 6-thioguanine. No association was found between microsatellite instability and chemosensitivity for either the human or mouse cell lines.
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PMID:Microsatellite instability, chemosensitivity and mutant frequency in a series of 1,2-dimethylhydrazine induced murine colon adenocarcinoma models. 968 89

While inheritance of mutated alleles of highly penetrant tumor suppressor genes such as retinoblastoma or p53 predisposes individuals to a greatly increased risk of developing cancer, epidemiological data indicate that the majority of sporadic tumors in humans result from interactions of environmental and host genetic factors. The host genetic factors are poorly penetrant tumor susceptibility genes that determine the likelihood that a cancer will arise from carcinogen exposure. The majority of colon tumors in humans are sporadic in nature. 1,2-dimethylhydrazine (DMH)-induced colon tumors in mice provide a useful animal model to identify genes that influence susceptibility to carcinogen-induced colon tumors in humans. A genome-wide scan of genetic crosses of relatively sensitive C57BL/6J with relatively resistant CBA mice treated with DMH revealed a linkage of DMH susceptibility with the distal end of mouse chromosome 3, suggesting that one or more tumor susceptibility genes may map to this region.
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PMID:A locus that influences susceptibility to 1, 2-dimethylhydrazine-induced colon tumors maps to the distal end of mouse chromosome 3. 1064 36

Transgenic mice with germ-line p53 alleles disrupted by gene targeting are sensitive to the development of some spontaneous tumors and have provided researchers with much information with respect to cancer. In the present study, to cast light on the organ specificity of chemically induced carcinogenesis, we evaluated carcinogen-induced cell proliferation in target organs in heterozygote p53 knockout mice (p53-deficient mice). Groups of 9- or 10-week-old wild-type(+/+) and p53-deficient mice were respectively treated with one of the following carcinogens for 4 weeks: N-butyl-N-(4-hydroxybutyl)nitrosamine (0.0075% in drinking water); dimethylnitrosamine (0.001% in drinking water); dihydroxy-di-N-propylnitrosamine (0.1% in drinking water); 1,2-dimethylhydrazine (10 mg/kg body weight s.c. injection once a week); 4-nitroquinoline 1-oxide (4-NQO, 10 mg/kg b.w. s.c. injection once a week); or 7,12-dimethylbenz(a)anthracene (25 microg/kg body weight dermal application once a week). Cell proliferation was evaluated by measuring the 5-bromo-2'-deoxyuridine labeling indices in each target organ. The p53 and p21 statuses were evaluated by comparing the expressions of p53 protein, p21waf1/cip1 mRNA, and p21waf1/cip1 protein between the mice. 5-Bromo-2'-deoxyuridine labeling indices of the urinary bladder and the skin were significantly increased in p53-deficient mice as compared with the wild-type(+/+) mice. In the all organs examined, carcinogen-induced p21waf1/cip1 mRNA overexpression was detected with levels obviously lower in the p53-deficient animals. These data suggest that p53-deficient mice have an organ-specific increased sensitivity to the induction of cell proliferation in the urinary bladder and the skin. These are the same organs for which sensitivity to carcinogenesis has been reported. Because a decrease of p21waf1/cip1 protein overexpression was also observed in the organs in which cell proliferation did not appreciably differ from the level in wild-type(+/+) mice, this decrease might have no effect on sensitivity to cell proliferation and carcinogenesis. Alternatively, it might play an important role in the cell cycle regulation of only the sensitive organs.
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PMID:Organ-specific, carcinogen-induced increases in cell proliferation in p53-deficient mice. 1064 56

The tumor suppressor gene p53 is perhaps the most commonly mutated gene in human cancer, being mutated in a high percentage of colon, breast, skin, bladder, and many cancers of the aerodigestive tract. Individuals with Li-Fraumeni syndrome, who routinely have a germline mutation in the p53 tumor suppressor gene, are at high risk for lung cancer, confirming its intimate role in lung tumorigenesis in humans. In contrast, the majority of chemically induced or spontaneous cancers in rodents do not contain mutations in p53. Therefore, we examined a transgenic mouse that contains a dominant negative mutation (Arg135Val) in the p53 gene placed under the control of its own endogenous promoter. The resulting mice have 3 copies of the mutated transgene as well as 2 normal p53 alleles. In the chemical carcinogenesis studies, we employed mice containing the mutated p53 gene to examine for carcinogen susceptibility. We found that mice with the p53 mutation, on an A/J F1 background, were more susceptible to a number of potential lung carcinogens, including N-methyl-N-nitrosourea (MNU) and the known tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BP). Mice with a mutant p53 developed larger tumors and roughly 3 times as many tumors, emphasizing the potential effects of a p53 mutation both on tumor initiation and progression. In addition, we examined 2 nonlung carcinogens, 1,2-dimethylhydrazine (DMH), a colon carcinogen, and N-butyl-N-(4-hydroxybutyl)-nitrosamine (OHBBN), a bladder carcinogen. Interestingly a germline p53 mutation increased the incidence of DMH-induced colon, lung, hepatic, and uterine tumors, while having limited effects on OHBBN-induced bladder tumors. Because of its heightened susceptibility we are examining the use of this model in smoke-induced tumorigenesis in A/J mice as well. Employing the lung adenomas induced by NNK, we found that mice with or without a p53 mutation were equally susceptible to the chemopreventive effects of dexamethasone plus myo-inisitol and green tea. These tumors, which arise in a highly reproducible manner in p53 transgenic mice following carcinogen treatment, have mutations in both p53 and the K-ras oncogene. Thus, this model appears useful for examining for potential chemotherapeutic agents. p53-mutated or wild-type mice were equally susceptible to the therapeutic effects of Taxol or Adriamycin. Interestingly, piroxicam was similarly effective in inhibiting colon tumor formation by DMH in mice with or without a mutation in the p53 tumor suppressor gene. In contrast, lung and uterine tumors developing in these mice were not susceptible to the chemopreventive effects of piroxicam. In summary, mice with mutations in the p53 tumor suppressor gene appear to be particularly applicable for basic mechanistic studies, for screening for potential carcinogens, and for screening for chemopreventive or chemotherapeutic agents.
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PMID:Use of p53 transgenic mice in the development of cancer models for multiple purposes. 1119 57


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