Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.6 (catalase)
55,569 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the suppression, transformation, and transactivation functions of isolated segments of wild-type murine p53. Intact p53, but no segment of p53, inhibited cellular transformation by the activated ras and adenovirus E1A proteins. We conclude that most of p53 is needed for suppression of cellular proliferation. Nevertheless, the transactivating domain of herpesvirus protein VP16 was able to substitute for the N-terminal transactivating domain of p53 in cellular suppression. Thus, unless the interchanged p53 and VP16 acidic segments share additional functions, transactivation is required for suppression by p53. Interestingly, we found that all p53 segments containing amino acids 320-360 enhanced transformation by ras and E1A. This region has been associated with the oligomerization of p53 (Milner et al., 1991; Sturzbecher et al., 1992). Furthermore, no p53 segment lacking amino acids 320-360 transformed cells. Amino acids 320-360, therefore, may account for the major transforming activity of p53. Intact p53 and chimeric VP16-p53 transactivated the CAT gene under control of a p53-specific promoter, while transforming segments of p53 interfered with transactivation by wild-type p53. Our findings argue that transactivation by p53 is required for cellular suppression and that any nontransactivating p53 that retains the capacity to oligomerize with wild-type p53 would have transformation potential.
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PMID:p53 domains: suppression, transformation, and transactivation. 850 31

Accumulating evidence supports the hypothesis that tumor-suppressor p53 can act as a transcriptional activator. Insertion of high-affinity p53 DNA binding sites upstream of a promoter yields a p53-responsive vector. Chimeric proteins fusing p53 and the GAL4 DNA-binding domain demonstrate the presence of a transcriptional activating domain in the N-terminus of p53. GAL4-p53 chimeras constructed using naturally occurring p53 mutations at either codon 141 (Tyr-141) or 175 (His-175) of p53 had little ability to activate the reporter gene; in contrast, mutations at either codon 248 (Trp-248) or 273 (His-273) produced greater transcriptional activities than did wild-type p53. GAL4 chimeras can be used to analyse interactions between different domains of p53 and between different p53 alleles; a DNA binding site is defined, and a simple measurement can be made of function. We had expected that coexpression of GAL4 chimeras and p53 alleles would squelch transcriptional activation downstream of GAL binding sites. Surprisingly, coexpression of either p53 (Trp-248) or (His-273) with the GALA-p53 (wild-type, His-273, Trp-248, His-175, Tyr-141) effectors conferred an increase in transcriptional activation as compared with the effector alone. Oligomerization of p53 alleles with GAL4-p53 chimeras could underlie this effect, leading to an increase in transcription-activating motifs near the promoter. To test this possibility, we constructed a GAL4-p53 C-terminal chimera with p53 residues 160-393, lacking the transcriptional activating domain but retaining regions believed to be important in p53 oligomerization. Neither GAL4-p53 (C-terminus) nor p53 expression vectors were able to transactivate G5E1B-CAT alone. Both p53 (His-273) and (Trp-248) co-expressed with GAL4-p53 (C-terminus) were able to transactivate the G5E1B-CAT reporter gene; in contrast, p53 (Tyr-141) was not able to activate transcription. p53 (Tyr-141/His-273) behaved as a dominant negative mutant and inhibited the ability of the combination of p53 (His-273) and GAL4-p53 (C-terminus) to stimulate the reporter gene. Double immunoprecipitation by sequentially using GAL4 and p53 antibodies showed that p53 (His-273) and (Tyr-141/His-273), but not p53 (Tyr-141), can efficiently oligomerize in vivo to the C-terminal region of p53. Transcriptional activating function of p53 may be modulated by oligomerization; some mutations, such as His-273 and Trp-248, participate in these functions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mutant p53 proteins have diverse intracellular abilities to oligomerize and activate transcription. 851 Sep 27

AT cells are extremely sensitive to ionizing radiation. Since the AT gene has homology to phosphatidylinositol 3 kinases (PI 3-kinases), wortmannin, a specific inhibitor of PI 3-kinase, was used to determine if PI 3-kinase activity regulates radiation sensitivity. Human and murine cells exposed to wortmannin alone did not display significant cytotoxicity. Wortmannin in combination with radiation was an effective radiosensitizer of murine NIH-3T3 fibroblasts, with a sensitizer enhancement ratio of 1.8 at 10% survival, and had a similar effect on the human tumor cell lines HeLa, SW480, and MCF-7. Wortmannin inhibited the induction of p53 DNA-binding activity by actinomycin D and radiation and blocked the transcriptional activation of a p53 CAT reporter gene by actinomycin D. Wortmannin radiosensitized both wild-type (NIH-3T3 and MCF-7) and mutant (SW480 and HeLa) p53 cells, indicating that p53 induction was not required for radiosensitization by wortmannin. The results suggest that a wortmannin-sensitive pathway, possibly involving PI 3-kinase activity, may regulate the response of the cells to DNA damage.
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PMID:The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks induction of p53 following DNA damage. 854 74

Oxidative DNA damage by NAD(P)H in the presence of metal ions has been characterized by using 32P 5' end-labeled DNA fragments obtained from human p53 tumor suppressor gene and c-Ha-ras-1 protooncogene. NADH, as well as other endogenous reductants, induced DNA damage in the presence of Cu(II). The order of inducing effect on Cu(II)-dependent DNA damage was ascorbate > reduced glutathione (GSH) > NADH > NADPH. Although NADH caused no or little DNA damage in the presence of Fe(III)-EDTA, the addition of H2O2 induced the DNA damage. The Cu(II)-mediated DNA damage induced by NADH was inhibited by catalase and bathocuproine, a Cu(I)-specific chelator; but not by scavengers of hydroxyl free radical (.OH), suggesting the involvement of active species derived from hydrogen peroxide (H2O2) and Cu(I) rather than .OH. The predominant cleavage sites were thymine residues located 5' and/or 3' to guanine. The cleavage pattern was similar to that induced by Cu(II) plus GSH, Cu(II) plus ascorbate, or Cu(I) plus H2O2. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine by NADH increased with its concentration in the presence of Cu(II). UV-visible spectroscopy indicated the facilitation of reduction of Cu(II) by NADH under some conditions. ESR spin-trapping experiments and mass spectrometry showed that the carbon-centered radical was formed during the reaction of NADH with Cu(II). These results suggest that optimal molar ratios of DNA/metal ion yield copper with a high redox potential which catalyzes NADH autoxidation to NAD. being further oxidized to NAD+ with generation of superoxide radical and that H2O2 reacts with Cu(I) to form active oxygen species such as copper(I)-peroxide complex causing DNA damage.
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PMID:Site-specific DNA damage induced by NADH in the presence of copper(II): role of active oxygen species. 860 9

Biomodulated 5-flourouracil (5-FU) chemotherapy may limit disease progression in up to 50% of patients with metastatic or unresectable carcinoma of the colorectum. However, treatment is expensive and may be toxic. Thus any predictors of response may be clinically and economically valuable. The p53 gene is mutated in more than 50% of colorectal tumours, usually resulting in p53 overexpression. It may regulate cell cycle progression and cellular response to DNA damage. The principal anticancer activity of 5-FU is due to its ability to induce DNA damage. Fifty-nine patients received bolus intravenous 5-FU/folinic acid over 3 months. Response was assessed by CAT scan (WHO criteria). p53 protein overexpression was determined immunohistochemically from paraffin sections of the original primary tumour and resected metastases. Tumour over expression of p53 protein was associated with a lower rate of response and a higher rate of deterioration both radiologically (P < 0.03) and clinically (P < 0.05, chi 2 test for trend), but did not predict survival from start of treatment. Response was unrelated to age, sex, tumour grade, site of disease or chemotherapy schedule. Tumour p53 protein overexpression alone cannot be used to select advanced colorectal cancer patients for chemotherapy but may be useful in association with other markers of tumour biology.
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PMID:p53 protein overexpression and response to biomodulated 5-fluorouracil chemotherapy in patients with advanced colorectal cancer. 860 38

The level of p53 is markedly increased in human cells in response to expression of the Ad12 E1A proteins and, quite separately, to the Ad12 E1B 54K protein. The behaviour of p53 in these two circumstances has been examined using A549 cells infected with Ad12 dl620 (a mutant virus which does not express the larger E1B protein and is replication-defective) and human skin fibroblasts expressing the Ad12 E1B 54K protein (HSF 54K). In normal and E1A-expressing A549 cells, p53 is located predominantly in the nucleus, whereas in the HSF 54K cells it is primarily cytoplasmic as is the Ad12 E1B 54K protein. The half-life of p53 is increased in Ad12 dl620-infected A549 cells from about 10 min (in uninfected cells) to 2 hr. The half-life of p53 in HSF 54K cells is even longer-probably in excess of 48 hr. The capacity of p53 to regulate transcription was assessed using a transfected CAT construct linked to p53-responsive elements. p53 transcriptional activity was very low in the HSF 54K cells and in human embryo kidney cells expressing the Ad12 E1B 54K protein (and p53) at high level. It was, however, dramatically increased in response to the p53 expressed as a result of E1A expression. Additionally, MDM2 was present at low level in the HSF 54K cell lines, whilst, as we have previously shown, it is overexpressed in response to infection with Ad12 dl620. We conclude that there are two distinct mechanisms for up-regulation of p53 attributable to the adenovirus E1 proteins. When E1A only is present the p53 is nuclear and transcriptionally active and can probably induce apoptosis in the absence of the E1B 19K protein. When the E1B 54K protein is present, however, p53 is transcriptionally inactive and does not induce apoptosis.
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PMID:Control of p53 expression by adenovirus 12 early region 1A and early region 1B 54K proteins. 861 26

We show that the expression of the human cytokeratin 8 (CK8) gene is regulated by wild-type p53. DNA sequence data indicate that the 5' untranslated region of the CK8 gene contains a putative p53-like binding site. In this study we focused on the effect of the p53 protein on the regulation and expression of the CK8 gene. Cotransfection of the H358 p53-negative human lung cancer cell line with a CK8 promoter CAT expression vector and a plasmid expressing the wildtype p53 indicated that p53 induces CK8 expression. A transient assay in which a p53-negative cell line was cotransfected with a CK8 promoter CAT expression vector and a plasmid expressing wildtype or mutant p53 indicated that only wildtype p53 induces the CK8 promoter. Deletion of the putative p53-binding site from the CK8 promoter or introduction of mutations in the p53-binding sequences abolished the wild-type p53-mediated transactivation of CK8. A gel-retardation assay was used to measure DNA binding by the wild-type p53 protein. A 24-bp oligonucleotide corresponding to the putative p53 binding site was used for this assay. The wild-type p53 protein bound weakly to this DNA sequence but much more strongly when three tandem repeat of the binding sequences was used. These studies suggest that the CK8 gene is a downstream target whose expression is regulated by wild-type p53.
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PMID:p53 involvement in activation of the cytokeratin 8 gene in tumor cell lines. 861 94

p53 is an extensively studied tumor suppressor gene implicated in the genesis of a large number of varied tumors. However, the pathways of regulation for the wild-type p53 gene and its product are as yet unknown. In situ hybridization analyses of ETS1 and ETS2 expression during mouse embryogenesis, have shown a pattern similar to that of p53 gene expression. Significantly, we have identified several ETS-binding sites (EBS) in the promoter regions of the human and mouse p53 genes. In the human promoter two of these EBS are present in the form of a palindrome, with the two EBS cores being separated by four nucleotides. This report shows that the EBS palindrome of the human p53 promoter has a high affinity for ETS1 and ETS2 and that such binding interaction intracellularly is able to activate the transcription of a CAT reporter gene by 5-10-fold using COS cells. To investigate whether the spacing between the two EBS cores influences the DNA binding activity, we synthesized oligonucleotides with increasing distances (4,12,16, and 20 bases respectively) between the two EBS cores of the palindrome. We observed an inverse correlation between an increasing distance in the two EBS cores of the palindrome and the ETS1 and ETS2 DNA binding activity respectively. Interestingly, optimal DNA binding activity was observed when the distance between the two EBS cores was four bases, identical to that which occurs in the natural promoter. Furthermore we show that the p53 mRNA is expressed at higher levels in NIH3T3 cells overexpressing ETS2 gene product, suggesting that the ETS2 transcription factor is a likely candidate for regulating the expression of p53 in vivo.
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PMID:ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction. 864 21

The endogenous expression of p53 and p53-regulated genes has been examined in a thymidylate synthase-deficient colon carcinoma cell line (TS-) and a derived mutant clone (Thy4) that exhibit acute or delayed apoptotic responses, respectively, when released from G0 synchrony under conditions of dThd starvation. These cell clones demonstrate heterozygosity in p53, thereby expressing one wt allele and one with an A-->C point mutation at codon 240. Following release from G0, upregulated expression of both alleles occurred. During apoptosis in TS-, a wtp53 phenotype was expressed and in Thy4 during cytostasis, a mp53 phenotype was manifested, as determined from the ratios of wtp53/mp53 proteins, transactivation of p50-2 (a wtp53-responsive CAT reporter construct) and the endogenous expression of MDM2. Neither cytotoxicity nor cytostasis correlated with expression of p21Waf1/Cip1 Thy4 cells sustained accumulation of high levels of Bax in a wtp53-independent and dThd-independent manner and survival was associated with upregulated expression of Bcl-2. In contrast, Bax expression decreased in TS- during apoptosis, except in a highly resistant subpopulation that retained high levels of Bax. Data suggest that resistant cells (Thy4) can sustain high Bax expression and that Bcl-2 is upregulated in response to an apoptotic stimulus due to the absence of negative regulation by wtp53.
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PMID:Acute and delayed apoptosis induced by thymidine deprivation correlates with expression of p53 and p53-regulated genes in colon carcinoma cells. 866 31

Using DNA sequencing and immunohistochemical staining, p53 gene mutation and overexpression were investigated in 23 formalin-fixed and paraffin-embedded specimens of nasopharyngeal carcinoma (NPC). All patients were from regions of low NPC incidence in China. Sequencing of exon 7 and exon 8, revealed p53 gene mutation in 15 of the 23 specimens (65.2%). All the mutations were at codon 273(CGT-->CAT), so that arginine encoded by this codon was replaced by histidine. In addition, p53 overexpression was found in another NPC specimen without mutation in exon 7 or 8 of p53 gene. The results suggest that p53 gene mutation is of common occurrence in NPC. The hot-spot mutation at codon 273 might be related to some special carcinogen in the environment, or this change be essential in the multi-step process of carcinogenesis of the nasopharynx.
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PMID:[A hot-spot mutation of p53 gene in nasopharyngeal carcinoma]. 869 86


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