UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dementia in Alzheimer's disease (AD) is correlated with cell loss that is mediated by apoptosis, mitochondrial (Mt) dysfunction, and possibly necrosis. Previous studies demonstrated increased expression of the nitric oxide synthase 3 (NOS3) gene in degenerating neurons of AD brains. For investigating the role of NOS3 overexpression as a mediator of neuronal loss, human PNET2 central nervous system-derived neuronal cells were infected with recombinant adenovirus vectors that expressed either human NOS3 or green fluorescent protein cDNA under the control of a CMV promoter. NOS3 overexpression resulted in apoptosis accompanied by increased levels of p53, p21/Waf1, Bax, and CD95. In addition, NOS3 overexpression impaired neuronal Mt function as demonstrated by the reduced levels of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and nicotinamide adenine dinucleotide (reduced form)-tetrazolium reductase activities and MitoTracker Red fluorescence. These adverse effects of NOS3 were associated with increased cellular levels of reactive oxygen species and impaired membrane integrity and were not produced in cells that were transfected with a cDNA encoding catalytically inactive NOS3. Importantly, modest elevations in NOS3 expression, achieved by infection with low multiplicities of adenovirus-NOS3 infection, did not cause apoptosis but rendered the cells more sensitive to oxidative injury by H(2)O(2) or diethyldithiocarbamate. In contrast, treatment with NO donors did not enhance neuronal sensitivity to oxidative injury. These results suggest that NOS3-induced neuronal death is mediated by Mt dysfunction, oxidative injury, and impaired membrane integrity, rather than by NO production, and that neuroprotection from these adverse effects of NOS3 may be achieved by modulating intracellular levels of oxidative stress.
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PMID:Nitric oxide synthase-3 overexpression causes apoptosis and impairs neuronal mitochondrial function: relevance to Alzheimer's-type neurodegeneration. 1259 42

The p53 mutant 143Ala is a human temperature-sensitive mutant with two conformational states. To definitively determine whether the Fas signal transduction pathway and the function of the pathway are dependent on p53 status, we have established stable transfectants of p53 mutant 143Ala in two human cancer cell lines: H1299 (lung cancer line) and PC-3 (prostate cancer line), the native state of which contains null p53 status and can grow at 37 degrees C and 32.5 degrees C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis showed inhibition of the growth of cells overexpressing p53 mutant 143Ala in the wild-type p53 form at 32.5 degrees C because of induction of G0/G1 arrest. Transfected cells had increased protein expression of p21, Fas, and MDM2 at the wild-type p53 conformation at 32.5 degrees C, but not in the mutant p53 form at 37 degrees C. However, there was no change in protein expression of FADD, FAP-1, Bcl-2, or Bax at 32.5 or 37 degrees C. Assays for apoptosis demonstrated that anti-Fas antibody CH-11 and FasL induced apoptosis only in cells that overexpress p53 mutant 143Ala at 32.5 degrees C with the wild-type p53 form. Both caspase-3 and caspase-8 activities were increased by anti-Fas antibody CH-11 only in cells at 32.5 degrees C with wild-type p53. Our results demonstrated that Fas-mediated apoptosis in H1299 and PC-3 cells expressing p53 mutant 143Ala occurred only with the wild-type p53 phenotype. These results support the hypothesis that Fas-mediated apoptosis is dependent, at least partially, on the presence of a functional wild-type p53 state. This model may be a useful tool for dissecting the specific interactions between wild-type p53 and the Fas signal transduction pathway in human cancer cells.
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PMID:Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143. 1267 Sep

The activity in vitro of four types of colicins (A, E1, E3, U) against one human standard fibroblast line and against 11 human tumor-cell lines carrying defined mutations of the p53 gene was quantified by MTT (tetrazolium bromide) assay. Flow cytometry showed that the pore-forming colicins A, E1 and U affected the cell cycle of 5 of these cell lines. Colicins E3 and U did not show any distinct inhibitory effects on the cell lines, while colicins E1 and especially A inhibited the growth of all of them (with one exception concerning colicin E1). Colicin E1 inhibited the growth of the tumor lines by 17-40% and standard fibroblasts MRC5 by 11%. Colicin A exhibited a differentiated 16-56% inhibition, the growth of standard fibroblasts being inhibited by 36%. In three of the lines, colicins A and E1 increased the number of cells in the G1 phase (by 12-58%) and in apoptosis (by 7-58%). These results correlated with the data from sensitivity assays. Hence, the inhibitory effect of colicins on eukaryotic cells in cell-selective, colicin-specific and can be considered to be cytotoxic.
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PMID:Human tumor cells are selectively inhibited by colicins. 1274 87

Several chaperone-binding drugs based on geldanamycin (GA) have been synthesized, and one of them, 17-allylamino-17-demethoxygeldanamycin (17-AAG), is being developed in the clinic. Interest in the use of 17-AAG in combination with cytotoxic drugs led us to study both GA and 17-AAG with cisplatin (DDP) in the human colon adenocarcinoma cell lines HT29 and HCT116. We performed isobologram analysis of combinations of DDP with GA or 17-AAG in these cell lines using the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to evaluate cell survival. In HCT116, the effects of GA and 17-AAG with DDP were additive and schedule dependent. In HT29 both GA and 17-AAG antagonized DDP effects resulting in cytotoxicity less than expected. We hypothesized that the antagonism in HT29 cells might be a consequence of altered p53 function in this cell line. Accordingly, we tested GA/17-AAG and DDP in combination in the HCTp5.2 cell line, which expresses a dominant-negative form of p53. In these cells too, the GA analogues antagonized DDP, suggesting a role for p53 in the observed effects. Investigation of the DDP-induced signaling pathways revealed that ansamycins block the activation of mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase pathways and c-Jun expression in HT29 cells while exerting incomplete inhibitory effects in HCT116 and HCTp5.2 cell lines. Therefore, effects on signaling are thought not to underlay the antagonism in the latter model. The ansamycins inhibited DDP-induced activation of caspases 8 and 3 in HT29 and HCTp5.2 but not in HCT116 cells, which we postulate to be the basis for higher survival of p53-deficient cells when treated with combinations of the two drugs.
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PMID:Geldanamycin and its 17-allylamino-17-demethoxy analogue antagonize the action of Cisplatin in human colon adenocarcinoma cells: differential caspase activation as a basis for interaction. 1281 Jun 54

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1*0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.
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PMID:Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes. 1287 24

Alzheimer's disease, Parkinson's disease, cystic fibrosis, prion diseases, and many types of cancer are considered to be protein conformation diseases. Most of them are also known as amyloidogenic diseases due to the occurrence of pathological accumulation of insoluble aggregates with fibrillar conformation. Some neuroblastomas, carcinomas, and myelomas show an abnormal accumulation of the wild-type tumor suppressor protein p53 either in the cytoplasm or in the nucleus of the cell. Here we show that the wild-type p53 core domain (p53C) can form fibrillar aggregates after mild perturbation. Gentle denaturation of p53C by pressure induces fibrillar aggregates, as shown by electron and atomic force microscopies, by binding of thioflavin T, and by circular dichroism. On the other hand, heat denaturation produced granular-shaped aggregates. Annular aggregates similar to those found in the early aggregation stages of alpha-synuclein and amyloid-beta were also observed by atomic force microscopy immediately after pressure treatment. Annular and fibrillar aggregates of p53C were toxic to cells, as shown by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] reduction assay. Interestingly, the hot-spot mutant R248Q underwent similar aggregation behavior when perturbed by pressure or high temperature. Fibrillar aggregates of p53C contribute to the loss of function of p53 and seed the accumulation of conformationally altered protein in some cancerous cells.
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PMID:Fibrillar aggregates of the tumor suppressor p53 core domain. 1288 35

Malignant tumours contain zones of chronic or acute hypoxia, which influence their prognosis and progression. The goal of our study was to understand the role of hypoxia in radio-resistance in a squamous cell carcinoma cell line of the head and neck (KB-3-1 cells). Cell growth was evaluated by Trypan blue exclusion under chronic hypoxia (3-5% O2) for 4 weeks or under normal conditions (21% O2). Cells were then gamma-irradiated either by X-ray (2-6 Gy) or UV-C radiation (0.001-10 J/cm(2)). Apoptosis was estimated by double staining with orange acridine and ethydium bromide and fluorescence microscopy. DNA content was estimated by FACS analysis. Expression of Bax, Bcl-2 and P53 was assessed by immunofluorescence and Western blotting. ROS production was measured by dichlorofluorescein fluorescence. Cell growth depends on oxygen tension. It decreased by 42 and 70% at 5 and 3% O2 compared to control with a significant cell cycle arrest rather than increased mortality. Hypoxic cells are more radio-resistant (x2.5) than normoxic cells. Under chronic hypoxia, Bcl-2 increased considerably in cells compared to control, while Bax and P53 did not change. After irradiation, in hypoxic cells very weak expression of the pro-apoptotic Bax protein and no translocation of Bax to the mitochondria were observed. In addition, irradiation of control KB-3-1 cells demonstrated a large increase in ROS production (x2) compared to cells irradiated identically under hypoxia. In conclusion, chronic hypoxia: i) seems to slow-down cell growth of KB-3-1 cells without inducing apoptosis, ii) induces Bcl-2 overexpression and prevents radiation-induced apoptosis by inhibiting ROS production and altering Bax subcellular redistribution and conformational changes.
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PMID:Chronic hypoxia protects against gamma-irradiation-induced apoptosis by inducing bcl-2 up-regulation and inhibiting mitochondrial translocation and conformational change of bax protein. 1296 83

The differential effects of arsenic compounds and the effect of selenium on arsenic-induced changes in cytotoxicity, viability, and cell cycle of porcine aorta endothelial cells (PAECs) were investigated. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay indicated that arsenic trioxide (As(2)O(3)) and sodium arsenite (NaAsO(2)) showed similar cytotoxicity, whereas sodium arsenate (Na(2)HAsO(4)) did not show cytotoxicity in PAECs. As(2)O(3) and NaAsO(2) at 20 microM decreased PAEC viability, decreased G0/G1 phase, and increased apoptosis. An increased G2/M phase was observed in NaAsO(2)-treated PAECs, whereas an increase in secondary necrosis (late apoptosis) was observed in As(2)O(3)-treated PAECs. As(2)O(3)-induced apoptosis was associated with upregulation of p53 and caspase 3, whereas NaAsO(2)-induced apoptosis was associated with p53 upregulation. Sodium selenite (Na(2)SeO(3)) at 1 nM reduced 20 microM As(2)O(3)-induced cytotoxicity, but not apoptosis, at 24 h. Increased glutathione peroxidase (GPX) activity by Na(2)SeO(3) pretreatment in 20 microM As(2)O(3)-treated PAECs suggests that Na(2)SeO(3) modulates As(2)O(3)-induced cytoxicity by GPX modulation.
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PMID:Modulation of the arsenic effects on cytotoxicity, viability, and cell cycle in porcine endothelial cells by selenium. 1312 16

We have developed a method that we call 'drug-sensitivity pattern analysis', or DSPA, for analysis of protein function. Cells are transfected with cDNA of the test molecule, followed by analysis of the sensitivity of the transfected cells to multiple growth-inhibitory drugs. If two cDNA products have similar functions, their transfected cells should show similar drug-sensitivity patterns. The cDNAs of some signaling molecules were transfected into NIH3T3 or Ha-ras-transformed NIH3T3 (ras-NIH) cells and stable transfectants, which expressed high amounts of the gene product, were isolated. Chemosensitivity of the transfected clone was compared with the parental cells by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method using more than 40 drugs. The chemosensitivity changes caused by the transfected gene were calculated and expressed numerically as 'drug chemosensitivity index' (DCI). When the DCI values were analyzed by regression analysis, a significant positive relationship between IkappaBalpha superrepressor and dominant-negative IKKbeta and an inverse relationship between p53 and Mdm2 were consistent with previous reports. Thus, the DSPA method is useful for identifying functional similarities between gene products.
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PMID:Drug-sensitivity pattern analysis for study of functional relationship between gene products. 1452 83

The tumor suppressor p53-related p73 shares significant amino-acid sequence identity with p53. Like p53, p73 recognizes canonical p53 DNA-binding sites and activates p53-responsive target genes and induces apoptosis. Moreover, transcription coactivator p300/CBP binds to and coactivates with both p53 and p73 in stimulating the expression of their target genes. Here, we report that coactivator PCAF binds to p73. The N-terminal transactivation domain (TAD) and the conserved oligomerization domain (OD) of p73 are both required for its interaction with PCAF. Conversely, PCAF's HAT-domain is required for and both the N-terminal region and Bromo domain enhance binding of PCAF to p73. Significantly, PCAF stimulates p73-mediated transactivation, and binding of PCAF to p73 is necessary for p73's transactivation activity. PCAF-specific siRNA dramatically reduces p73-mediated transactivation. Stimulation of p73-mediated transactivation by PCAF requires the HAT domain of PCAF and the p53-binding site within the p21 promoter. In vivo, coexpression of wild-type, but not HAT-deficient PCAF with p73beta markedly increases p21 expression. Furthermore, cotransfection of PCAF and p73 leads to increased apoptosis and reduced colony formation. Collectively, these data suggest that p73 recruit PCAF to specific promoters to activate the transcription of p73 target genes.
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PMID:PCAF is a coactivator for p73-mediated transactivation. 1461 55

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