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)

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

To evaluate the effects of adenovirus (Ad)-mediated transfer of p53 and p16 on human bladder cancer cells EJ, EJ were transfected with Ad-p53 and Ad-p16. Cell growth, morphological change, cell cycle, apoptosis were measured using MTT assay, flow cytometry, cloning formation, immunocytochemical assays. Ad-p16 or Ad-p53 alone could inhibit the proliferating activity of EJ cells in vitro. Ad-p53 could induce apoptosis of partial EJ cells. G1 arrest was observed 72 h after infection with Ad-p16, but apoptosis was not obvious. The transfer of Ad-p16 and Ad-p53 could significantly inhibit the growth of EJ cells, decrease the cloning formation rate and induce apoptosis of large number of EJ cells. The occurrence time of subcutaneous tumor was delayed and the tumor volume in 4 weeks was diminished by using Ad-p53 combined with Ad-p16 and the difference was significant compared with using Ad-p53 or Ad-p16 alone. It was suggested that the transfer of wild-type p53 and p16 could significantly inhibit the growth of human bladder cancer in vitro and in vivo.
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PMID:Adenovirus-mediated transfer of p53 and p16 inhibiting proliferating activity of human bladder cancer cell EJ in vitro and in vivo. 1267 70

Pentachlorophenol (PCP) is a widely used biocidal compound with several industrial, agricultural and domestic applications. Although it has been shown to induce systemic toxicity and carcinogenesis in several experimental studies, the literature is scarce regarding its toxic mechanisms of action. Recent investigations in our laboratory have shown that PCP induces cytotoxicity and transcriptionally activates stress genes in human liver carcinoma (HepG2) cells [1]. We hypothesized that PCP-induced expression of stress proteins may play a role in the molecular events leading to toxicity and tumorigenesis in liver cells. To test this hypothesis, we performed the MTT-assay for cell viability, and the Western Blot and densitometric analyses to assess the expression of cellular protein including CYP1A1, c-fos, HSP70, and p53. Data obtained from the MTT-assay indicated a strong dose-relationship with respect to PCP cytotoxicity. The LD50 was computed to be 23.0 +/- 5.6 micrograms/mL. Western Blot and densitometric analyses also demonstrated a linear dose-response relationship with regard to CYP1A1 expression within the dose range of 0-50 micrograms/mL. However, a biphasic response was obtained with regard to HSP70, c-fos, and p53 expression, showing a peak induction at 25 micrograms/mL, and a drastic reduction in protein expression at 50 micrograms/mL, probably due to cell death at higher level of PCP exposure. At lower level of exposure, PCP was found to be mitogenic.
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PMID:CYP1a1, HSP70, P53, and c-fos expression in human liver carcinoma cells (HepG2) exposed to pentachlorophenol. 1272 25

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

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

PC-SPES is an eight herbal mixture that was shown to have activity against prostate cancer. Recently, we purified oridonin from Rabdosia rubescens, one component of PC-SPES, by high performance liquid chromatography (HPLC). The ability of oridonin to inhibit the proliferation of cancer cells was examined by MTT assay. Oridonin effectively inhibited the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138) with ED50s ranging from 1.8 to 7.5 micro g/ml. TUNEL assay and cell cycle analysis showed that oridonin induced apoptosis and G0/G1 cell cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in LNCaP and NCI-H520 cells in a p53-dependent manner. Interestingly, when p53 was suppressed by over-expression of E6 from human papilloma virus type 16 (HPV-16), these cells lost their sensitivity to oridonin-induced growth inhibition and apoptosis. Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies and probably represents one of the major, active components of PC-SPES.
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PMID:Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. 1296 3

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

DNA-dependent protein kinase (DNA-PK) is involved in non-homologous end joining which repairs DNA double-strand breaks introduced by irradiation and radiomimetic agents. DNA-PK interacts with p53 but may also have p53-independent functions. The present study investigated whether disruption of the gene for the catalytic subunit DNA-PKcs affects chemosensitivity in p53-deficient cells. Drug sensitivity of DNA-PKcs(+/+)/p53(+/+), DNA-PKcs(+/+)/p53(-/-), DNA-PKcs(-/-)/p53(+/+), and DNA-PKcs(-/-)/p53(-/-) mouse lung-fibroblasts was determined by the MTT assay, the clonogenic assay, and trypan blue exclusion. Susceptibility to apoptosis was determined by DNA fragmentation (TUNEL) and by caspase-3 cleavage. We show that p53-deficient cells were 2 to 3-fold resistant to treatment with doxorubicin, epirubicin, cisplatin, and docetaxel as compared to wild-type cells. We further demonstrate that the additional loss of DNA-PKcs function in p53-deficient cells resulted in a 2-fold increase in sensitivity to doxorubicin and epirubicin as documented by the MTT assay, clonogenic assay, and trypan blue exclusion. Doxorubicin-induced hypersensitivity in these cells correlated with a transient G2/M checkpoint activation but did not seem to correlate with apoptosis. The data indicate that additional loss of DNA-PKcs in p53-deficient cells reverses anthracycline-resistance imposed by p53-deficiency, and that DNA-PKcs modulates p53-independent pathways responding to DNA damage induced by anthracyclines. They also indicate that processes other than apoptosis may contribute to the increased cytotoxicity to anthracyclines. DNA-PKcs may thus be a potential target for functional inhibition, which might increase the efficacy of some anti-tumour agents in the treatment of cancers mutated in the p53 gene.
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PMID:p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase. 1453 87

Polyozellus multiplex, a Korean wild mushroom, was extracted using methanol, and the extract was further fractionated with water and ethylacetate. Assay of each fraction with MTT revealed significant tumoristatic effects of the water fraction of Polyozellus multiplex against human gastric and other cancer cells but not normal human lymphocytes. Modifying effects of the water fraction on glandular stomach mucosa were investigated in male Wistar rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The dietary 0.5% or 1% water fraction of Polyozellus multiplex significantly increased glutathione S-transferase (GST) and superoxide dismutase (SOD) activities, and showed a tendency for increase in glutathione (GSH) levels, compared to the MNNG alone group. It also caused a significant reduction in proliferating cell nuclear antigen (PCNA)-labeling index of the glandular stomach epithelium, along with increase in p53 tumor suppressor gene expression. These results suggest that Polyozellus multiplex is a candidate for chemoprevention against gastric cancer.
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PMID:Polyozellus multiplex, a Korean wild mushroom, as a potent chemopreventive agent against stomach cancer. 1456 27

It has been recently established that low-frequency electromagnetic field (EMFs) exposure induces biological changes and could be associated with increased incidence of cancer, while the issue remains unresolved as to whether high-frequency EMFs can have hazardous effect on health. Epidemiological studies on association between childhood cancers, particularly leukemia and brain cancer, and exposure to low- and high-frequency EMF suggested an etiological role of EMFs in inducing adverse health effects. To investigate whether exposure to high-frequency EMFs could affect in vitro cell survival, we cultured acute T-lymphoblastoid leukemia cells (CCRF-CEM) in the presence of unmodulated 900 MHz EMF, generated by a transverse electromagnetic (TEM) cell, at various exposure times. We evaluated the effects of high-frequency EMF on cell growth rate and apoptosis induction, by cell viability (MTT) test, FACS analysis and DNA ladder, and we investigated pro-apoptotic and pro-survival signaling pathways possibly involved as a function of exposure time by Western blot analysis. At short exposure times (2-12 h), unmodulated 900 MHz EMF induced DNA breaks and early activation of both p53-dependent and -independent apoptotic pathways while longer continuous exposure (24-48 h) determined silencing of pro-apoptotic signals and activation of genes involved in both intracellular (Bcl-2) and extracellular (Ras and Akt1) pro-survival signaling. Overall our results indicate that exposure to 900 MHz continuous wave, after inducing an early self-defense response triggered by DNA damage, could confer to the survivor CCRF-CEM cells a further advantage to survive and proliferate.
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PMID:Exposure to 900 MHz electromagnetic field induces an unbalance between pro-apoptotic and pro-survival signals in T-lymphoblastoid leukemia CCRF-CEM cells. 1460 34


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