Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several genes have been implicated in the regulation of apoptosis including bcl-2, bax, bcl-X and p53. These genes may be important in the development of nitrogen mustard (NM) drug resistance in B-cell chronic lymphocytic leukemia (B-CLL). Using Western blot analysis, we examined the levels of Bcl-2, Bax, Bcl-X and p53 protein expression and determined whether the levels of these proteins correlated with in vitro drug resistance in CLL patients' lymphocyte samples. Our investigations suggest that in CLL, NM drug resistance develops without any detectable alteration of Bcl-2, Bax or Bcl-X. In addition, we determined the presence of p53 mutations in 14 samples in order to assess if there is an association between in vitro drug resistance and the presence of p53 mutations. Using single-stranded conformational polymorphism (SSCP) and sequencing analysis, we observed a p53 mutation in two out of seven resistant samples. The mutation occurring in both cases was a G:C --> A:T transition at codon 273 (exon 8). One of these cases was de novo resistant to the nitrogen mustards. Only one of six samples with acquired resistance to the nitrogen mustards had a p53 mutation suggesting that p53 mutations are not a prominent feature of acquired NM resistance in CLL.
 ...
PMID:Relationship between nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia (B-CLL) and protein expression of Bcl-2, Bax, Bcl-X and p53. 945 75

Meat cooked at high temperatures contains mutagens and carcinogens known as heterocyclic amines (HCA). Cooking temperature and time determine the amount of HCA produced. The present study examined the DNA of liver, colon, and stomach from rats fed a high level of HCA for 27 weeks. Male Sprague-Dawley rats were fed a high-fat AIN-76A-based diet containing 60% by weight cooked beef containing a high level of HCA, especially 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, 72 ng/g cooked beef), the most abundant HCA in cooked meat products. At the end of 27 weeks the rats were terminated, and small portions of liver, colon, and stomach were quick-frozen in liquid nitrogen. The DNA was isolated from the thawed tissue by phenol-chloroform extraction, and the genomic DNA was analyzed for the presence of PhIP adducts by 32P-postla-beling analysis. The DNA was also used in polymerase chain reactions to amplify the rat p53 and Apc genes, then direct dye-terminator DNA sequencing was carried out. Results showed no PhIP adducts in any tissue. In addition, no signature p53 or Apc gene mutations were seen in colon or stomach DNA. These results indicate that the high level of HCA present in a diet of well-cooked meat does not cause 1) persistent PhIP adducts similar to those produced by feeding pure PhIP at high doses or 2) p53 and Apc gene mutations in nontumor tissue.
 ...
PMID:Absence of PhIP adducts, p53 and Apc mutations, in rats fed a cooked beef diet containing a high level of heterocyclic amines. 963 95

High concentrations of nitric oxide (NO) cause DNA damage and apoptosis in many cell types. Thus, regulation of NO synthase (NOS) activity is essential for minimizing effects of cytotoxic and genotoxic nitrogen oxide species. We have shown previously that NO-induced p53 protein accumulation down-regulates basal and cytokine-modulated inducible NOS (NOS2) expression in human cells in vitro. To further characterize the feedback loop between NOS2 and p53, we have investigated NO production, i.e., urinary nitrate plus nitrite excretion, and NOS2 expression in homozygous p53 knockout (KO) mice. We report here that untreated p53 KO mice excreted 70% more nitrite plus nitrate than mice with wild-type (wt) p53. NOS2 protein expression was constitutively detected in the spleen of untreated p53 KO mice, whereas it was undetectable in the spleen of wt p53 controls. Upon treatment with heat-inactivated Corynebacterium parvum, urinary nitrite plus nitrate excretion of p53 KO mice exceeded that of wt controls by approximately 200%. C. parvum treatment also induced p53 accumulation in the liver. Splenectomy reduced the NO output of C. parvum-treated p53 KO mice but not of wt p53 controls. Although NO production and NOS2 protein expression were increased similarly in KO and wt p53 mice 10 days after injection of C. parvum, NOS2 expression returned to baseline levels only in wt p53 controls while remaining up-regulated in p53 KO mice. These genetic and functional data indicate that p53 is an important transrepressor of NOS2 expression in vivo and attenuates excessive NO production in a regulatory negative feedback loop.
 ...
PMID:Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53 knockout mice. 967 63

Germ-line mutations of the BRCA1 and BRCA2 genes predispose women to develop cancers of the breast and ovary, but the biologic functions of these genes remains unclear. We have investigated the responses of the BRCA1 and BRCA2 gene products to cytotoxic agents in 3 human ovarian cancer cell lines: SK-OV-3 (which contains a p53 deletion mutation), CAOV-3 (which over-expresses a mutant p53) and PA-1 (which expresses wild-type p53). In screening studies, we determined the effects of 7 different agents on BRCA1 and BRCA2 expression. We found that Adriamycin (ADR) and ultraviolet (UV)radiation significantly down-regulated BRCA1 and BRCA2 mRNA expression in SK-OV-3 cells. On the other hand, camptothecin, nitrogen mustard, taxol, vincristine and etoposide had no effect on BRCA1 or BRCA2 mRNA levels at doses that yielded degrees of cytotoxicity similar to or greater than ADR. The down-regulation of BRCA1 and BRCA2 mRNAs was dose and time dependent; significant down-regulation was first observed at 8-16 hr after exposure to ADR. BRCA1 protein levels were also down-regulated following treatment of SK-OV-3 cells with ADR. Similar results were observed in CAOV-3 and PA-1 cells treated with ADR, and this finding could not be directly attributed to ADR-induced changes in the cell cycle distribution. The ADR doses required for significant decreases of BRCA1 and BRCA2 were about 10-15, 5-10 and 2 microM, respectively, for SK-OV-3, CAOV-3 and PA-1; the IC50 doses for loss of cell viability (determined by Trypan blue dye exclusion) were 23, 14 and 0.4 microM, respectively. Thus, at equitoxic doses of ADR, PA-1 cells were more resistant to down-regulation of BRCA1 and BRCA2 than SK-OV-3 or CAOV-3. Our findings suggest that 1) BRCA1 and BRCA2 expression in human ovarian cancer cell lines is selectively down-regulated by 2 DNA-damaging agents (ADR and UV radiation); 2) these responses are not due to non-specific cytotoxicity; and 3) the BRCA1 and BRCA2 responses may be dependent, in part, on the p53 functional status of the cells. We speculate that the down-regulation of BRCA1 and BRCA2 may be part of a cellular survival response activated by certain forms of DNA damage.
 ...
PMID:Down-regulation of BRCA1 and BRCA2 in human ovarian cancer cells exposed to adriamycin and ultraviolet radiation. 967 65

P53 has been reported to be one of tumor suppressor genes that play a major role in signal transduction following many kinds of stresses, including ionizing radiation. Changes in p53 expression during radiation therapy in tumor tissues have not yet been reported. We determined whether radiotherapy changes p53 expression in human squamous cell carcinomas of the head and neck, and established the possible correlations between p53 expression and the therapeutic effects of radiation therapy. 30 patients with tumors of the oral cavity, oropharynx, and maxillary sinus were examined, and all the tumors were confirmed as squamous cell carcinomas. Biopsies were performed on the cancer tissues before treatment and at doses of 4, 10, and 20 Gy of radiotherapy, and the specimens were preserved in liquid nitrogen for further examination. Samples were immunohistochemically stained using streptoavidin-biotin peroxidase method and a monoclonal antibody against p53 (Ab-3, mutant type). For all the samples p53 PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) assays were performed. 14 of the 30 patients with squamous cell carcinomas showed expression of p53 in their tumor cells before and/or at 4 Gy or 10 Gy of radiotherapy. Eleven of the 14 tumors showed high radiosensitivity. Results of the p53 PCR-SSCP assays revealed mutations of p53 in 13 of 30 patients examined, and percentages of mutated p53 DNA varied at radiation doses of 4 Gy and 10 Gy. Ten of 12 patients with mutated p53 in their tumors showed decreased percentages of mutated p53 DNA during radiotherapy. The relationship between the immunohistochemical findings and the antitumor effect of a radiation dose of 20 Gy was examined on the correspondent hematoxylin-eosin sections. In patients whose p53 expressions in tumor cells were grades + or ++ or before radiotherapy and/or at 4 Gy of radiotherapy, the tumors responded significantly well to radiation therapy but the patients responded with significantly unfavorable clinical courses. The high radiosensitivity of squamous cell carcinomas in our samples could be explained by an overexpression of mutant type p53 in the tumor cells, and these mutant type p53-positive tumor cells possibly showed radioresponsiveness.
 ...
PMID:Changes of mutant-type p53 expression in squamous cell carcinoma of the head and neck during radiation therapy and its clinical significance: comparison of an immunohistochemical method and PCR-SSCP assay. 968 7

DNA repair status is recognized as an important determinant of the clinical efficacy of cancer chemotherapy. To assess the role that a mammalian DNA glycosylase plays in modulating the toxicity and clastogenicity of the chemotherapeutic DNA cross-linking alkylating agents, we compared the sensitivity of wild-type murine cells to that of isogenic cells bearing homozygous null mutations in the 3-methyladenine DNA glycosylase gene (Aag). We show that Aag protects against the toxic and clastogenic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C (MMC), as measured by cell killing, sister chromatid exchange, and chromosome aberrations. This protection is accompanied by suppression of apoptosis and a slightly reduced p53 response. Our results identify 3-methyladenine DNA glycosylase-initiated base excision repair as a potentially important determinant of the clinical efficacy and, possibly, the carcinogenicity of these widely used chemotherapeutic agents. However, Aag does not contribute significantly to protection against the toxic and clastogenic effects of several chemotherapeutic nitrogen mustards (namely, mechlorethamine, melphalan, and chlorambucil), at least in the mouse embryonic stem cells used here. We also compare the Aag null phenotype with the Fanconi anemia phenotype, a human disorder characterized by cellular hypersensitivity to DNA cross-linking agents, including MMC. Although Aag null cells are sensitive to MMC-induced growth delay and cell cycle arrest, their sensitivity is modest compared to that of Fanconi anemia cells.
 ...
PMID:Mammalian 3-methyladenine DNA glycosylase protects against the toxicity and clastogenicity of certain chemotherapeutic DNA cross-linking agents. 973 10

Genetic and epigenetic alterations in oncogenes, tumor suppressor genes, cell adhesion molecules, telomere and telomerase activity as well as genetic instability at several microsatellite foci are responsible for multistep process of human stomach carcinogenesis. The scenario of these alterations found in gastric cancer differs depending on the two histological types, indicating that different genetic pathways exist for well differentiated or intestinal type and poorly differentiated or diffuse type gastric cancers, even though both types of gastric cancer may arise from epithelial "stem cells" which express human telomerase reverse transcriptase (hTRT) and telomerase activity. Infection with Helicobacter pylori, which evidently causes the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), may be a strong trigger for "stem cell" hyperplasia in intestinal metaplasia, followed by telomere reduction and increase telomerase activity as well as hTRT overexpression. They may precede DNA replication error, DNA hypermethylation, CD44 abnormal transcript and p53 mutations, all of which occur in at least 30% of intestinal metaplasia as early events of multistep pathogenesis of well differentiated type gastric cancer.
 ...
PMID:Molecular mechanism of human stomach carcinogenesis implicated in Helicobacter pylori infection. 978 10

DNA damage in the cell activates expression of the p53 tumor suppressor gene, whose role is associated with cell arrest in G1 or apoptosis. The aim of this study was to examine the cell cycle position-related changes in expression of p53, as well as induction of apoptosis, in mitogen-stimulated normal human lymphocytes and in human leukemic MOLT-4 cells (which express mutated p53), following DNA damage by the alkylating agent nitrogen mustard. Measurement of p53 expression and DNA content by flow cytometry followed by bivariate analysis of the data made it possible to correlate the drug-induced changes in p53 expression in individual cells with their cell cycle position without the need for cell synchronization. Expression of p53 was detected immunocytochemically using the AB-6 mAb, which reacts with the product of the wild-type p53 tumor suppressor gene and with most of its mutated forms. Exposure of normal lymphocytes to 5 microM nitrogen mustard caused their arrest in G1, an increase in p53 expression which was maximal in such cells, and significant apoptosis in cells located beyond the arrest point (S and G2 + M cells). In contrast, neither arrest in G1 nor significant apoptosis of MOLT-4 cells was seen after administration of either 0.5 or 5 microM nitrogen mustard for up to 24 h, although the drug reduced the rate of cell progression in the S-phase at both concentrations. Expression of p53 was highest for S and G2 + M MOLT-4 cells in response to the nitrogen mustard. Although a severalfold lower level of p53 was detected in lymphocytes compared to MOLT-4 cells prior to drug treatment, the relative increase in p53 expression in response to the drug was 2-fold higher in lymphocytes. These data suggest that DNA damage caused by nitrogen mustard provides a signal that results in stabilization of wild-type p53, preferentially in G1 cells, causes cell arrest in G1, and induces apoptosis of the cells that either were in the S-phase at the time of drug administration and/or escaped G1 arrest. The increase in expression of mutated p53, in response to DNA damage, is unrelated to the cell cycle position, and neither provides a signal for cell arrest in G1 nor a trigger for immediate apoptosis.
 ...
PMID:Induction of apoptosis and cell cycle-specific change in expression of p53 in normal lymphocytes and MOLT-4 leukemic cells by nitrogen mustard. 981 57

DNA topoisomerases regulate the organization of DNA and are important targets for many clinically used antineoplastic agents. In addition, DNA topoisomerases modulate the cellular sensitivity toward a number of DNA damaging agents. Increased topoisomerase II activities were shown to contribute to the resistance of both nitrogen mustard- and cisplatin-resistant cells. Similarly, cells with decreased topoisomerase II levels show increased sensitivity to cisplatin, carmustine, mitomycin C and nitrogen mustard. Recent studies propose that topoisomerases may be involved in damage recognition and DNA repair at several different levels including: 1) the initial recognition of DNA lesions; 2) DNA recombination; and 3) regulation of DNA structure. The stress-activated oncogene suppressor protein p53 can modulate the activity of at least three different human topoisomerases, either directly by molecular associations or by transcriptional regulation. Since DNA topoisomerases have considerable recombinase activities, inappropriately activated topoisomerases in tumor cells lacking functional p53 may contribute to the genetic instability of these cells.
 ...
PMID:DNA topoisomerases as repair enzymes: mechanism(s) of action and regulation by p53. 982 82

Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid to prostaglandins (PGs) and other eicosanoids. Nitric oxide synthase (NOS) is the enzyme that catalyzes the formation of nitric oxide (NO), a regulator of vascular permeability, from the guanidino nitrogen atom of L-arginine. Two isoforms of both enzymes occur: a constitutive one, Cox-1 and the inducible counterpart Cox-2; also NOS has a constitutive counterparts (cNOS) and an inducible form, called iNOS. The inducible isoforms of both enzymes are of maximum interest. It has been recently shown that cyclooxygenase-2 (Cox-2) is inducible by a variety of stimuli and that eicosanoids, mainly of the PGE2 species, are inducers of basic regulator of angiogenesis, including VEGF/VPF, bFGF, TGF-beta, PDGF, and endothelin-1. In addition, iNOS is inducible by Cox-2. p53 down-regulates the angiogenic process at various levels: it induces thrombospondin-1, a powerful antiangiogenic factor, down-regulates VEGF and NOS and, in addition, down-regulates hypoxia-induced angiogenesis, either inducing apoptosis or enhancing antiangiogenetic factors. It is noteworthy how important the p53 oncosuppressor is in the angiogenesis of solid tumor growth. Cox-2, iNOS and p53 are thus fundamental play-makers of the angiogenic process: they are discussed in detail and a tentative hierarchical cascade is proposed.
 ...
PMID:Cox-2, iNOS and p53 as play-makers of tumor angiogenesis (review). 985 Jul 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>