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)

We have studied the role of the oxygen-dependent pyrimidine metabolism in the regulation of cell cycle progression under moderate hypoxia in human cell lines containing functional (T-47D) or non-functional (NHIK 3025, SAOS-2) retinoblastoma gene product (pRB). Under aerobic conditions, pRB exerts its growth-regulatory effects during early G1 phase of the cell cycle, when all pRB present has been assumed to be in the underphosphorylated form and bound in the nucleus. We demonstrate that pRB is dephosphorylated and re-bound in the nucleus in approximately 90% of T-47D cells located in S and G2 phases under moderately hypoxic conditions. Under these conditions, no T-47D cells entered S-phase, and no progression through S-phase was observed. Progression of cells through G2 and mitosis seems independent of their functional pRB status. The p21WAF1/CIP1 protein level was significantly reduced by moderate hypoxia in p53-deficient T-47D cells, whereas p16(INK4a) was not expressed in these cells, suggesting that the hypoxia-induced cell cycle arrest is independent of these cyclin-dependent kinase inhibitors. The addition of pyrimidine deoxynucleosides did not release T-47D cells, containing mainly underphosphorylated pRB, from the cell cycle arrest induced by moderate hypoxia. However, NHIK 3025 cells, in which pRB is abrogated by expression of the HPV18 E7 oncoprotein, and SAOS-2 cells, which lack pRB expression, continued cell cycle progression under moderate hypoxia provided that excess pyrimidine deoxynucleosides were present. NHIK 3025 cells express high levels of p16INK4a under both aerobic and moderately hypoxic conditions, suggesting that the inhibitory function of p16(INK4a) would not be manifested in such pRB-deficient cells. Thus, pRB, a key member of the cell cycle checkpoint network, seems to play a major role by inducing growth arrest under moderate hypoxia, and it gradually overrides hypoxia-induced suppression of pyrimidine metabolism in the regulation of progression through S-phase under such conditions.
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PMID:The retinoblastoma protein-associated cell cycle arrest in S-phase under moderate hypoxia is disrupted in cells expressing HPV18 E7 oncoprotein. 952 26

Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is still poorly understood. In the HCT116 colon carcinoma cell line, which retains a wild-type inducible p53 gene, we show that the anthracycline daunomycin is a potent inducer of p53 and NF-kappaB transcription factors. Nuclear accumulation of p53 protein occurred because of increased protein stability and enhanced gene expression. In addition, daunomycin induced the p53 promoter through the binding of p50/p65 NF-kappaB heterodimers to the kappaB site in the p53 promoter. Under our conditions, the free radical scavengers NAC and PDTC were not able to block NF-kappaB activation or p53 induction, indicating that reactive oxygen intermediates were not involved in the cellular response to daunomycin stimulation. Overexpression of a stable unresponsive IkappaBalpha mutant in HCT116 cells resulted in a complete inhibition of the NF-kappaB activation but only a partial impairment of the p53 protein accumulation induced by daunomycin. We conclude that the p53-activating signal generated by daunomycin is partially regulated by NF-kappaB.
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PMID:Nuclear factor - kappaB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug. 952 61

Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the wild-type p53 gene, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulates the transcription of several genes that are associated with hypoxia. Here we show that these treatments induce accumulation of wild-type p53 through HIF-1alpha-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1alpha or embryonic stem cells derived from mice lacking HIF-1beta. HIF-1alpha is found in p53 immunoprecipitates from MCF7 cells that express wild-type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1alpha and wild-type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1alpha stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active wild-type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1alpha.
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PMID:Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. 953 26

2,5-Dimethyl-4-hydroxy-3(2H)-furanone (2,5-DMHF), a caramel-like fragrant compound found in may processed foodstuff, has been reported to be mutagenic. 4,5-Dimethyl-3-hydroxy-2(5H)-furanone (4,5-DMHF), which is a similar characteristic fragrant compound, has no report concerning its mutagenicity. DNA damage by 2,5-DMHF and 4,5-DMHF was investigated by using DNA fragments obtained from the p53 tumor suppressor gene. 2,5-DMHF induced DNA damage extensively in the presence of Cu(II), but only slightly in the presence of Fe(III). 4,5-DMHF did not cause metal-dependent DNA damage. Bathocuproine, a Cu(I)-specific chelator, and catalase inhibited DNA damage induced by 2,5-DMHF plus Cu(II), whereas free hydroxyl radical scavengers did not. The order of DNA cleavage sites was thymine, cytosine > guanine residues. The site-specific DNA damage and effects of scavengers show that DNA-copper-oxygen complex rather than free .OH are involved in the DNA damage. Formation of 8-oxodeoxyguanosine (8-oxodG) by 2,5-DMHF increased with its concentration in the presence of Cu(II), whereas 8-oxodG formation increased only slightly in the presence of Fe(III). Degradation of 2,5-DMHF was efficiently accelerated by Cu(II), but only slightly accelerated by Fe(III). The degradation of 4,5-DMHF was little even in the presence of metal ions. Examination using cytochrome c suggest that superoxide was generated from 2,5-DMHF. Stoichiometric study of Cu(II) reduction revealed that autoxidation of 2,5-DMHF could offer 4-electron reduction. These results suggest that, at least in vitro and in an acellular system, 2,5-DMHF generates superoxide and subsequently hydrogen peroxide to induce metal-dependent DNA damage.
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PMID:Superoxide formation and DNA damage induced by a fragrant furanone in the presence of copper(II). 954 43

The biologic functions attributed to the nucleophosphoprotein p53 have been increasing in recent years. Some studies suggested that wild type p53 is responsible for cell cycle arrest brought about as a response to exposure of mammalian cells to DNA-damaging agents. This cell cycle arrest occurs in order for cells to repair the damaged macromolecules. Extensively damaged cells are also thought to undergo apoptosis via the p53-dependent or -independent signal transduction pathways. In this study, we investigated the ability of diaziridinylbenzoquinones to increase p53 levels in the human breast cancer cell line MCF-7. Diaziquone (AZQ), an anticancer agent, and its derivatives, diaziridinequinone (DZQ) and methyldiaziridinequinone (MeDZQ), induced p53 in a dose- and time-dependent manner as measured by the electrophoretic mobility shift assay. Wild type p53 induction by AZQ was suppressed when DT-diaphorase activity was inhibited by pretreating the cells with dicumarol. Aside from their potent alkylating activity, these agents also undergo redox cycling as evidenced by oxygen consumption and the production of reactive oxygen species (ROS). Inhibition of ROS production by the antioxidant enzyme catalase reduced AZQ- and DZQ-mediated p53 induction by about 45%. Thiotepa, a non-quinone aziridine-containing agent, and 1,4-benzoquinone (p-BQ), a redox cycling quinone, increased p53 levels. The nonalkylator oxygen-radical-generating agent menadione (MD) caused p53 induction only when MCF-7 cells were allowed to recover in drug-free media. On the basis of these data, we propose that the bioreductive activation of AZQ is a prerequisite for p53 induction. Moreover, the induction of p53 by AZQ requires both the quinone and the aziridine moieties of the AZQ molecule. Although AZQ and its analogues increased p53 levels in MCF-7 cells, p53 induction in these cells may not be responsible for the apoptosis seen upon treatment of MCF-7 cells with these agents. The uncoupling of p53 induction and apoptosis is evidenced by the generation of nucleosomal DNA laddering in aziridinequinone-treated T47D cells, a breast cancer cell line bearing a p53 mutation.
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PMID:Induction of p53 by the concerted actions of aziridine and quinone moieties of diaziquone. 954 7

The biological effects of antioxidants are often considered in terms of their effects on oxygen or lipid radicals. However, antioxidants can also exert their effects through altering the cellular redox potential. Herein, we report that sulfur-containing antioxidants such as N-acetylcysteine and dimercaptopropanol induced apoptosis in several transformed cell lines and transformed primary cultures but not in normal cells. In contrast, chain-breaking antioxidants such as vitamin E lacked this activity. An increased glutathione level was not required for apoptosis; however, all apoptosis-inducing antioxidants elevated the total cellular thiol levels. Antioxidant-induced apoptosis required the p53 tumor suppressor gene. N-Acetylcysteine elevated p53 expression posttranscriptionally by increasing the rate of p53 mRNA translation rather than by altering the protein stability. The p53 induction occurred in normal cells. These observations indicate a redox sensor for p53 induction in vivo, with additional transformation-specific information being required for apoptosis. Manipulating p53-dependent apoptosis with nontoxic antioxidants may have a direct clinical application.
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PMID:Antioxidant action via p53-mediated apoptosis. 956 90

Two hair dye components, carcinogenic 4-nitro-2-aminophenol and 5-nitro-2-aminophenol, induced Cu(II)-dependent DNA cleavage frequently at thymine and guanine residues in DNA fragments obtained from the c-Ha-ras-1 protooncogene. When the p53 tumor suppressor gene was used, 4-nitro-2-aminophenol caused Cu(II)-dependent piperidine-labile sites at poly G sequences. In the presence of Cu(II), both components increased 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in DNA. The inhibitory effects of catalase and bathocuproine on DNA damage suggest the involvement of H2O2 and Cu(I). It is speculated that nitro-2-aminophenols undergo Cu(II)-mediated autoxidation to generate active oxygen species causing DNA damage which leads to their carcinogenesis.
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PMID:Metal-mediated oxidative DNA damage induced by nitro-2-aminophenols. 956 50

Although the physiological effects of positive pressure ventilation are numerous, sometimes undesirable and have varying degrees of significance, positive pressure ventilation still plays a major role in the resuscitation and treatment of critically ill patients. Advances in the various methods of delivering positive pressure, especially when incorporating spontaneous breathing, have reduced the severity of complications. Despite serious complications, mechanical ventilation has advantages. When it is instituted for ventilatory and hypoxaemic respiratory failure, the benefits can be viewed in the context of the work of breathing. Spontaneous breathing normally requires 5% of total oxygen delivery to meet its demands. In lung disease, the ratio of oxygen consumption by the respiratory muscles to whole body oxygen consumption can increase to 25-30% (Henning 1986, Pinksy 1990). Mechanical ventilation reduces the energy demand of respiratory muscles and increases the oxygen delivery to other vital organs. When mechanical ventilation improves hypoxaemia and/or hypercarbia, or significantly decreases the work of breathing, it may also normalize associated changes in heart rate (Perel & Pizov 1991 p53). When cardiac output is increased in response to the increased work of breathing and associated stress, the institution of mechanical ventilation may beneficially lower the cardiac output simply due to the decrease in oxygen demand; thus the physiological reduction in cardiac output may not necessarily be regarded as a complication. The effects of raised intrathoracic pressure during mechanical ventilation may be beneficial when used to prevent or reduce pulmonary oedema, though problematic in some other situations. Mechanical ventilation is a life-saving treatment which has many associated complications; nurses have to accept the unavoidable hazards and adapt their nursing care to minimize their effects.
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PMID:Physiological changes occurring with positive pressure ventilation: Part Two. 956 54

Exposure of cultured renal (LLC-PK1) cells for 7 weeks to non-cytotoxic concentrations of S-(1,2-dichlorovinyl)-L-cysteine had resulted in the induction of morphologically and biochemically dedifferentiated clones, which retained their altered properties after removal of the chemical. In this study we investigated by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis and direct sequencing if S-(1,2-dichlorovinyl)-L-cysteine-induced LLC-PK1 clones display mutations in the p53 gene in comparison with wild-type clones. In addition, the characteristics of S-(1,2-dichlorovinyl)-L-cysteine-induced clones were compared with clones induced by carcinogens/metabolites of carcinogens with different mechanisms of action: (i) The potent alkylating agent and bacterial mutagen chloroethylcysteine, the key metabolite of the carcinogen dichloroethane; (ii) potassium bromate, a nephrocarcinogen inducing reactive oxygen species, which give rise to the formation of 8OHdG and DNA strand-breaks; (iii) cis-platinum, a bifunctional cross-linking agent and strand-break inducer and (iv) styrene oxide, the main intermediate metabolite of styrene, an epoxide whose carcinogenicity is thought to be based on cytotoxicity. Three essential markers of the physiological integrity and renal tubule origin of the wild-type LLC-PK1 cells were disrupted in all chemical-derived clones: (i) the polarisation of the plasma membrane into a luminal and basolateral part; (ii) the sodium-dependent glucose uptake and (iii) the pH-dependent ammonia production. Compared with the wild-type clones, poly(ADP-ribosyl)ation, a posttranslational modification of nuclear proteins, was clearly increased in clones induced by S-(1,2-dichlorovinyl)-L-cysteine, potassium bromate and cis-platinum. These clones displayed also band shifts of p53 exon 7, indicating mutations, which were confirmed by sequencing: a double mutation consisting of a base substitution followed by one base insertion in the case of S-(1,2-dichlorovinyl)-L-cysteine and potassium bromate and a base substitution in the case of cis-platinum. The base insertions both lead to the formation of the stop codon UGA resulting in loss of protein function.
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PMID:S-(1,2-dichlorovinyl)-L-cysteine-induced dedifferentiation and p53 gene mutations in LLC-PK1 cells: a comparative investigation with S-(2-chloroethyl)cysteine, potassium bromate, cis-platinum and styrene oxide. 957 11

Reactive oxygen species generated during the metabolism of the antitumor quinone 3,6-diaziridinyl-1,4-benzoquinone (DZQ) in human colonic carcinoma HCT116 cells lead to the induction of p21 (WAF1, Cip1, or sdi1), an upstream regulator of the retinoblastoma gene product pRb involved G1 cell cycle control. We here demonstrate that the cell cycle was arrested in G2/M phase following supplementation with DZQ of human osteosarcoma Saos-2 cells (lacking both p53 and pRb) and HCT116 cells. DZQ also induced p21 and apoptosis in Saos-2 cells. The transfection of the Rb gene into Saos-2 cells did not alter the level of p21 induction, but changed cell cycle arrest into G1 phase and prevented apoptosis. These findings suggest that quinones may lead to a p53-independent and pRb-preventable G2/M arrest and apoptosis, which correlate with p21 induction.
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PMID:Anticancer quinones induce pRb-preventable G2/M cell cycle arrest and apoptosis. 958 15


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