Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Living organisms are continuously exposed to reactive oxygen species as a consequence of biochemical reactions as well as external factors. Oxidative DNA damage has been implicated in aging, carcinogenesis and other degenerative diseases. The urinary excretion of the DNA repair product 8-hydroxydeoxyguanosine (8OHdG) has been proposed as a noninvasive biomarker of oxidative DNA damage in humans in vivo. We have developed a three-dimensional HPLC analysis with electrochemical detection for the analysis of 8OHdG in urine and studied factors affecting the excretion of this biomarker in 83 healthy humans and in various laboratory animals, including dog, pig, and rat. Previously, other groups have used comparable HPLC methods or gas chromatography-mass spectrometry with selective ion monitoring for measuring the excretion of 8OHdG in humans, rats, mice, and monkeys. In the 169 humans studied so far, the average 8OHdG excretion was 200-300 pmol/kg per 24 h with a sevenfold range, and the coefficient of variation was 30-40%. This excretion corresponds 140-200 oxidative modification of guanine bases per cell per day. Thirty-two smokers from our study population excreted 50% (31-69%; 95% confidence interval) more 8OHdG than 53 nonsmokers. This indicates a 50% increased rate of oxidative DNA damage from smoking, adding to the other well-known health hazards of smoking. The biochemical-physiological basis is unknown but may be related to smoke constituents including or generating reactive oxygen species and/or consuming antioxidants and/or the well-known enhancing effect of smoking on the metabolic rate. In our 83 healthy subjects the 8OHdG excretion correlated with body composition. Thus, lean and/or male subjects excreted more than obese and/or female subjects, possibly related to differences in metabolic rate. In accordance, the excretion of 8OHdG decreased after calorie restriction, which will cause a decline in the metabolic rate. Across the investigated species, humans, dogs, pigs, and rats, the excretion of 8OHdG correlated with the specific metabolic rate, confirming data from other groups on humans, monkeys, rats, and mice. The excretion of 8OHdG decreased with age in rats in parallel with the decline in metabolic rate with advancing age. The excretion of 8OHdG reflects the formation and repair of only one out of approximately 20 described oxidative DNA modifications. So far, methods are not available for the determination of the corresponding repair products, except 8OHdG and thymidine glycol, in urine. Moreover, the importance in terms of mutagenicity, particularly regarding tumour suppressor genes and oncogenes, is mainly documented for 8OHdG in DNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:8-Hydroxydeoxyguanosine as a urinary biomarker of oxidative DNA damage. 823 Mar 10

In aerobic life, oxidative stress arises from both endogenous and exogenous sources. Despite antioxidant defence mechanisms, cell damage from oxygen free radicals (OFR) is ubiquitous. OFR-related lesions that do not cause cell death can stimulate the development of cancer. This review discusses the effects of oxidative stress at the different stages of carcinogenesis. Mutagenesis through oxidative DNA damage is widely hypothesised to be a frequent event in the normal human cell. A large body of evidence suggests important roles of OFR in the expansion of tumour clones and the acquisition of malignant properties. In view of these facts, OFR may be considered as an important class of carcinogens. Therefore, the ineffectiveness of preventive antioxidant treatments, as documented in several recent clinical trials, is surprising. However, the difficulties of antioxidant intervention are explained by the complexity of both free radical chemistry and cancer development. Thus, reducing the avoidable endogenous and exogenous causes of oxidative stress is, for the present, the safest option. In the near future, new insights in the action of tumour suppressor genes and the DNA repair mechanisms may lead the way to additional tools against carcinogenesis from OFR.
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PMID:Role of oxygen free radicals in cancer development. 869 38

Possible chemopreventive mechanisms include carcinogen-blocking activities, antioxidant/anti-inflammatory activities and antiproliferation/antiprogression activities. Carcinogen-blocking activities encompass inhibition of carcinogen uptake, inhibition of carcinogen formation or activation, deactivation or detoxification of carcinogens, prevention of carcinogen binding to DNA, and enhancement of the level or fidelity of DNA repair. Antioxidant/anti-inflammatory activities include scavenging of reactive electrophiles and oxygen radicals, and inhibition of arachidonic acid metabolism. Antiproliferation/antiprogression activities comprise modulation of signal transduction, modulation of hormonal and growth factor activity, inhibition of aberrant oncogene activity, inhibition of polyamine metabolism, induction of terminal differentiation, restoration of immune responses, enhancement of intercellular communication, restoration of tumour suppressor function, induction of apoptosis, telomerase inhibition, correction of DNA methylation imbalances, inhibition of angiogenesis, inhibition of basement membrane degradation, and activation of antimetastasis genes. In evaluating the potential efficacy of chemopreventive agents several mechanistic parameters are weighed: (1) the number of chemoprevention-related pharmacological activities, (2) the impact of the agent on likely carcinogenesis pathways to the targeted cancer, (3) pharmacodynamics, and (4) specificity for chemopreventive activity compared with interference with normal cellular function. Mechanistic data are important throughout the development process for chemopreventive drugs, and they are particularly important in the earlier phases of identifying promising candidate agents and characterizing efficacy. In vitro mechanistic assays are a first step in evaluating chemopreventive potential. Mechanistic considerations are also useful in defining animal efficacy models and in interpreting the results of assays in these models. Mechanistic data are also applied in designing short-term Phase II clinical chemoprevention trials that use reductions in intermediate biomarkers of cancer rather than cancer incidence as end points. The basis for identifying and evaluating these biomarkers is in understanding carcinogenesis and chemopreventive mechanisms.
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PMID:Mechanistic considerations in the evaluation of chemopreventive data. 892 32

One of the major goals of cancer research is to identify and understand the causes of cellular proliferation. The role of cell death, or lack thereof, in carcinogenesis, tumour growth, metastatic spread and response to treatment has been largely overlooked even though the morphology of apoptosis (programmed cell death) was clearly described over 20 years ago, and its importance in cancer speculated on at that time. Over the last 5 years, however, an explosion of research has focused on delineating the molecular components of the apoptotic pathways and examining the role of apoptosis in a tumour's growth and response to treatment. This review highlights the aspects of apoptosis most relevant to radiation oncologists and radiobiologists. The apoptotic pathways will be described, with attention to the stimuli that initiate apoptosis, the oncogenes and tumour suppressor genes that mediate apoptosis, and the effector enzymes (proteases and endonucleases) responsible for the execution of apoptosis. In addition, we review the effect of classically described radiobiology cell survival parameters-cell cycle stage, dose rate, linear energy transfer, oxygen, total dose, and fractionation-on radiation induced apoptosis.
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PMID:The molecular regulation of apoptosis and implications for radiation oncology. 919 90

Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.
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PMID:The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. 1035 37

Mortality connected with tobacco smoke-associated laryngeal cancer in Poland markedly exceeds the relevant epidemiological data from other European countries. The main groups of genotoxic agents considered as potential carcinogens present in tobacco smoke are polycyclic aromatic hydrocarbons, aromatic amines, N-nitrosoamines and reactive oxygen species. Aromatic DNA adducts, N7-alkylated guanosines and oxidative DNA damage derived from tobacco smoke exposure were detected in laryngeal and oral (tumour and non-tumour) biopsies, and white blood cells of cancer subjects. Further, DNA lesions were analysed to estimate the significance of such confounders as intensity of smoking, subject's sex, age, topography of larynx, cancer staging and genetic factor. The number of cigarettes smoked per day was found to be the main determinant of an individual's DNA adduct level. The occurrence of DNA lesions was established as a reliable marker of former exposure to tobacco smoke genotoxicants. On the other hand, a comparison of DNA lesion levels in various regions of larynx indicates limited usefulness of DNA adduct analysis as an estimate of cancer risk. For a better risk estimation one has to take into account DNA lesions in proto-oncogenes and tumour suppressor genes and the efficacy of DNA repair. Altogether, DNA adducts formation and removal has to be considered as a single stage in the multistep carcinogenesis.
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PMID:Carcinogen: DNA adducts in tobacco smoke-associated cancer of the upper respiratory tract. 1054 29

The p53 tumour suppressor protein exerts multiple, antiproliferative effects in response to genotoxic exposures. Reactive oxygen intermediates (ROI) play several distinct roles in the p53 pathway. First, they are important activators of p53 through their capacity to induce DNA strand breaks. Second, they regulate the DNA-binding activity of p53 by modulating the redox status of a critical set of cysteines in the DNA-binding domain, which are also involved in the coordination of zinc. Third, they play a role in the signalling pathways regulated by p53, as several genes encoding redox effectors are transcriptionally controlled by p53. In this review, we summarize the evidence for the involvement of ROI at these three levels. Emphasis is placed on the role of metals and ROI as potential regulators of p53 protein conformation and functions, and on the putative toxicological consequences of such a regulation.
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PMID:Redox signalling and transition metals in the control of the p53 pathway. 1060 31

Reactive oxygen species are widely generated in biological systems. Consequently humans have evolved antioxidant defence systems that limit their production. Intracellular production of active oxygen species such as *OH, O2- and H2O2 is associated with the arrest of cell proliferation. Similarly, generation of oxidative stress in response to various external stimuli has been implicated in the activation of transcription factors and to the triggering of apoptosis. Here we review how free radicals induce DNA sequence changes in the form of mutations. deletions, gene amplification and rearrangements. These alterations may result in the initiation of apoptosis signalling leading to cell death, or to the activation of several proto-oncogenes and or the inactivation of some tumour suppressor genes. The regulation of gene expression by means of oxidants, antioxidants and the redox state remains as a promising therapeutic approach. Several anticarcinogenic agents have been shown to inhibit reactive oxygen species production and oxidative DNA damage, inhibiting tumour promotion. In addition, recombinant vectors expressing radical-scavenging enzymes reduce apoptosis. In conclusion, oxidative stress has been implicated in both apoptosis and the pathogenesis of cancer providing contrived support for two notions: free radical reactions may be increased in malignant cells and oxidant scavenging systems may be useful in cancer therapy.
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PMID:Role of reactive oxygen species in apoptosis: implications for cancer therapy. 1068 51

It is now well established that oxidized LDL (OxLDL) is involved in the progression of the atheromatous plaque via several mechanisms, including its cytotoxicity toward the arterial wall. Our study demonstrates that a 4-h incubation of cultured human fibroblasts with 25-75 microg/ml OxLDL induced a dose-dependent increase in the intracellular levels of reactive oxygen species (ROS) and lipid peroxidation end products (TBARS). This effect was markedly prevented by the antioxidant vitamin E. The lipid extract of OxLDL partially reproduced the action of the LDL particle itself. Concomitantly, OxLDL enhanced the DNA binding activity of p53 measured by electrophoretic mobility shift assay, and the intracellular protein level of p53 determined by immunoblot analysis. Cycloheximide prevented the OxLDL-induced augmentation in both p53 binding activity and intracellular level. Again, the lipid extract of OxLDL reproduced the effect of OxLDL on p53 binding activity, whereas vitamin E prevented it. These results indicate that OxLDL initiates an intracellular oxidative stress by means of its lipid peroxidation products, leading to the activation of the tumour suppressor p53 by enhancement of p53 protein synthesis. This effect might be related to the cytotoxic effect of OxLDL since the activation of p53 is known to lead to cell cycle arrest, necrosis or apoptosis.
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PMID:Oxidized LDL induces an oxidative stress and activates the tumor suppressor p53 in MRC5 human fibroblasts. 1102 37

The tumour suppressor gene, p53, plays an important role in tumour development. Under low levels of oxygen (hypoxia), cells expressing wild-type p53 undergo programmed cell death (apoptosis), whereas cells expressing mutations in the p53 gene may survive and express angiogenic growth factors that stimulate tumour vascularization. Given that cells expressing mutations in the p53 gene have been observed in many forms of human tumour, it is important to understand how both wild-type and mutant cells react to hypoxic conditions. In this paper a mathematical model is presented to investigate the effects of alternating periods of hypoxia and normoxia (normal oxygen levels) on a population of wild-type and mutant p53 tumour cells. The model consists of three coupled ordinary differential equations that describe the densities of the two cell types and the oxygen concentration and, as such, may describe the growth of avascular tumours in vitro and/or in vivo. Numerical and analytical techniques are used to determine how changes in the system parameters influence the time at which mutant cells become dominant within the population. A feedback mechanism, which switches off the oxygen supply when the total cell density exceeds a threshold value, is introduced into the model to investigate the impact that vessel collapse (and the associated hypoxia) has on the time at which the mutant cells become dominant within vascular tumours growing in vivo. Using the model we can predict the time it takes for a subpopulation of mutant p53 tumour cells to become the dominant population within either an avascular tumour or a localized region of a vascular tumour. Based on independent experimental results, our model suggests that the mutant population becomes dominant more quickly in vivo than in vitro (12 days vs 17 days).
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PMID:Estimating the selective advantage of mutant p53 tumour cells to repeated rounds of hypoxia. 1114 80


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