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)

Selenodiglutathione (SDG), the initial metabolite of selenite, is shown to be a more powerful inhibitor of cell growth in vitro than selenite itself. This has been established both with mouse erythroleukaemia (MEL) cells and an ovarian cell line (A2780) which is known to contain wild-type p53. Other seleno-compounds, such as selenomethyl selenocysteine (SMS) and dimethyl selenoxide (DMS), which are potent chemopreventive agents and are known to be metabolized to methylated selenium derivatives directly rather than via SDG, are also growth inhibitory to both MEL and A2780 cells, although less so than SDG or selenite. However, cells growth-inhibited by DMS are more viable than cells growth-inhibited to the same extent by SDG or selenite, suggesting that the methylated seleno-compounds may inhibit cell growth in a different manner from that of SDG or selenite. Our studies of the mechanism of growth inhibition by SDG, have established two facts. First, SDG induces p53 protein levels in cells that contain wild-type p53 (A2780 cells), suggesting that SDG induces the DNA damage-recognition pathway. Secondly, SDG induces apoptosis in MEL cells, as judged by flow cytometry and formation of nucleosomal DNA ladders. However, since p53 mutations have been found to be targetted events in all MEL cells examined, our evidence suggests that induction of apoptosis by SDG is not absolutely dependent on the p53 response pathway.
 ...
PMID:The selenium metabolite selenodiglutathione induces p53 and apoptosis: relevance to the chemopreventive effects of selenium? 803 15

Chemical and physical carcinogens, present in our environment and encountered in a variety of occupations, produce damage to DNA. X-rays produced direct ionizations and indirect hydroxyl radical attack. UV light in the short wavelength is specifically absorbed by unsaturated bonds in DNA, RNA, and proteins. There are a number of genetic sites that are specifically affected by environmental agents, and an increased sensitivity is found in certain genetic diseases. The development of a fully malignant tumor involves the activation or altered expression of oncogenes or the inactivation of tumor-suppressor genes that control normal cellular development. Mutations in the p53 tumor-suppressor gene are common in diverse types of cancer and could perhaps provide clues to the etiology of some cancers and to the effect of various environmental and occupational carcinogens in cancer development. The fact that environmental factors are involved to a great extent in cancer suggest that cancer may be preventable. Experimental as well as epidemiological data indicate that a variety of nutritional factors can act as anticarcinogens and inhibit the process of cancer development and reduce cancer risk. The interaction of cells with a number of environmental and occupational genotoxic substances such as X-rays, UV light, and a variety of chemicals including ozone results in an enhanced generation of free oxygen radicals and in modified pro-oxidant states. A number of nutritional factors such as vitamins A, C, E, beta-carotene, and micronutrients such as selenium act as antioxidants and anticarcinogens. Certain hormones such as thyroid hormones enhance oxidative processes and act as a co-transforming factor in carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Molecular mechanisms in cancer induction and prevention. 814 24

Progress in development of a genetic model for colorectal tumorigenesis and human chemoprevention research may allow the mechanism-based identification of targets and chemopreventive agents that will protect against colorectal cancer. For example, numerous mutagenic events can occur throughout colorectal carcinogenesis, including loss of heterozygosity in tumor suppressor genes such as APC, MCC, DCC, and p53, as well as in oncogenes such as K-ras. Chemopreventive agents that inhibit mutagenic activity such as N-acetyl-l-cysteine, oltipraz, and nonsteroidal anti-inflammatory drugs may protect against these mutations. Also, agents such as perillyl alcohol and lovastatin that interfere with protein isoprenylation and, hence, inhibit oncogene activation may protect against aberrant K-ras expression. Hyperproliferation in normal mucosa, leading to growth and progression of neoplasia, are also aspects of colorectal carcinogenesis that can be controlled by chemopreventive agents. Calcium is a chemopreventive agent for which there is both clinical and experimental evidence of inhibition of cell proliferation in colon mucosa. Other examples of antiproliferative agents with potential chemopreventive efficacy in colon are 2-difluoromethylornithine, dehydroepiandrosterone, and selenium. Differentiating agents such as retinoids and deltanoids also may slow proliferation and progression. Antioxidants have potential for interfering with both mutagenicity and proliferation (e.g., by preventing oxidative activation of carcinogens and scavenging activated oxygen species generated during inflammation). The same mechanistic principles apply to identification of dietary chemopreventive intervention for colorectal carcinogenesis. For example, lowering dietary fat and increasing dietary fiber lead to lower colorectal mucosal proliferation, and cruciferous vegetables contain agents such as indoles and dithiolthiones that have shown antimutagenic activity.
 ...
PMID:Genetic and cellular changes in colorectal cancer: proposed targets of chemopreventive agents. 867 84

The effects of two types of selenium compounds on the expression levels of growth arrest and DNA damage-inducible (gadd) genes and on selected cell death genes were examined in mouse mammary MOD cells to test the hypothesis that the diversity of selenium-induced cellular responses to these compounds could be distinguished by unique gene expression patterns. Whereas the expression patterns of known cell death-related genes (bcl-2 and bax) were not informative with respect to the cellular response patterns upon exposure to selenium compounds, time-dependent and selenium species-specific induction patterns were observed for gadd34, gadd45 and gadd153 genes. It was also observed that the MOD cells expressed a truncated p53 transcript but no detectable immunoreactive P53 protein, indicating a null p53 phenotype. The fact that selenium compounds induced growth arrest and death of these cells and that these compounds induced specific patterns of expression of gadd genes indicates that these genes may mediate some selenium-induced cellular responses. The findings further imply that selenium compounds may be effective chemopreventive agents for human breast carcinogenesis, in which p53 mutations are frequent.
 ...
PMID:Differential induction of growth arrest inducible genes by selenium compounds. 917 4

There is strong evidence that selenium protects against certain human cancers, but the underlying mechanism is unknown. Glutathione peroxidase (GPX1) and thioredoxin reductase (TR), the most abundant antioxidant selenium-containing proteins in mammals, have been implicated in this protection. We analyzed the expression of TR and GPX1 in the following model cancer systems: (1) liver tumors in TGFalpha/c-myc transgenic mice; (2) human prostate cell lines from normal and cancer tissues; and (3) p53-induced apoptosis in a human colon cancer cell line. TR was induced while GPX1 was repressed in malignancies relative to controls in transgenic mice and prostate cell lines. In the colon cell line, p53 expression resulted in elevated GPX1, but repressed TR. The data indicate that TR and GPX1 are regulated in a contrasting manner in the cancer systems tested and reveal the p53-dependent regulation of selenoprotein expression. The data suggest that additional studies on selenoprotein regulation in different cancers are required to evaluate future implementation of selenium as a dietary supplement in individuals at risk for developing certain cancers.
 ...
PMID:Contrasting patterns of regulation of the antioxidant selenoproteins, thioredoxin reductase, and glutathione peroxidase, in cancer cells. 979 1

Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se. There is extensive evidence that monomethylated forms of Se are critical metabolites for chemopreventive effects of Se. Induction of apoptosis in transformed cells is an important chemopreventive mechanism. Apoptosis can be triggered by micromolar levels of monomethylated forms of Se independent of DNA damage and in cells having a null p53 phenotype. Cell cycle protein kinase cdk2 and protein kinase C are strongly inhibited by various forms of Se. Inhibitory mechanisms involving modification of cysteine residues in proteins by Se have been proposed that involve formation of Se adducts of the selenotrisulfide (S-Se-S) or selenenylsulfide (S-Se) type or catalysis of disulfide formation. Selenium may facilitate reactions of protein cysteine residues by the transient formation of more reactive S-Se intermediates. A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors. A time-limited activation mechanism for such proteins, with deactivation facilitated by Se, would allow normalization of critical cellular processes in the early stages of transformation. There is uncertainty at the present time regarding the role of selenoproteins in chemoprevention model systems where supranutritional levels of Se are employed. Mammalian thioredoxin reductase is one selenoprotein that shows increased activity with Se supplementation in the nutritional to supranutritional range. Enhanced thioredoxin reduction could have beneficial effects in oxidative stress, but possible adverse effects are considered. Other functions of thioredoxin reductase may be relevant to cell signaling pathways. The functional status of the thioredoxin/thioredoxin reductase system during in vivo chemoprevention with Se has not been established. Some in vitro studies have shown inhibitory effects of Se on the thioredoxin system correlated with growth inhibition by Se. A potential inactivating mechanism for thioredoxin reductase or other selenoenzymes involving formation of a stable diselenide form resistant to reduction is discussed. New aspects of Se biochemistry and possible functions of new selenoproteins in chemoprevention are described.
 ...
PMID:Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. 1046 8

Gastric cancer, the second most common cancer in the world, kills about one million people a year, almost half of whom are Chinese. Chinese, Japanese and Koreans as well as east Europeans top the list with over 40 per 100,000 population per year, with a wide margin over Americans, Indians and Zimbabweans in whom the rates are below 1 per 100,000. The excellent prognosis of early gastric cancer is well established, and survival of cancer involving beyond the submucosa remains poor and there is little new in management. However, recent years have witnessed a breakthrough in the understanding of causative factors and molecular genetic abnormalities in gastric cancer that should pave the way for prevention, early detection and prognostication. Established carcinogens for gastric cancer now include Helicobacter pylori and N-nitroso compounds; other causative factors include salt and salted food intake, cigarette smoking, male sex, and familial genetic abnormalities. H. pylori infection increases cancer risk by about 5 in a 10-year period. Diet high in salt carries a relative risk of up to 6, and a highly significant correlation between 24 h urinary salt content and incidence of gastric cancer has been shown in 24 countries. The risk from smoking and male sex is under 2. Many N-nitroso compounds, which come from nitrites, which in turn come from nitrates in food following bacterial transformation in a hypochlorhydric environment, are established carcinogens in animals, but their risk for human gastric cancer is still debatable. The intestinal type of gastric cancer, according to Correa's hypothesis, develops from chronic inflammation leading to intestinal metaplasia, dysplasia and cancer, and is more associated with H. pylori and early gastric cancer. The diffuse type of gastric cancer does not go through these precancerous conditions and moves straight from inflammation to cancer. Associated with inflammation are an increase in proliferation and apoptosis, and this fine balance between proliferation and apoptosis may be uncoupled by genetic mutations. It is believed that as a result of the accumulation of molecular genetic abnormalities, a cancer eventually develops and metastasizes. p53 mutation, cyclin overexpression (especially in intestinal type), microsatellite instability, down regulation of E-cadherin (especially in diffuse type), and telomerase reactivation are some prominent examples. These molecular abnormalities have the potential for screening, early detection and prognostication. Fruits and vegetables, green tea, alpha-tocopherol and other micronutrients such as selenium have been shown to reduce the risk for gastric cancer. In fact, it has been reported that diet consisting of vegetables and fruits, low in salt, together with the avoidance of cigarette smoking would prevent two-thirds to three-quarters of gastric cancer. Furthermore, eradication of H. pylori, and for that matter future vaccination, has the theoretical potential of preventing gastric cancer, and the potential use of COX2 inhibiting NSAID in inducing apoptosis may reverse precancerous conditions of the stomach. Both approaches are being intensely studied.
 ...
PMID:9th Seah Cheng Siang Memorial Lecture: gastric cancer--where are we now? 1067 11

Lung cancer remains the leading cause of cancer death in the United States and is one of the world's leading causes of preventable death. Technologic advances have brought new modalities that may be useful for the early detection of lung cancer. However, because of the large number of persons at increased risk for lung cancer, screening is a formidable task. There are several risk factors that can be identified, including potential susceptibility factors, which may aid in pinpointing individuals who need to participate in regular screening programs. Aside from recognized environmental exposures including cigarette smoking, there are a number of genetic and metabolic susceptibility factors that have been examined. These include polymorphisms in the cytochrome p450 enzymes and the metabolizing capability of glutathione s-transferase or acetylation. Additionally, defects in DNA repair and in bleomycin sensitivity assays may also aid in identifying individuals who are at an increased risk for lung cancer. Additional work has been done in the area of characterizing the molecular alterations in the bronchial epithelium in high-risk smokers. This manuscript addresses only selected molecular alterations that have been examined in preneoplastic bronchial epithelium. In addition to mutations in the k-ras oncogene and the p53 gene, which are frequently seen in malignancy, alterations in the p16 gene, microsatellite instability and loss of heterozygocity are also promising potential markers of preneoplasia. The hnRNP A2/B1 gene also shows some promising increased expression in preneoplasia. Lung cancer prevention has made some strides. A number of trials with molecular and morphologic intermediate endpoints have been conducted and have suggested that some of the molecular alterations and morphologic alterations are reversible. However, the rate of spontaneous regression of these lesions is, as yet, uncharacterized. Two recent large studies, the beta-carotene and retinol efficacy trial (CARET) trial conducted in the United States and the Alpha-Tocopherol Beta Carotene (ATBC) trial conducted in Finland, both demonstrated an unexpected increased risk for lung cancer associated with beta-carotene supplementation. The EUROSCAN trial evaluation of vitamin A and N-acetylcystine also showed no benefit to supplementation in reducing risk for lung cancer. Results from the Intergroup study of 1 3-cis-retinoic acid are pending, and plans are underway for an Intergroup trial studying high selenium yeast to reduce lung cancer risk. Hopefully, the combination of identifying markers of increased risk among the numerous current and former smokers will identify high-risk populations to participate in future trials of promising agents that may lead to reduction in incidence and mortality of the leading cause of cancer death.
 ...
PMID:Early detection and prevention of lung cancer. 1075 Jul 26

Previous research suggested that the beta-lyase-mediated production of a monomethylated selenium metabolite from Se-methylselenocysteine is a key step in cancer chemoprevention by this agent. In an attempt to affirm the concept, the present study was designed to evaluate the activity of methylseleninic acid, a compound that represents a simplified version of Se-methylselenocysteine without the amino acid moiety, thereby obviating the need for beta-lyase action. The in vitro experiments showed that methylseleninic acid was more potent than Se-methylselenocysteine in inhibiting cell accumulation and inducing apoptosis in TM12 (wild-type p53) and TM2H (nonfunctional p53) mouse mammary hyperplastic epithelial cells, and these effects were not attributable to DNA damage, as determined by the comet assay. In general, methylseleninic acid produced a more robust response at one-tenth the concentration of Se-methylselenocysteine. It is possible that these cell lines may have only a modest ability to generate a monomethylated selenium species from Se-methylselenocysteine via the beta-lyase enzyme. In contrast, methylseleninic acid already serves as a preformed active monomethylated metabolite, and this could be an underlying reason why methylseleninic acid acts more rapidly and exerts a more powerful effect than Se-methylselenocysteine in vitro. Interestingly, the distinction between these two compounds disappeared in vivo, where their cancer chemopreventive efficacies were found to be very similar to each other [in both methylnitrosourea and dimethylbenz(a)anthracene rat mammary tumor models]. The beta-lyase enzyme is present in many tissues; thus, animals have an ample capacity to metabolize Se-methylselenocysteine systemically. Therefore, Se-methylselenocysteine would be expected to behave like methylseleninic acid if beta-lyase is no longer a limiting factor. Taken together, the present in vitro and in vivo results provide strong evidence in support of our earlier hypothesis that a monomethylated selenium metabolite is important for cancer chemoprevention. Methylseleninic acid could be an excellent tool, especially for molecular mechanism studies in cell culture, and some of these attributes are discussed.
 ...
PMID:In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. 1085 Apr 32

Two previously unevaluated selenium compounds, Se-allylselenocysteine (ASC) and Se-propylselenocysteine (PSC), have been shown recently to be active in the chemoprevention of experimentally induced mammary carcinogenesis. Other than their potential as chemopreventive agents, little is known about the pharmacological properties of these compounds. In this article, we report on the in vitro effects of ASC and PSC on cell growth inhibition, apoptosis, and the induction of DNA damage. The effects of ASC and PSC were examined in two mouse mammary epithelial cell lines derived from mammary hyperplasias. These cell lines, designated TM2H and TM12, have mutant or wild-type p53, respectively. It was observed that ASC but not PSC reduced, in a concentration- and time-dependent manner, the number of adherent cells in culture, and this suppressive effect was more prominent in TM12 than in TM2H cells. ASC was also found to induce alkaline-labile DNA damage and the oxidation of pyrimidines, and it also increased the rate of apoptosis. These changes were not seen by exposure to PSC or the sulfur analog of ASC. However, additional data obtained from the intact rat mammary gland suggest that the loss of DNA integrity induced by ASC might not be manifest in vivo at doses of ASC that inhibit carcinogenesis.
 ...
PMID:In vitro effects of Se-allylselenocysteine and Se-propylselenocysteine on cell growth, DNA integrity, and apoptosis. 1102 Apr 48


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