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

Several recent studies have implicated oncogenes and tumour suppressor genes in the regulation of programmed cell death (apoptosis). Lesions in the cell death pathway appear to be important in both carcinogenesis and the evolution of drug resistance in tumours. They include deregulated expression of genes such as bcl-2, loss of p53, and autocrine activation of anti-apoptotic signal transduction pathways. Paradoxically, a number of dominant oncogenes appear to act as potent inducers of apoptosis. This suggests that the pathways of cell proliferation and cell death may be tightly coupled, an idea that may have dramatic implications for models of oncogene co-operation and carcinogenesis.
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PMID:Oncogenes and cell death. 819 31

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

Colorectal carcinogenesis is a complex multistage process and occurs through the accumulation of gene mutations in both oncogenes and tumour suppressor genes. Frequent genetic abnormalities include mutation of the familial adenomatous polyposis (APC) and/or the mutated in colorectal cancer (MCC) genes on chromosome 5q21, activation of K-ras and loss of the tumour suppressor genes p53 and DCC (deleted in colorectal cancer). In our laboratory we have developed human in vitro colonic cell culture model systems, to determine the biological consequences of these well characterised genetic changes, and how such changes can uncouple proliferation from differentiation and ultimately lead to the malignant phenotype.
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PMID:Biological consequences of the genetic changes which occur during human colorectal carcinogenesis. 831 91

In recent years a 4-mutation paradigm for carcinogenesis was developed for mutations in tumour suppressor genes. The major tenet of this paradigm is that transformation of a normal cell into a malignant cell is the result of an accumulation of a set of 4 specific cancer mutations. In this paper we show that this paradigm can explain the characteristic differences between benign and malignant tumours. We surmise that benign tumour cells are due to 2 or 3 specific cancer mutations, whereas malignant tumour cells contain 4 specific cancer mutations and 1-3 tumour progression mutations. The following characteristics, essential for differentiating benign and malignant tumours, are explained by our paradigm: (a) differentiation--anaplasia, (b) rate of growth, (c) encapsulation--invasion, (d) metastasis, and (e) the differences in size of benign epithelial and mesenchymal tumours and the relation between tumour size and malignancy.
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PMID:The difference between benign and malignant tumours explained with the 4-mutation paradigm for carcinogenesis. 835 41

The p53 tumour suppressor gene is turning out to be a useful reporter for the stigmata of past genotoxic exposure. About half of all human cancers contain p53 mutations most of which occur in those regions (exons 5-8) of the gene that are highly conserved during evolution. Mutations are mainly of the missense type and their frequency and distribution vary among different kinds of cancer. The ability to detect all six possible base-substitution mutations in the p53 gene in human tumours makes it possible to construct mutational spectra for different cancers at a locus clearly implicated in carcinogenesis. Transitions at one particular hotspot--the CpG dinucleotide--occur frequently in many cancers and may reflect endogenous mutation. A reduction in the proportion of CpG mutations at the expense, for example, of an increase in GC to TA transversions may signal the effect of an exogenous mutagen. We exploited these features of the p53 gene to examine the evidence that a previously unsuspected genotoxic exposure may contribute to the high incidence of breast cancer in women living in rich industrialized countries. We compiled a mutational spectrum of p53 from 120 breast cancers and compared it with the spectrum from 145 colorectal cancers and 246 lung cancers. A germline p53 spectrum was constructed using data from 27 patients. Two hundred germline mutations in the haemophilia B gene served as a 'background' spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does a genotoxic carcinogen contribute to human breast cancer? The value of mutational spectra in unravelling the aetiology of cancer. 837 45

Mutations of the p53 detected in human hepatocellular carcinomas suggest that its inactivation is a critical step in hepatocellular carcinogenesis. In order to test whether the expression of p53 is compatible with the transformed phenotype of hepatoma cells, we transfected Hep 3B cell line with p53 expression vectors. This cell line, which contains integrated hepatitis B virus sequences, is a good model to study whether the wild-type p53 can function as a tumour suppressor gene in virus-related hepatocellular carcinoma. Wild-type and mutant p53 (Ala143)-expression vectors containing a neoR gene were used. The number of antibiotic-resistant colonies was six times lower after transfection with wild-type p53 vector as compared to the mutant vector. As measured by a specific radioimmunoassay, six of eight (75%) colonies randomly selected after mutant p53 transfections expressed the transfected mutant p53 protein. In contrast, out of eight colonies from wild-type p53-transfections, none expressed detectable p53 protein. The absence of p53 protein was due to the selective deletion of transfected wild-type p53 cDNA sequences. These studies demonstrate that the growth of hepatocellular carcinoma cells is not compatible with the expression of wild-type p53. Therefore, p53 should be considered as a tumour suppressor gene in hepatocytes.
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PMID:p53 as a growth suppressor gene in HBV-related hepatocellular carcinoma cells. 838 Dec 23

It has been established that loss of tumour suppressor genes is crucial in carcinogenesis. There has been no reported study on searching for tumour suppressor genes in cholangiocarcinomas as yet. In order to investigate the loss of heterozygosity (LOH), which may represent such gene loss, in cholangiocarcinoma, we studied 14 patients with this tumour using restriction fragment length polymorphism analysis. Twenty-two probes assigned to chromosomes 1, 5, 7, 9, 11, 12, 13, 14, 16, 17 and 18 were used. Allelic losses were found in chromosomal regions 5q35-qter and 17p13. Loss of genetic material in these regions in cholangiocarcinoma was shared with hepatocellular carcinoma. Probes for other chromosomes have as yet shown no consistent LOH. In conclusion, this study for the first time showed LOH on chromosomes 5 and 17 in cholangiocarcinoma.
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PMID:Loss of constitutional heterozygosity on chromosomes 5 and 17 in cholangiocarcinoma. 838 28

Alterations of the p53 tumour suppressor gene are considered critical events in multistage carcinogenesis of a wide range of human cancers. In an attempt to elucidate the role of various p53 mutations in tumorigenesis and to investigate their relationship to the p53 protein accumulation and subcellular localization, we have raised a new series of 21 mouse monoclonal antibodies (MAbs) to human recombinant p53. The new MAbs (designated the Bp53 series) appear to recognize mainly denaturation-resistant epitopes in immunoblotting and the majority of them are suitable for immunostaining of p53 in cultured cells and frozen sections. Furthermore, at least three MAbs (Bp53-11, Bp53-12, and Bp53-28) proved to be reliable reagents for immunohistochemistry on paraffin-embedded specimens. The immunohistochemical analysis of paraffin sections from 118 human tumours of various histogeneses with Bp53-11 and Bp53-12 showed nuclear accumulation of the p53 protein in variable proportion of tumour cells in 76 cases (64 per cent). The influence of three parameters of tissue processing (type of fixative, period of fixation, and duration of autolysis) on p53 protein detection was also investigated. The results of this study provide the necessary basis for wider application of these novel MAbs as tools in both routine histopathology and functional analyses of the p53 oncoprotein.
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PMID:Immunohistochemical analysis of the p53 oncoprotein on paraffin sections using a series of novel monoclonal antibodies. 843 13

Two distinct gene classes have been implicated in colorectal carcinogenesis. Tumour promoter genes (oncogenes, dominant oncogenes) produce an excessive positive stimulus to cell proliferation. The ras family of oncogenes are an example. Acquired mutations of the c-k-ras gene are commonly found in colonic adenomas and carcinomas. Tumour suppressor genes (anti-oncogenes, recessive oncogenes) normally constrain or regulate cell proliferation. Loss of this function through gene deletion or mutation is oncogenic. Inherited tumour suppressor gene mutations have now been identified in several of the familial cancer syndromes. Acquired tumour suppressor gene mutations are found in both sporadic and hereditary cancers. Together with the tumour promoter genes they provide the genetic basis for the cellular changes occurring during carcinogenesis. The retinoblastoma gene was the first human tumour suppressor gene to be characterized and exemplifies the class. More recently, linkage studies in the hereditary cancer syndromes and the detection of specific deletions in sporadic tumours have helped to identify several new tumour suppressor genes. At least four of these (MCC, APC, p53 and DCC) apparently contribute to sporadic colorectal carcinogenesis. Germ line APC mutations produce the inherited colorectal cancer syndrome familial adenomatous polyposis (FAP). Detection of these mutations using linked markers has already found clinical application in the screening of families with this disease. In the future, genetic diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) and the recognition of those genetically susceptible to sporadic colorectal cancer may become possible. At the same time, as our understanding of the genes involved improves, new avenues for treatment and prevention of colorectal cancer may emerge.
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PMID:Tumour suppressor genes and colorectal neoplasia. 847 56

The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 receptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.
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PMID:Mechanisms and pathogenesis of thyroid cancer in animals and man. 853 19


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