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)

One of the major debates in hepatocellular carcinogenesis at present is whether the hepatitis-B and -C viruses are directly carcinogenic or exert their effect indirectly by causing chronic necro-inflammatory hepatic disease, which in turn is responsible for malignant transformation of hepatocytes. This debate has been fueled by the observation that hepatitis C virus is a single-stranded RNA virus with no precedent for inducing cancer but with a marked propensity to cause chronic necro-inflammatory hepatic disease and by the findings in Chisari's transgenic mouse model, which suggest that severe and prolonged hepatocellular injury per se induces a proliferative response that progresses to tumour formation. Recent reports of a guanine to thymine mutation of the third base of codon 249 of the tumour suppressor gene, p53, in 50% of patients with hepatocellular carcinoma in regions of high aflatoxin exposure, and mutagenic experiments showing that aflatoxin B1 binds particularly to guanine residues in G-C-rich domains and that codon 249 is a preferred target have suggested a mechanism whereby aflatoxin might induce malignant transformation.
 ...
PMID:Tumours of the liver. 133 85

Liver cancer is one of the most prevalent forms of cancer in the world. Hepatitis B virus (HBV) is considered to be a major aetiological factor. Evidence from epidemiological studies has also indicated that environmental contaminants such as mycotoxins may, either in combination with HBV or independently, be important aetiological factors in the pathogenesis of primary hepatocellular carcinoma (PHC). Laboratory data also suggest an interplay between viral and chemical factors in the multifactorial aetiology of PHC. Aflatoxin B1, the chemical carcinogen most frequently implicated in the aetiology of hepatocellular carcinoma is a procarcinogen that must be activated by mixed-function oxidases to an electrophilic metabolite before it can exert its carcinogenic effects. Interindividual differences (greater than 10-fold) in the metabolic activation of aflatoxin B1 are observed. These differences may play a part in an individual's oncogenic susceptibility to aflatoxin B1. Chemical carcinogens and integrated HBV may activate cellular oncogenes, eg N-ras, and inactivate tumour suppressor genes. Recently developed methods that allow monitoring of aflatoxin B1 and HBV exposures and also genetic damage caused by these agents in individuals should help in biochemical and molecular epidemiological studies concerning the aetiology of hepatocellular carcinoma. We identify areas of uncertainties and of future experimentation and propose a hypothesis of liver carcinogenesis.
 ...
PMID:Interactive effects of chemical carcinogens and hepatitis B virus in the pathogenesis of hepatocellular carcinoma. 304 Feb 43

To examine the significance of mutation of the p53 tumour suppressor gene in the development of human hepatocellular carcinoma in a high-prevalence area for hepatitis B viral infection but a low-exposure area for aflatoxin B1, the spectrum of p53 gene mutations was examined in 21 tumour samples from Hong Kong Chinese patients, all of whom were HBsAg positive. DNA sequencing covering exons 5 to 9 of the p53 gene and Hae III restriction enzyme digestion for preliminary assessment of mutation at codon 249 were performed. Immunohistochemical staining with anti-p53 monoclonal antibodies was done on both tumour and nontumour liver tissues. Six tumours (28.6%) showed a p53 mutation and all were point mutations. Of the six point mutations, two (9.5%) were at codon 249 and both were G to T transversions (AGG-->ATG and AGG-->AGT transversions). The remaining point mutations were transversions scattered at codon 172 (exon 5), 214 (exon 6), 273 (exon 8) and 330 (exon 9). Mutated p53 protein was detected in five of these six cases with demonstrable point mutations by DNA sequencing, in contrast to none detected in all of the 15 cases without demonstrable point mutations. The presence of p53 mutations, including those at codon 249, did not show a significant association with tumour size, sex, age, tumour invasiveness in terms of liver invasion, microsatellites and venous permeation, cirrhosis and encapsulation, but tumours with low cellular differentiation tended to have a higher incidence (71%) of point mutations than those with high cellular differentiation (8%). In conclusion, both the overall p53 mutation rate and that a codon 249 in HCC in Hong Kong Chinese are lower than those reported in tumours from China and sub-Saharan Africa. The low mutation rate at codon 249 is compatible with a low aflatoxin exposure. A special type of p53 mutation has not been found to be associated with hepatitis B viral infection. Mutations of p53 gene tends to occur in tumours with low cellular differentiation, suggesting a late occurrence in the event of tumour progression.
 ...
PMID:p53 gene mutation spectrum in hepatocellular carcinomas in Hong Kong Chinese. 810 45

Human hepatocellular carcinomas (HCC) and hepatoblastomas (HB) from patients in France and Italy, respectively, which are both areas with a low incidence of HCC and a low dietary exposure to aflatoxin B1 (AFB1), were analysed for alterations of the p53 tumour suppressor gene. An abnormality in the p53 gene was detected in only one of the seven HCCs examined. Sequencing of the cDNA of this HCC revealed a G to T transversion at the first nucleotide of codon 245 that was not found in normal tissue, excluding the possibility of germinal transmission of this alteration. All tumours had the wild-type sequence at codon 249, which has been reported to be a mutational hot spot in the p53 gene in HCCs from high incidence areas, such as China and Southern Africa. Seven samples of HB, the most common hepatic tumour of children, were also tested for loss of heterozygosity (LOH) and mutations in the p53 gene. In contrast to what is observed in HCC of adulthood, for which environmental conditions are important etiological risk factors, HB probably stems uniquely from genetic disorders. PCR-direct sequencing of exons 4 to 8 and PCR-single strand conformation polymorphism (PCRSSCP) of exons 2, 3 and 9 revealed no mutations in the coding sequences examined. LOH was observed in one of the five informative cases when codon 72 and intron 6 were subjected to polymorphism analysis.
 ...
PMID:Analysis of the p53 gene in European hepatocellular carcinomas and hepatoblastomas. 839 66

Aberrations of the p53 and Rb tumour suppressor genes were examined in 12 human hepatocellular carcinoma (HCC)-derived cell lines from different geographic areas and 9 local HCCs by restriction fragment length polymorphisms (RFLP), polymerase chain reaction-single-strand conformation polymorphisms (PCR-SSCP) and DNA sequencing. The relationships between genetic changes and hepatitis B virus (HBV) DNA integration in samples were compared. None of the cell lines and tumours showed structural changes in the Rb gene, while 6 cell lines and 2 tumours had mutation or deletion in exons 5 to 8 of p53. Mutations include an AGG --> AGT (Arg --> Ser) transversion at codon 249 in PLC/PRF/5 and Mahlavu, an AAT --> AAA (Asn --> Cys) transversion at codon 200 in TONG/HCC, an AAG --> GAG (Lys --> Glu) transition at codon 139 in HCC-T, a CAT --> CGT (His --> Arg) transition at codon 214 in SC4, and a CCC --> CTC (Pro --> Leu) transition at codon 250 in SC8. In Huh4, an 18-bp deletion from codon 264 to 270 resulted in loss of Leu-Gly-Arg-Asn-Ser-Phe from the amino acid sequences 265 to 270, whereas Hep3B had a 7-kb deletion after exon 7 of p53. Our data indicate that whereas Rb may not have pleiotropic effects on HCC, p53 aberrations are frequently involved in hepatocarcinogenesis. Further, HBV infection appears to be unrelated to the micro-genetic changes of p53. The G to T codon-249-mutation is consistent with HCCs arising from areas at high risk for both aflatoxin B1 (AFB1) exposure and HBV infection.
 ...
PMID:Tumour suppressor p53 and Rb genes in human hepatocellular carcinoma. 877 41

The gene encoding the tumour suppressor protein p53 is one of the most commonly mutated genes in human cancers. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure.
 ...
PMID:The p53 tumour suppressor gene: a model for molecular epidemiology of human cancer. 879 49

Transgenic mice carrying an integrated subgenomic human hepatitis B virus (HBV) DNA fragment coding for the viral envelope polypeptides, represent a model for the study of the mechanisms involved in hepatocarcinogenesis. The mice develop a progressive liver injury characterized by inflammation, regenerative hyperplasia and dysplasia terminating in hepatocellular carcinoma (HCC) at around 18-21 months of age. No alterations in specific oncogenes and tumour suppressor genes in the HCC arising in this transgenic model have been observed. However, onset of liver tumours is significantly earlier in mice treated with aflatoxin B1 (AFB1). In order to examine more generally for genetic rearrangements during the natural history of the disease, DNA multilocus fingerprinting was performed using probes recognizing mouse minisatellites. Liver tumour samples from HBV transgenic mice either untreated or treated with AFB1 transplacentally were included in the study. In a total of 28 tumour samples from HBV transgenic mice receiving no carcinogen treatment, using three minisatellite probes, no alterations were detected. The frequency of rearrangements using any one of the three probes is calculated to be below 0.2%. This result demonstrates that genetic instability in minisatellite sequences is not a common event associated with HBV gene expression and liver injury in this model. In 11 liver tumours from mice exposed to AFB1 transplacentally six had minisatellite alterations (band gains and losses) revealed by at least one of the three probes used. The frequency of rearrangements was between 1.1% and 2% depending on the minisatellite probe. These data show that genetic alterations can be induced by transplacental exposure to AFB1 and suggest that genetic instability could be important in hepatocarcinogenesis with combined exposures to AFB1 and HBV.
 ...
PMID:Minisatellite rearrangements are increased in liver tumours induced by transplacental aflatoxin B1 treatment of hepatitis B virus transgenic mice, but not in spontaneously arising tumours. 911 Nov 92

The tumour suppressor gene p53 is expressed in response to DNA-damage; its protein product blocks cells in the G1-phase of the cell cycle. This gives cells additional time to repair their DNA-damage. However, it may trigger apoptosis if damage is too high. Loss of p53 function appears to be an important step in carcinogenesis because 50% of human tumours have lost functional p53. In order to study the role of p53 in experimental hepatocarcinogenesis, we determined the expression of p53 in rat liver in response to various hepatocarcinogenic and hepatotoxic compounds. Administration of hepatocarcinogenic compounds increased p53 protein levels in the liver as detected by immunoprecipitation followed by SDS-PAGE and Western blotting with ECL-detection. The hepatocarcinogens included N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and diethylnitrosamine. Their structural analogues N-hydroxy-4-acetylaminobiphenyl and ethyl methane-sulphonate which are not hepatocarcinogenic, did not induce p53. Also, two hepatotoxic compounds (carbon tetrachloride, D-galactosamine) did not induce p53. Other compounds that induced p53 in the rat liver were 2-aminofluorene (administered by drinking water for two weeks) and tris-(2,3-dibromopropyl)phosphate. Benzo[a]pyrene did not induce p53. N-Hydroxy-2-acetylaminofluorene, aflatoxin B1, and diethylnitrosamine are potent hepatic tumour promoters. At the same time, they induce p53 protein expression and inhibit proliferation of normal hepatocytes. Because this is not observed with non-hepatocarcinogenic analogues, it suggests an involvement of p53 expression in hepatic tumour promotion. A possible mechanism is discussed.
 ...
PMID:p53 protein expression by hepatocarcinogens in the rat liver and its potential role in mitoinhibition of normal hepatocytes as a mechanism of hepatic tumour promotion. 916 91

Among genetic alterations, the activation of proto-oncogenes and inactivation of tumour suppressor genes in affected cells are considered to be the core molecular events that provide a selective growth advantage and clonal expansion during the multistep process of carcinogenesis. The TP53 tumour suppressor gene is mutated in about half of all human cancer cases. The p53 protein modulates multiple cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence and apoptosis. Mutations in the TP53 gene can abrogate these functions, leading to genetic instability and progression to cancer. The molecular archaeology of the TP53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of each type of cancer. The spectrum of somatic mutations in the TP53 gene, of which 75% are missense mutations, implicates environmental carcinogens and endogenous processes in the etiology of human cancer. The presence of a characteristic TP53 mutation can also manifest a molecular link between exposure to a particular carcinogen and a specific type of human cancer, e.g. exposure to aflatoxin B1 (AFB1) and codon 249 mutations in hepatocellular carcinoma; exposure to ultraviolet (UV) light and C:C-->T:T tandem mutations in skin cancer; and cigarette smoking and the prevalence of G-->T transversions in lung cancer. Although exogenous carcinogens have been shown to target p53 selectively, evidence supporting the endogenous insult of TP53 from oxyradicals and nitrogen-oxyradicals is also accumulating. TP53 mutations can be a biomarker of carcinogen effect. Determining the characteristic TP53 mutation load in non-tumorous tissue, using a highly sensitive mutation assay, can indicate exposure to a specific carcinogen and may also help in identifying individuals at an increased risk of cancer.
 ...
PMID:TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. 1505

The tumour suppressor protein p53 mediates cell-cycle arrest, DNA repair and apoptosis after activation by multiple forms of cellular stresses. When activated, this "master protein" modulates its response depending on the type and intensity of the stress. The TP53 gene with its nearly 20,000 described mutations is the most mutated gene in cancer. Most mutations are missense and occur at over 200 codons within the central portion of the gene. In several cancers, the distribution of mutation types and sites follow a specific pattern reflecting the effects of environmental mutagens. An example for such a "mutagen fingerprint" is TP53 mutation at codon 249 in hepatocellular carcinoma in regions of the world characterised by high levels of the mutagen aflatoxin B1 and endemic HBV infection. Recently, TP53 mutations have been detected in surrogate sources of genetic material such as free circulating DNA isolated from plasma. Plasma TP53 mutations can be detected in the blood of pre-cancer and cancer patients, with potential application for early cancer detection. Thus, TP53 mutations have multiple applications as markers of mutagenic exposures, or as intermediate end-points in assessment of cancer occurrence and progression.
 ...
PMID:Somatic mutations in human cancer: applications in molecular epidemiology. 1622 13


1 2 Next >>