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)

Oxyradical overload disease develops in conditions involving chronic inflammation and may be of inherited etiology, e.g. haemochromatosis and Wilson disease, be acquired, e.g. infection with hepatitis B or C virus or Helicobactor pylori, or be chemically induced, e.g. acid reflux in Barrett oesophagus. Susceptibility to cancer is frequently a pathological consequence of extensive oxyradical damage that leads to a cycle of cell death and regeneration and causes mutations in cancer-related genes. In this brief review, we focus on the possible interactive effects of nitric oxide and the p53 tumour suppressor gene in human carcinogenesis.
 ...
PMID:Cancer-prone oxyradical overload disease. 1062 29

Loss of heterozygosity (LOH) on chromosome 13q is one of the most common genetic alterations in hepatocellular carcinoma (HCC) and might be involved in liver cancer development through inactivation of tumour suppressor genes. In order to narrow down the region of 13q loss, we examined the pattern of loss of heterozygosity (LOH) in tumours from 88 HCC patients, using 18 microsatellite markers on 13q. Thirty-eight of the 88 tumours (43%) showed LOH for at least one marker. Of these, two tumours (5%) showed 13q whole arm allelic loss, while the remaining 36 tumours (95%) had partial allelic loss. The LOH pattern defined by the 36 tumours suggested the existence of at least three different smallest common deleted regions which might be involved in the carcinogenesis of HCC. The first, the most centromeric in the 13q12.3 is, close to the BRCA2 gene, defined by D13S171; the second, the most telomeric region in the 13q31-32 band, is defined by D13S154 and D13S157; the third, the intermediate region at 13q14.3, which is near the RB gene, is defined by loci D13S268. The rate of LOH at 13q31-32 was significantly higher in Hepatitis B-surface antigen (HBsAg)-positive patients than HBsAg-negative HCC patients, pointing to a candidate gene related to the development of HBsAg-positive HCCs.
 ...
PMID:Loss of heterozygosity at chromosome 13q in hepatocellular carcinoma: identification of three independent regions. 1067 21

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-induced malignant transformation is, however, incompletely understood. HBx, the protein encoded by the X open reading frame, is a transcriptional activator that has been implicated in hepatocarcinogenesis. HBx inhibits the function of the tumour suppressor protein p53 in what is thought to be an early event in hepatocyte transformation before the later accumulation of inactivating p53 point mutations. HBx inhibits apoptosis but also exerts pro-apoptotic effects. The effects of HBx on apoptosis may be important not only for the development of HCC but also for the establishment of HBV infection. Further implication of HBx in hepatocyte transformation has been the demonstration that it inhibits the repair of damaged hepatocyte DNA. This effect may be mediated by interaction with p53 or through binding to the damaged DNA binding protein (DDB), which plays an accessory role in nucleotide excision repair. In addition, HBx activates cell signalling cascades involving mitogen-activated protein kinase (MAPK) and Janus family tyrosine kinases (JAK)/signal transducer and activators of transcription (STAT) pathways. The implications of these modulating effects of HBx are not fully understood, but they are likely to have wide-ranging effects on hepatocyte proliferation, apoptosis and the regulation of cell growth checkpoints. The cellular functions ascribed to HBx are unusually diverse, and defining the biologically important role of HBx during HBV replication will go some way to understanding the sequelae of chronic HBV infection.
 ...
PMID:Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. 1082 73

Mutations of p53 tumour suppressor gene often occur in hepatocellular carcinoma and, in particular, codon 249 hot-spot mutation is displayed by hepatocellular carcinomas occurring in hepatitis B virus-endemic areas with high dietary aflatoxin intake. This study was done to determine the frequency of p53 codon 249 mutation in hepato-cellular carcinoma in Nigerian patients with this tumour. Tumour samples were obtained from 18 Nigerian patients (all from the Southwest of the country) with histologically confirmed hepatocellular carcinoma by autopsy (n = 14), surgical resection (n = 3) and ante-mortem liver biopsy (n = 1). Fourteen of them had co-existing cirrhosis. Amplification of exon 7 of p53 gene from DNA samples of hepatocellular carcinoma tissue was undertaken by nested polymerase chain reaction followed by restriction enzyme analysis. One out of the 18 tumour samples tested (5.5%) demonstrated codon 249 mutation. This study suggests that, in Nigeria, especially the south-western region, aflatoxins appear to play a limited role in hepatocarcinogenesis.
 ...
PMID:P53 codon 249 mutation in hepatocellular carcinomas from Nigeria. 1451 Jan 67

Hepatocellular carcinoma (HCC) is the most important primary hepatic cancer and is a common cancer type worldwide. Many aetiological factors have been related to HCC development, such as liver cirrhosis, hepatitis viruses and alcohol consumption. Inactivation of the p53 tumour suppressor gene is one of the most common abnormalities in many tumours, including HCC. p53 is of crucial importance for the regulation of the cell cycle and the maintenance of genomic integrity. In HCC, hepatitis B and C virus (HBV and HCV) effect carcinogenic pathways, independently leading to anomalies in p53 function. Several authors have reported that some HCV proteins, such as the core, NS5A and NS3 proteins, interact with p53 and prevent its correct function. The mechanisms of action of these HCV proteins in relation to p53 are not completely clear, but they might cause its cytoplasmic retention or accumulation in the perinuclear region where the protein is not functional. The identification of the interactions between p53 and HCV proteins is of great importance for therapeutic strategies aimed at reducing the chronicity and/or carcinogenicity of the virus.
 ...
PMID:Hepatocellular carcinoma: molecular interactions between hepatitis C virus and p53 in hepatocarcinogenesis. 1498 3

The hepatitis B virus X protein (HBx) is implicated in liver cancer development, and this presumably involves its ability to bind and functionally inactivate the p53 tumour suppressor. For example expression of HBx in cultured cells has been shown to inhibit global nucleotide excision repair, a p53-dependent subpathway of nucleotide excision repair (NER) which eliminates helix-distorting DNA adducts, e.g., UV-induced cyclobutane pyrimidine dimers (CPDs), from the genome overall. However it remains undetermined whether HBx also interferes with transcription-coupled NER (TCNER), another NER subpathway which removes DNA adducts uniquely from the transcribed strand (TS) of active genes. To address this, we employed the model human lymphoblastoid strain TK6 and its isogenic p53-null counterpart NH32, in conjunction with derivatives of these strains constitutively expressing HBx (TK6-HBx and NH32-HBx). Relative to TK6, following exposure to either UVB (290-320 nm) or UVC (254 nm), TK6-HBx, NH32 and NH32-HBx manifested significantly reduced apoptotic capacity to varying degrees, although no striking differences in clonogenic survival between the four strains were observed. As previously documented in our laboratory [Proc. Natl. Acad. Sci. 100 (2003) 7219-7224], ligation-mediated PCR analysis revealed NH32 to be deficient compared with TK6 in CPD removal along the TS strand of the chromosomal c-jun locus following UVB exposure, but to be proficient in this respect following UVC exposure, i.e., the requirement for p53 in TCNER exhibits wavelength dependence in human cells. Remarkably however, in contrast to the situation for NH32, TK6-HBx and NH32-HBx manifested defective repair along the TS of c-jun after irradiation with either UVB or UVC. The data demonstrate that HBx expression can reduce the efficiency of TCNER in addition to GNER in human cells via p53-independent as well as p53-dependent pathways.
 ...
PMID:Expression of hepatitis B virus X oncoprotein inhibits transcription-coupled nucleotide excision repair in human cells. 1545 Apr 28

Hepatitis B viral (HBV) infection is the commonest cause of hepatocellular carcinoma. HBV DNA is the most important predictor of hepatocarcinogenesis in HB surface antigen positive patients. We reviewed the mechanism of hepatocarcinogenesis on molecular level with a special emphasis on the role of X-protein. Hepatitis B X-protein communicates with host targets and disturbs cellular functions including cell cycle regulation, apoptosis, signalling, transcriptional regulation, encoding of cytoskeleton, cell adhesion molecules, oncogenes and tumour suppressor genes.
 ...
PMID:Hepatitis B virus and hepatocarcinogenesis. 1862 29

The incidence of hepatocellular carcinoma is increasing worldwide as well as the associated risk factors, some of which include exposure to aflatoxin B1, Hepatitis B (HBV) virus and hepatitis C (HCV) virus. Mutation of tumour suppressor gene p53 at codon 249(ser) at exon 7 has been found to contribute significantly to replication of damaged DNA and subsequent tumour progression. The x gene of HBV (HBx) is the most common open reading frame integrated into the host genome in hepatocellular carcinoma and the integrated HBx is frequently mutated in hepatocellular carcinoma. Mutant HBx proteins still retain their ability to bind to p53 thereby attenuating DNA repair and p53-mediated apoptosis.
 ...
PMID:Hepatocellular carcinoma and the underlying mechanisms. 2081 32

Currently available evidence supports a role for the hepatitis B virus (HBV) x gene and protein in the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). HBx gene is often included, and remains functionally active, in the HBV DNA that is frequently integrated into cellular DNA during hepatocellular carcinogenesis. HBx protein promotes cell cycle progression, inactivates negative growth regulators, and binds to and inhibits the expression of p53 tumour suppressor gene and other tumour suppressor genes and senescence-related factors. However, the molecular mechanisms responsible for HBx protein-induced HCC remain uncertain. Only some of the more fully documented or more recently recognised mechanisms are reviewed. During recent years evidence has accumulated that HBx protein modulates transcription of methyl transferases, causing regional hypermethylation of DNA that results in silencing of tumour suppressor genes, or global hypomethylation that results in chromosomal instability, thereby playing a role in hepatocarcinogenesis. HBx protein has both anti-apoptotic and pro-apoptotic actions, apparently contradictory effects that have yet to be explained. Particularly important among the anti-apoptotic properties is inhibition of p53. Recent experimental observations suggest that HBx protein may increase the expression of TERT and telomerase activity, prolonging the life-span of hepatocytes and contributing to malignant transformation. The protein also interferes with nucleotide excision repair through both p53-dependent and p53- independent mechanisms. Carboxy-terminal truncated HBx protein loses its inhibitory effects on cell proliferation and pro-apoptotic properties, and it may enhance the protein's ability to transform oncogenes. Dysregulation of IGF-II enhances proliferation and anti-apoptotic effects of oncogenes, resulting in uncontrolled cell growth.
 ...
PMID:Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. 2119 26

Epigenetic silencing of tumour suppressor genes has been observed in various cancers. Looking at hepatocellular carcinoma (HCC) specific protein silencing was previously demonstrated to be associated with the Hepatitis C virus (HCV). However, the proposed HCV dependent promoter methylation of DNA mismatch repair (MMR) genes and thereby enhanced progression of hepatocarcinogenesis has been the subject of controversial discussion. We investigated promoter methylation pattern of the MMR genes MLH1, MSH2 and PMS2 as well as the cyclin-dependent kinase inhibitor 2A gene (p16) in 61 well characterized patients with HCCs associated with HCV, Hepatitis B virus infection or alcoholic liver disease. DNA was isolated from formalin-fixed, paraffin-embedded tumour and non-tumour adjacent tissue and analysed by methylation-specific PCR. Moreover, microsatellite analysis was performed in tissues showing methylation in MMR gene promoters. Our data demonstrated that promoter methylation of MLH1, MSH2, PMS2 and p16 is present among all considered HCCs. Hereby, promoter silencing was detectable more frequently in advanced-stage HCCs than in low-stage ones. However, there was no significant correlation between aberrant DNA methylation of MMR genes or p16 and HCV infection in related HCC specimens. In summary, we show that promoter methylation of essential MMR genes and p16 is detectable in HCCs most dominantly in pT3 stage tumour cases. Since loss of MMR proteins was previously described to be not only responsible for tumour development but also for chemotherapy resistance, the knowledge of mechanisms jointly responsible for HCC progression might enable significant improvement of individual HCC therapy in the future.
...
PMID:Promoter methylation of MLH1, PMS2, MSH2 and p16 is a phenomenon of advanced-stage HCCs. 2440 91


<< Previous 1 2 3 Next >>