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)

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.
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PMID:Hepatocellular carcinoma and the underlying mechanisms. 2081 32

Hepatocellular carcinoma is related to various etiologies including hepatitis B, hepatitis C, high alcohol intake, aflatoxin B1 and metabolic syndrome. Most of the time HCC developed on cirrhosis. Consequently, the mechanisms of carcinogenesis of these different risk factors are difficult to separate from the events leading to cirrhosis. In contrast, aflatoxin B1 and hepatitis B have a clear direct oncogenic role through point mutations in the TP53 tumour suppressor gene and insertional mutagenesis respectively. Finally, next-generation sequencing and transcriptome analysis will refine our knowledge of the relationship between aetiology and the genetic events that draw the mutational landscape of hepatocellular carcinoma.
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PMID:Pathogenesis of hepatocellular carcinoma according to aetiology. 2526 Mar 19

Aflatoxin B1 (AFB1) is produced by species of Aspergillus, and is a known human carcinogen. AFB1-induced oxidative DNA damage, specifically 8-hydroxy-2-deoxyguanosine (8-OHdG) lesions, has been demonstrated in both animal models and in humans, and is repaired by base excision repair (BER). The tumour suppressor gene p53 is implicated in the regulation of DNA repair, and heterozygous p53 knockouts have an attenuated nucleotide excision repair response to AFB1. Male heterozygous p53 knockout mice and their wild-type controls were exposed to 0, 0.2 or 1.0ppm AFB1 for 26 weeks in their diet. BER activity of lung and liver was assessed with an in vitro assay, using 8-OHdG-damaged plasmid DNA as a substrate. BER activity did not differ between livers or lungs from untreated wild-type versus heterozygous p53 knockout mice. In wild-type mice, repair was 65% lower in liver extracts from mice exposed to 1.0ppm AFB1 than in liver extracts from mice exposed to 0.2ppm AFB1 (p<0.05), but not significantly lower than that in liver extracts from control mice. AFB1 did not affect BER in lung extracts from wild-type mice, or in lung and liver extracts from heterozygous p53 knockout mice. In liver and lung, AFB1 exposure did not alter levels of 8-oxoguanine glycosylase protein, a key enzyme in the repair of 8-OHdG, and did not cause hepatotoxicity, as indicated by plasma alanine aminotransferase levels. In conclusion, chronic exposure to AFB1 did not affect BER in lungs or livers of heterozygous p53 knockout mice. BER activity was lower in livers from p53 wild type mice exposed to 1.0ppm AFB1 versus those exposed to 0.2ppm AFB1, an effect that was not attributable to liver cell death or altered levels of 8-oxoguanine glycosylase.
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PMID:The impact of chronic Aflatoxin B1 exposure and p53 genotype on base excision repair in mouse lung and liver. 2584 22

Liver cancer (hepatocellular carcinoma, HCC) is one of the most prevalent cancers worldwide. Several etiological factors of HCC, including hepatitis B or hepatitis C virus infection, liver cirrhosis and aflatoxin B1 intake has been identified. HBx, which is an oncogenic protein encoded by the hepatitis B virus, is strongly associated with hepatocarcinogenesis. Using stable HBx-expressing cell, we showed that HBx induced chromosome gain, with amplification of centrosomes numbers and deregulation of centrosome ultrastructure. To dissect the mechanism for chromosome instability, our result revealed that HBx contributed to a hyperactive centrosome-microtubule dynamics by accelerating microtubule nucleation and polymerization. Further investigations suggested that HBx interacted with a centrosome linker protein TAX1BP2, which has previously been shown to function as an intrinsic block of centrosome amplification and a tumour suppressor in HCC. Restoring TAX1BP2 was able to block HBx-mediated centrosome amplification and abolish the HBx-mediated centrosome aberration, thereby suppressing chromosome instability. Thus, we demonstrate here a mechanism by which HBx deregulates centrosome-microtubule dynamics through interacting with TAX1BP2, which underlines the possibility of restoration of TAX1BP2 to rescue cells from chromosome instability.
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PMID:Centrosomal protein TAX1BP2 inhibits centrosome-microtubules aberrations induced by hepatitis B virus X oncoprotein. 3282 1


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