Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidence has demonstrated that aberration of the p53 tumour-suppressor gene is one of the pivotal genetic events in hepatocellular carcinogenesis. Recent reports suggest that the product of hepatitis B virus (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein reduces p53 expression. A novel p73 gene, which is related to p53, has recently been identified and mapped to chromosome 1p36.3, which is a locus of multiple tumour-suppressor genes for many cancers, including hepatocellular carcinoma (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and mutation of p73 in 48 HCCs obtained from untreated patients. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was expressed ubiquitously at low levels in all the tumour tissues, as well as in the adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP) analysis showed no mutations in the 48 tumours except for three types of polymorphisms. These results suggest that p73 may play a role in hepatocellular carcinogenesis in a different manner from a Knudson two-hit model. The regulatory mechanism of interaction between p73 and hepatitis viruses remains to be determined.
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PMID:Absence of mutation of the p73 gene localized at chromosome 1p36.3 in hepatocellular carcinoma. 1040 9

Transcription of hepatitis B Virus (HBV), an important risk factor of hepatocellular carcinoma (HCC), is controlled by cellular transcription activators including some of the cellular signaling targets. Consequently, HBV transcription rate changes in response to the cellular physiological conditions. In this report we investigated HBV gene expression and the role of physiological levels of the viral X protein (pX) under cisplatin induced genotoxic stress. We show that under these conditions the RNA level of an HBV mutant which does not express pX is sharply reduced. Studies revealed that transcription repression is responsible for the observed reduction in HBV RNA level. Repression of HBV transcription was obtained only in the p53 proficient cells. Furthermore, HBV transcription rate is recovered by the cotransfected p53 dominant negative plasmid, indicating that p53 is directly responsible for HBV transcription repression. Unexpectedly, p73, the recent p53 homologue, does not repress but rather activates HBV transcription. Interestingly, pX produced either by the HBV genome or by a cotransfected plasmid, relieves the p53 mediated repression. Collectively, these results attribute a physiological role to p53-inactivation by pX, and explain how pX may support HCC development.
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PMID:HBV transcription repression in response to genotoxic stress is p53-dependent and abrogated by pX. 1060 9

Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies, but the molecular mechanisms of hepatocarcinogenesis remain unclear. Although p53 mutations are frequently observed in Asian HCC, it is not a common event in Western HCC. Recent studies suggest that tumor suppressor genes (TSGs) can also be silenced through epigenetic disruption, such as promoter CpG island methylation, during carcinogenesis. To further understand the molecular mechanism of hepatocarcinogenesis, we have investigated the promoter methylation status of nine TSGs (SOCS-1, GSTP, APC, E-cadherin, RAR-beta, p14, p15, p16, and p73) in 51 cases of HCC using methylation-specific polymerase chain reaction. We found that 82% of HCCs had methylation of at least one TSG promoter. The most frequently methylated TSGs in HCC were: SOCS-1 (65%), GSTP (54%), APC (53%), E-cadherin (49%), and p15 (49%). Methylation of SOCS-1, GSTP, APC, E-cadherin, and p15 was more frequent in HCC than in nontumor liver (P < 0.05). Methylation of SOCS-1, GSTP, and p15 was also significantly more frequent in HCC than cirrhotic liver (P < 0.05). Although methylation of one or two genes could be seen in both nontumor and cirrhotic livers, 53% of the HCC cases had three or more TSG promoters methylated, in comparison to 0% in nontumor liver and 13% in cirrhosis (P = 0.001). Methylation of SOCS-1, APC, and p15 was more frequently seen in hepatitis C virus-positive HCC than hepatitis C virus/hepatitis B virus-negative HCC. Our data suggest that promoter hypermethylation of TSGs is a common event in HCC and may play an important role in hepatocarcinogenesis.
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PMID:Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. 1293 51

Hepatitis B virus (HBV) is a causative agent of chronic hepatitis and hepatocellular carcinoma. Recent findings demonstrating p73 and specifically N-terminally truncated p73 (DeltaTAp73) accumulation in hepatocellular carcinoma suggest that p73 plays a role in the malignant phenotype. Here, we investigated the mechanism of HBV pregenomic core promoter/enhancer II (cp/EII) regulation by full-length TAp73 and its oncogenic counterpart DeltaTAp73. Ectopic and endogenous expression of TAp73 leads to a significant downregulation of cp/EII activity in p53-deficient hepatoma cell lines. In contrast, overexpression of DeltaTAp73 results in significant cp/EII activation and increased HBV core (HBc) expression. TAp73-mediated repression of HBV transcription was substantially abolished by DeltaTAp73. We show that both TAp73 and DeltaTAp73 proteins directly bind to the Sp1 transcription factor, a key stimulator of HBV gene expression. However, only TAp73 abolishes Sp1 binding to cp/EII, whereas the DeltaTAp73-Sp1 complex further persists on the DNA. The inhibitory effect of p53/p73 on HBc expression is associated with the inhibition of viral replication, while DeltaTAp73 is not. These data strongly support the fact that the p73-isoform-related interaction with Sp1 is the underlying mechanism of the diverse outcome on HBc expression, suggesting a new mechanism by which oncogenic DeltaTAp73 could enhance the carcinogenic process in liver cells.
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PMID:Molecular mechanism of p73-mediated regulation of hepatitis B virus core promoter/enhancer II: implications for hepatocarcinogenesis. 1834 33