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

More than a decade ago an association between acute intermittent porphyria (AIP) and hepatocellular carcinoma (HCC) was reported, but still the cause of the increased prevalence is unknown. Paraffin sections of formalin-fixed HCC from 17 AIP patients were reexamined and also screened for relevant mutations using several methods. The tumor diagnosis was verified, and in several cases precirrhosis and cirrhosis were also found. The clinically founded AIP diagnosis was verified at the gene level in most cases, demonstrating the Norrland type of mutation, i.e., G(593)-to-A substitution in codon 198 of the porphobilinogen deaminase (PBGD) gene. The second allele was neither mutated nor missing, contradicting the possibility that the PBGD gene might function as a tumor suppressor gene. Subsequent sequencing showed that cases not cleaved by the restriction enzyme NheI lacked the specific Norrland mutation. In recent years, selective mutations at codons 249 and 166 of the p53 gene have been described in HCC associated with aflatoxin and hepatitis B virus. In our area, with low exposure to those agents, no mutations in codon 249 were found, and mutation in codon 166 was excluded in all tumors except one; no traces of hepatitis B DNA were observed. Nor did we find mutations in H-ras 12 or 61. Intrinsic aberrations in AIP, including reduced heme synthesis and endogenous oxidative damage to DNA, may incite carcinogenic mutations elsewhere in the genome of liver cells. The increased cell proliferation coupled to precirrhosis and cirrhosis perhaps represents promotion in the initiation-promotion sequence of hepatocarcinogenesis.
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PMID:Hepatocellular carcinoma in patients from northern Sweden with acute intermittent porphyria: morphology and mutations. 916 6

The human hepatitis B virus (HBV) protein pX is a multifunctional regulatory protein that is known to affect both transcription and cell growth. Here we describe induction of apoptosis in NIH 3T3 polyclonal cell lines upon stimulation of pX expression from a dexamethasone inducible mouse mammary tumor virus (MMTV)-X expression vector. The effect of long-term pX expression on the cell survival of mouse fibroblasts was confirmed in colony generation assays. This effect is not shared either by the other HBV products and it is c-myc mediated, as shown by the use of a dominant negative deletion mutant of c-myc. pX also sensitize cells to programmed cell death after exposure to DNA damaging agents. Taking advantage of stable transfectants carrying the p53val135 temperature-sensitive allele, we directly demonstrate that induction of apoptosis by pX requires p53. In p53 null mouse embryo fibroblasts pX activates transcription and confers an evident growth advantage without loss of cell viability. Although pX protein was not detectable in the experimental conditions we used, our results indicate that its expression affects both cell growth and cell death control.
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PMID:The hepatitis B virus X gene induces p53-mediated programmed cell death. 922 32

Full length cDNAs for p53 were made by reverse transcription-polymerase chain reaction of total RNA from two normal woodchuck livers. Two randomly chosen clones from each liver were sequenced and shown to be identical. This sequence revealed 80% or more identity with p53 sequences from human, monkey, and mouse. The cDNA was translated into a 55 kD protein in vitro that was immunoprecipitated by antibodies to p53. Cotranslation of woodchuck p53 with woodchuck hepatitis virus X antigen, followed by immunoprecipitation suggested X/p53 complex formation. Similar complexes were also immunoprecipitated from extracts of infected liver, but not from uninfected liver. The finding of X/p53 complexes in vivo and in vitro in the woodchuck hepadnavirus system, combined with analogous data with hepatitis B, suggests a common mechanism by which these viruses contribute to hepatocellular transformation.
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PMID:Partial characterization of the woodchuck tumor suppressor, p53, and its interaction with woodchuck hepatitis virus X antigen in hepatocarcinogenesis. 923 67

Recent studies have implicated aflatoxin B1 (AFB1) exposure as an etiological agent in hepatocellular carcinoma (HCC) and suggested an interaction with chronic hepatitis B virus (HBV) infection. Worldwide AFB1 exposure correlates with a specific mutation at codon 249 in the p53 tumor suppressor gene in liver tumors. This study investigated the roles of HBV and AFB1 in the HCC carcinogenic pathway involving p53 mutations. In cases and controls, chronic HBV infection was assessed by serum hepatitis B surface antigen (HBsAg) and AFB1 exposure by immunohistochemical detection of AFB1-DNA adduct in liver tissue. p53 protein mutations in tumor tissues of HCC cases were identified by immunohistochemistry and DNA mutations by single-stranded conformational polymorphism and sequencing analysis. Both chronic HBsAg carrier status and liver AFB1-DNA adducts were significantly higher in cases than in controls with odds ratios (OR) of 8.4 and 3.9, respectively (P < 0.01). Moreover, HCC risk was greatest in individuals with both AFB1-DNA adducts and HBsAg, suggesting a viral-chemical interaction. Mutant p53 protein, mutations in the p53 gene, and specific codon 249 mutations were detected in 37, 29, and 13%, respectively, of the HCC cases. Most of the DNA mutations were transversions, and the only major clustering site for mutations was codon 249. AFB1-DNA adducts were associated with p53 protein (OR = 2.9, P = 0.054) and DNA mutations (OR = 2.9, P = 0.082) but with borderline significance. All of the codon 249 mutations (n = 12) occurred in HBsAg-seropositive carriers, resulting in an OR of 10.0 (P < 0.05), suggesting that HBV may be involved in the selection of these mutations. The ORs between HBsAg and p53 DNA and protein mutations were 2.6 (P = 0.077) and 1.8 (P > 0.05), respectively. Both p53 DNA and protein mutations were related to tumor stage, suggesting that they are late events. These studies provided further support for the role of aflatoxin exposure in HCC in Taiwan and insight into viral-chemical interactions and molecular pathogenesis.
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PMID:p53 mutations, chronic hepatitis B virus infection, and aflatoxin exposure in hepatocellular carcinoma in Taiwan. 927 15

We demonstrated that introduction and expression of wild-type p53 gene in the human hepatocellular carcinoma cell line, Hep3B, resulted in up-regulation of both p21WAF1/CIP1 and bax gene expression and apoptosis. This cell line contains integrated hepatitis B virus sequences and lacks the expression of both p53 and retinoblastoma tumor suppressor genes because of deletions. Our results suggest that whereas an increased level of bax expression mediates apoptosis, an increased level of p21WAF1/CIP1 expression does not induce arrest of cell growth, presumably because of the deletion of the retinoblastoma gene. This study also confirms reported observations that p53 is a tumor suppressor gene, which induces apoptosis in malignant cells that lack normal p53 activity because of mutation, deletion, or inactivation of the gene by the presence of oncogenic viral proteins.
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PMID:Wild-type p53 induces apoptosis in Hep3B through up-regulation of bax expression. 935 71

It has been suggested that hepatitis B virus (HBV) X gene activates X gene expression by disrupting the function of p53 tumor suppressor gene (Takada et al., 1996). To find out their connection, effect of X protein expression on the nuclear localization of p53 protein in human hepatoma cells was examined by the immunofluorescent double-staining technique. The location of transiently-expressed p53 protein was examined in X gene-transfected cells, where X protein was detected in the cytoplasm. The nuclear location of transiently-expressed p53 protein was changed to the cytoplasm by X protein co-expression. Endogenous p53 protein was also observed in the cytoplasm by X protein expression. The transcriptional activation domain of X protein and the carboxy-terminal region of p53 protein were found mutually responsible for the cytoplasmic retention of p53 protein in X gene-transfected cells. Therefore, the cytoplasmic retention of p53 protein may be closely correlated to the function of X protein expressed in transfected cells.
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PMID:Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells. 936 35

Transactivation of viral and host genes expression by hepatitis B virus X protein (HBx) is believed to be involved in hepatocarcinogenesis. The interaction of HBx with the tumor suppressor p53 and its inhibitory effect on p53 functions have been reported recently. However, the question of whether p53 is directly involved in HBx transactivation has not yet been addressed. In this study, we delineated the interaction sites of HBx and p53 using far-Western blotting and glutathione S-transferase-resin pull-down assays. The results indicate that the HBx-binding sites are located within the oligomerization and specific DNA-binding domains of p53 and that the p53-binding site was confined to a small region in the HBx transactivation domain. Mutual interference of the transactivations by HBx and p53 was detected by CAT assays in a transient transfection system. Strikingly, transactivation by HBx was observed in the p53-negative cells, Saos-2 and Hep3B, indicating that the transactivation and the p53-inhibiting functions of HBx are mutually interfering but distinct.
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PMID:The transactivation and p53-interacting functions of hepatitis B virus X protein are mutually interfering but distinct. 937 15

Codon 249 (exon 7) of the putative tumor suppressor gene p53 is a mutational hot-spot for hepatocellular carcinoma (HCC) but not other tumors. DNA samples from primary HCC patients from Tongan, an area of high HCC incidence in China (> 40 per 100,000 population), were analyzed for specific mutations in codon 249 of the p53 gene using polymerase chain reaction (PCR)/restriction-digest methods and direct DNA sequencing. Seven of the 21 samples screened were found to have a point mutation at the third base position of codon 249 (AGG to AGT). The result is consistent with previous reports that the G-->T transversion is positively associated with the level of dietary aflatoxin B1 (AFB1) contamination, which has been implicated as one of the risk factors in Tongan area. Of the 7 HCC patients that contained the codon 249 point mutation, one was hepatitis B virus (HBV)-negative. This is only the second documentation of an HCC patient harboring the p53 codon 249 mutation, who was HBV-negative.
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PMID:Mutations at codon 249 of p53 gene in human hepatocellular carcinomas from Tongan, China. 940 27

We have reported previously that the hepatitis B virus oncoprotein, HBx, can bind to the C terminus of p53 and inhibit several critical p53-mediated cellular processes, including DNA sequence-specific binding, transcriptional transactivation, and apoptosis. Recognizing the importance of p53-mediated apoptosis for maintaining homeostasis and preventing neoplastic transformation, here we further examine the physical interaction between HBx and p53 as well as the functional consequences of this association. In vitro binding studies indicate that the ayw and adr viral subtypes of HBx bind similar amounts of glutathione S-transferase-p53 with the distal C terminus of HBx (from residues 111 to 154) being critical for this interaction. Using a microinjection technique, we show that this same C-terminal region of HBx is necessary for sequestering p53 in the cytoplasm and abrogating p53-mediated apoptosis. The transcriptional transactivation domain of HBx also maps to its C terminus; however, a comparison of the ability of full-length and truncated HBx protein to abrogate p53-induced apoptosis versus transactivate simian virus 40- or human nitric oxide synthase-2 promoter-driven reporter constructs indicates that these two functional properties are distinct and thus may contribute to hepatocarcinogenesis differently. Collectively, our data indicate that the distal C-terminal domain of HBx, independent of its transactivation activity, complexes with p53 in the cytoplasm, partially preventing its nuclear entry and ability to induce apoptosis. These pathobiological effects of HBx may contribute to the early stages of hepatocellular carcinogenesis.
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PMID:Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. 940 77

To clarify the relative role of hepatitis C virus (HCV) and hepatitis B virus (HBV) in hepatocarcinogenesis in hepatitis B surface antigen (HBsAg)-negative hepatocellular carcinoma (HCC) in Taiwan, polymerase chain reaction (PCR) was used to detect the HCV-RNA and HBV-DNA sequences in the serum and liver tissues from 31 HBsAg-negative HCC patients. Twenty-one were positive for antibody to HCV (group 1) and 10 were negative (group 2). Hepatitis C virus-RNA was detected by PCR in the serum of 16 group 1 patients and in the liver tissue of 17; while HBV-DNA was found in the liver tissue of only four, and no HBV-DNA was found in the serum. Hepatitis C virus RNA was detected in the serum of one group 2 patient and in the liver tissue of another. In contrast, HBV viral DNA was found in the serum of four group 2 patients and in the liver tissues of five patients. This indicates that HCV plays an important role in hepatocarcinogenesis in HBsAg-negative patients in Taiwan, especially in those with antibody to HCV. In those without antibody to HCV, HBV might still be associated with the development of HCC in a significant proportion of such patients. In order to study the role of the p53 mutation in hepatocarcinogenesis, we investigated the status of the p53 mutation in 61 HCC samples from Taiwan. The exon 5 to 8 of the p53 gene in the tumour tissue of 61 HCC were amplified and sequenced. A total of 20 cases (32.8%) were found to have mutations: 36.6% (15/41) from the HBsAg-positive group and 25.0% (5/20) from the HBsAg-negative group. The corresponding normal liver showed no mutation. The mutation is widely distributed throughout the exon 5 to 8. Only four cases (6.6%), all positive for HBsAg, had a specific hotspot mutation at codon 249 with G to T transversion. These results show that scattered point mutations in p53 are not uncommon in HCC samples from Taiwan and may be important in the development of this cancer. However, the aflatoxin-related specific mutation seems much less related to the genesis of HCC in Taiwan. To study the role of telomerase activity in hepatocarcinogenesis, a total of 39 HCC tissues and the corresponding non-tumour liver tissues were analysed. The results showed that telomerase activity was detected in all the 39 tumour tissues, while it could be detected in six of the 39 non-tumour liver tissues. The high positive rate of telomerase activity in HCC samples suggests that telomerase activity is closely related to the development or progression of HCC. To determine whether exon 1 and exon 2 of the p16 gene are altered in HCC, thirty-four tumours from 30 HCC patients were examined by DNA sequencing analysis of PCR-amplified genomic DNA. Homozygous deletions of MTS1/p16/CDKN2 exon 1 were identified in 1/34 primary tumours (3%), no mutations or rearrangements were found in these specimens. These data suggest that alterations of MTS1/p16/CDKN2 gene are rarely found in HCC, and might play little role in the development of this cancer. To study the clonality of HCC, 18 patients with multiple HCC, most of them small in size, were analysed by DNA fingerprinting. In patients positive for hepatitis B surface antigen, the integration pattern of hepatitis B viral DNA in liver tissue was also analysed. The results by both methods showed that 8/9 hepatitis B surface antigen-positive patients were different in clonality. In the remaining nine patients negative for hepatitis B surface antigen, four had different band patterns in their tumours by DNA fingerprinting. This study indicated that polyclonality of multiple HCC was rather frequent and it highlighted the importance of eliminating the underlying cause of liver injury to improve the survival of these patients. Microsatellite markers were used to study the genetic changes of HCC. Thirty cases of HCC, most of them small in size, were studied. A total of 242 microsatellite markers mapping to 1-22 and X chromosomes was used. The results showed that the range of loss of het
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PMID:Molecular mechanism of hepatocarcinogenesis. 940 51


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