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)

To test the hypothesis that hepatitis B x antigen (HBxAg) binds to the tumor-suppressor protein p53, immunoprecipitation was carried out with monoclonal anti-x or monoclonal anti-p53 using radiolabeled HBxAg and p53 made by in vitro translation. The results showed that anti-p53 specifically immunoprecipitates HBxAg only in the presence of p53 and that anti-x specifically immunoprecipitates p53 only in the presence of HBxAg. to determine whether HBxAg binds p53 in vivo, immunoprecipitation and Western blot analysis of liver samples from 10 hepatitis B virus (HBV)-infected patients with primary hepatocellular carcinoma (PHC) were carried out. A protein band at 53,000 daltons that specifically immunoprecipitated with a monoclonal anti-x was identified as p53 by Western blotting with a monoclonal anti-p53. Anti-p53 specifically immunoprecipitated bands of 28,000, 17,000 and 13,000 daltons, which were identified as HBxAg polypeptides by Western blotting with anti-HBx. These findings suggest that HBxAg binds to p53 and that this association is important to the development of PHC.
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PMID:Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. 838 23

A G:C-->T:A mutational hotspot at codon 249 of the p53 tumor suppressor gene has previously been identified in hepatocellular carcinoma (HCC) of patients from Qidong, China and southern Africa in which aflatoxin B1 (AFB1) and hepatitis B virus (HBV) are known synergistic risk factors. We have examined p53 mutation patterns of HCC from geographic areas in which the risk factors vary. Nine HCC lines and four hepatoblastoma lines (HB) were examined for p53 gene mutations and the relationship with HBV infection. Five of the nine HCC lines had homozygous mutation or deletion randomly distributed in exons 6-8, whereas none of the four HB cell lines had p53 mutations. One of the four HB lines (HepG2) had an N-ras mutation at codon 61 position 2. The p53 point mutations in the three HCC cell lines from Japan resulted in the amino acid changes of cysteine for tyrosine in cell line HuH 7 at codon 220 (A:T-->G:C), alanine for glycine in cell line HLF at codon 244 (G:C-->C:G), and serine for arginine in cell line HLE at codon 249 (G:C-->C:G). In addition, the deletion of 18 base pairs from codon 264 position 3 to codon 270 position 1 has resulted in the deletion of Leu-Gly-Arg-Asn-Ser-Phe from the amino acids sequences 256-270 in the Japanese cell line HuH 4. The cell line PLC/PRF/5 that showed p53 mutation at codon 249 (G:C-->T:A) with substitution of serine for arginine was derived from a South African patient. Our results indicate that whereas the p53 gene is not mutated in the HB cell lines, the HCC cell lines frequently contain an abnormal p53 gene. In addition, p53 point mutations were not detected in the four Japanese HCC cell lines that were positive for genomic integration of HBV X-gene and surface antigen gene. The three Japanese HCC cell lines with p53 mutations did not contain HBV sequences, indicating that hepatocarcinogenesis associated with p53 mutation does not require the genomic integration of HBV sequences.
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PMID:p53 gene mutation and integrated hepatitis B viral DNA sequences in human liver cancer cell lines. 838 56

We examined the expression of mutant p53 gene products in primary malignant epithelial tumors of the liver. Fourteen of 68 hepatocellular carcinomas, one of seven hepatoblastomas and one of nine intrahepatic cholangiocarcinomas showed nuclear staining for p53 proteins. None of the surrounding non-tumorous tissues expressed nuclear staining. The detection of p53 proteins in tumor cells was significantly higher in hepatocellular carcinomas of Oriental patients (31.6%) compared to non-Orientals (6.7%, p < 0.015). No significant differences were seen in p53 antigen expression between hepatitis B and non-hepatitis B associated hepatocellular carcinomas in Oriental patients. These results suggest a role for other environmental factors, such as aflatoxin, in the etiology of p53 mutation in hepatocellular carcinoma in Oriental patients.
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PMID:The expression of p53 antigen in primary malignant epithelial tumors of the liver: an immunohistochemical study. 839 24

G-to-T transversion at codon 249 of the p53 gene has been shown to be specifically associated with human hepatocellular carcinomas, particularly that subset associated with exposure to the chemical hepatocarcinogen aflatoxin B1. We surveyed 47 North American adult hepatocellular carcinomas and three childhood liver tumors for codon 249 mutation. We report here a case of childhood hepatoblastoma in a patient, without known exposure to aflatoxin B1 or hepatitis B or C virus, whose tumor had a mutation at codon 249 involving G-to-T transversion.
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PMID:Mutation at codon 249 of p53 gene in a human hepatoblastoma. 839 58

Loss of heterozygosity (LOH) on chromosomes 1p, 4q, 5q, 8p, 13q, 16q, 17p, and 22q, and mutation of the p53 gene were simultaneously analyzed in 63 hepatocellular carcinomas (HCCs) with distinct histopathological grades, 80% of the tumors being from patients who had been exposed to hepatitis B virus (HBV) or hepatitis C virus (HCV). The frequencies of LOH on 8 chromosomes were 0-25% in 10 well differentiated HCCs, LOH being observed on 4q, 5q and 17p, 21-53% in 26 moderately differentiated HCCs, LOH on 8p and 17p being high, and 29-75% in 27 poorly differentiated HCCs, LOH on 17p, 4q and 8p being the most frequent. p53 gene mutation was detected in moderately and poorly differentiated HCCs at 15% and 52%, respectively, but not at all in well differentiated HCCs. Of the mutations detected, 42% were transition mutation and only 5% were CpG transition, in contrast to the high frequencies of these types of mutations in colon tumors (78% and 54%, respectively). LOH on every chromosome and p53 mutation were more frequent in more advanced tumors, and accumulation of genetic changes increased with increase of the histopathological grade. Frequency of genetic changes in HCCs from HBV-positive patients was comparable to that from HCV-positive patients. The present results suggest that accumulation of genetic changes in multiple tumor suppressor genes, especially LOH on 17p, 4q and 8p, and mutation in p53 gene, are involved in the progression of liver cancer, and LOH on 17p and 4q precedes other genetic changes. Differences in the direction of p53 mutation between HCC and colon carcinoma suggest that liver carcinogens are distinct from colon carcinogens. Furthermore, mechanisms affecting the frequency of LOH in HCCs in HBV-infected patients may be similar to those in HCV-infected patients.
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PMID:Genetic changes and histopathological grades in human hepatocellular carcinomas. 840 53

The p53 tumor suppressor gene product is a transcriptional transactivator and a potent apoptotic inducer. The fact that many of the DNA tumor virus oncoproteins bind to p53 and affect these p53 functions indicates that this interaction is an important step in oncogenic transformation. We and others have recently demonstrated that the hepatitis B virus oncoprotein, HBx, can form a complex with p53 and inhibit its DNA consensus sequence binding and transcriptional transactivator activity. Using a microinjection technique, we report here that HBx efficiently blocks p53-mediated apoptosis and describe the results of studies exploring two possible mechanisms of HBx action. First, inhibition of apoptosis may be a consequence of the failure of p53, in the presence of HBx, to upregulate genes, such as p21WAF1, Bax, or Fas, that are involved in the apoptotic pathway. Data consistent with this hypothesis include HBx reduction of p53-mediated p21WAF1 expression. Alternatively, HBx could affect p53 binding to the TFIIH transcription-nucleotide excision repair complex as HBx binds to the COOH terminus of p53 and inhibits its binding to XPB or XPD. Binding of p53 to these constituents of the core TFIIH is a process that may be involved in apoptosis. Because the HBx gene is frequently integrated into the genome of hepatocellular carcinoma cells, inhibition of p53-mediated apoptosis by HBx may provide a clonal selective advantage for hepatocytes expressing this integrated viral gene during the early stages of human liver carcinogenesis.
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PMID:Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. 852 83

Hepatitis B virus (HBV) X protein is thought to play an important role in the development of hepatocellular carcinoma. Recent studies on a transgenic mouse tumor model suggest that HBV X protein may contribute to transformation by binding to and inactivating the cellular growth suppressor protein p53. We have studied 31 hepatocellular carcinoma tissues from Chinese patients for the possible occurrence of such interactions. Although most of the samples contained markers of HBV infection, including free and/or integrated HBV DNA, there was no detectable expression of HBV X protein by Western blot, immunoprecipitation, or histochemical staining. There was also no evidence of HBV X protein associated with p53 immunoprecipitated from the tumors. These observations suggest that, in naturally occurring human hepatocellular carcinoma, such interactions are uncommon and, therefore, unlikely to be of relevance in the latter stages of tumor development. On the other hand, 29 of 31 (93%) samples contained mutated forms of p53, as determined by various antibodies that detect wild-type or mutant p53 or both, and by the association of heat shock protein 70 with immunoprecipitated p53. These results show that conformationally altered p53 protein is present in tumors at a much higher frequency than is suggested by the presence of known mutations in the gene. This mutant p53 is functionally inactive, as suggested by the lack of expression of the p53-induced M(r) 21,000 Cip1/Waf1 protein in the tumors. Because this inactivation of p53 was not correlated with the expression of HBV X protein, any interaction of HBV X protein with p53 may be relevant only during acute infection. Such an interaction could serve to relax cell growth control at a time when virus replication requires hepatocyte destruction to be balanced by regeneration.
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PMID:Mutant p53 but not hepatitis B virus X protein is present in hepatitis B virus-related human hepatocellular carcinoma. 852 97

Employing the glutathione S-transferase column retention method and far Western analysis, we found a physical association between tumor suppressor p53 and the hepatitis B virus X-gene product, which led us to study the function of observed interaction in relation to viral propagation. In the cell culture-based in vitro replication system, expression of p53 resulted in dramatic inhibition of viral replication, and this inhibition was relieved by the coexpression of the X-gene product in a dose-dependent manner. Furthermore, the activity of pregenomic/core promoter, responsible for the synthesis of pregenomic RNA, was almost completely inhibited upon expression of p53, and as in the replication assay, the inhibition was rescued by the coexpression of the X-gene product in a dose-dependent manner. Based on these results, we propose that the ratio of X-gene product to p53 is an important factor determining the fate of viral replication through modulation of the pregenomic/core promoter.
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PMID:X-gene product antagonizes the p53-mediated inhibition of hepatitis B virus replication through regulation of the pregenomic/core promoter. 853 15

p53 expression was studied by immunohistochemical methods in benign and malignant human epithelial liver lesions in 46 patients from Hungary. Positive immunostaining for p53 protein, indicating the overexpression or prolonged half-life of p53 protein, was detected in the nuclei of tumour cells of seven of the 16 hepatocellular carcinomas (HCC) (44%), including three HCC patients with hepatitis B virus infection. Immunostaining of p53 was seen in one of the seven hepatoblastomas, none of the 17 focal nodular hyperplasias, and none of the six hepatocellular adenomas. The detection of p53 in a relatively high percentage of the HCC cases in Hungary, a country in which aflatoxin contamination of the diet is rare, suggests that factors other than aflatoxin led to the accumulation or overexpression of p53 in these patients.
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PMID:p53 in malignant and benign liver lesions. 854 Nov 11

Oral contraceptives (OCs) are implicated in the development of hepatocellular carcinoma (HCC). Mitogenic stimulation may be the primary mechanism of tumorigenesis, but other factors may also contribute. Mutational spectrum analysis can provide insights into pathogenesis, therefore we analyzed the p53 tumor suppressor gene in 10 HCCs from women with a history of OC use. All were non-Asians whose average OC use was 6.7 years (range 2 months-13 years) and whose mean age at HCC diagnosis was 48.8 years (range 21-67 years). Each tumor was analyzed by immunohistochemistry, DNA sequencing and allelic deletion analysis. Three tumors were positive by p53 immunohistochemistry; allelic deletion analysis identified loss of heterozygosity in one of four informative cases. Two p53 point mutations were found in one tumor containing moderately and well-differentiated components; this patient was negative for all serological markers of hepatitis B and C infections. Both components showed p53 protein accumulation and a GTTval-->GCTala mutation at codon 274. In addition, a silent mutation (ACCthr-->ACTthr) at codon 140 of the p53 gene was detected in the moderately differentiated component of the tumor. These preliminary data indicate that p53 mutations are uncommon in OC-related HCCs. One of the two detected mutations was a G:C-->A:T transition at a non-CpG site, which is characteristic of DNA damage by free radicals. These data support a model whereby estrogens contribute to HCC development primarily through mitogen stimulation and secondarily by mutagenesis via hydroxyl radicals produced during estrogen metabolism. Confirmational analysis of a larger series is warranted.
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PMID:p53 mutations in hepatocellular carcinoma related to oral contraceptive use. 856 24


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