Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To search for genes related to hepatocarcinogenesis, the differential display technique for eukaryotic mRNA was conducted. We have cloned a gene that encodes the CD24 protein from the cDNA library of human hepatocellular carcinoma (HCC). A single 2.1-kb mRNA was identified in HCC specimens and the HuH-7 HCC cell line but only rarely in small amounts in nontumor livers. In 79 unicentric HCC, CD24 mRNA was overexpressed in 52 cases (66%), found in trace amounts in 11, and not detectable in 16 (20%). In 12 cases of multicentric HCC, CD24 mRNA was overexpressed in 21 (68%) of 31 tumor nodules and was helpful for the determination of tumor clonal origin. There was an increased frequency of CD24 mRNA overexpression in patients younger than 50 years with HCC (86% versus 59%, P < 0.025), in serum hepatitis B surface antigen-positive individuals (74% versus 48%, P < 0.023), in those with an elevated serum alpha-fetoprotein level (82%, versus 56%, P < 0.04), and in HCC with alpha-fetoprotein mRNA expression (82% versus 56%, P < 0.04). There was a strong correlation of CD24 mRNA overexpression with p53 gene mutation in HCC (91% versus 46%, P < 0.0005) and poorly differentiated HCC (82% versus 53%, P < 0.0008). Despite its correlation with p53 mutation and the unfavorable outcome of HCC with p53 mutation, the CD24 mRNA expression did not correlate with tumor size, tumor invasiveness, or patient's prognosis. Thus, the CD24 gene expression appears to be a common event in HCC and may serve as an early but not prognostic biomarker for malignant transformation of hepatocytes.
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PMID:Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation. 755 54

The X gene of the hepatitis B virus codes for a small basic protein and is able to transactivate viral and cellular genes, although the X protein exhibits no DNA-binding activity. The mechanism of transactivation by X protein has been suggested to be via protein-protein interaction(s). We first demonstrated that X protein had amino acid sequences homologous to the functionally essential domain of Kunitz-type serine protease inhibitors and that those sequences were indispensable for the transactivation function. We demonstrated that X protein exhibited an inhibitor activity against hepatic serine proteases, and subsequently found that the protein activated X gene transcription in HepG2 cells and that the X responsive element was localized in the minimal promoter of the X gene. In contrast, the tumor-suppressor gene p53, but not mutant p53, remarkably reduced transcription from the minimal promoter. This p53 repression on the X gene promoter was cancelled by X gene co-expression, probably indicating that the X protein disrupts the p53 tumor suppressor function in the nucleus. All data suggest that X protein leads to transactivation of cellular oncogenes by preventing an interaction between p53 and cellular transcription factor(s) consisting of the basal transcriptional machinery.
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PMID:Disruption of the function of tumor-suppressor gene p53 by the hepatitis B virus X protein and hepatocarcinogenesis. 755 43

Hepatic malignancy accounts for a large number of cancer-related deaths worldwide. Radiologic evaluation of the liver is critically important in the selection of patients for surgical treatment and newer modalities including computed tomographic arterial portography and intraoperative sonography show promise in the detection of small lesions. Advances in our understanding of the segmental anatomy of the liver, studies of intraoperative hepatic ischemia, and improved care of patients following major hepatic resections have extended the limits of surgical treatment of liver lesions, especially in cirrhotic patients with limited functional reserve. Along with hepatitis B, new data suggest that hepatitis C is also important as an agent causing hepatocellular carcinoma. In addition, the tumor suppressor gene p53 is frequently mutated in aflatoxin-induced hepatoma. In endemic regions, mass screening for early hepatocellular carcinoma appears to increase the surgical cure rate. Resectional surgery remains the best treatment for primary liver cancer and, in selected cases, liver transplantation is worthwhile. Liver resection for some patients with metastases of colorectal origin is now considered standard therapy and studies of regional chemotherapy for liver cancer are beginning to show promise. It remains to be seen whether adjuvant chemotherapy after liver resection will increase cure rates.
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PMID:Primary and secondary hepatic malignancies. 758 84

Intense research using animal models has indicated that chemically-induced rat liver cancer proceeds through multiple, distinct stages that can be characterised morphologically and biochemically. Primary human liver cancer, with hepatitis B and other environmental factors such as poor nutrition and food contaminating mycotoxins as contributing etiological factors, is one of the major causes of cancer deaths in African, Asian and some Western countries. Recent advances in surgical and diagnostic techniques have also allowed the identification of potential morphological precursors of primary human liver cancer, and suggested a model consistent with the concepts of initiation--promotion--progression as in the rat. The expression of proliferating cell nuclear antigen (PCNA), silver-staining nucleolar organiser regions (AgNOR), oncogenes and the tumor suppressor gene p53 in preneoplastic and neoplastic lesions of rat and human livers is presently reviewed. This undertaking is an attempt to evaluate whether the current knowledge regarding molecular mechanisms of carcinogenesis is sufficient to permit the use of these molecular parameters as 'intermediate' markers in studies of risk assessment and cancer prevention, without having to resort to tumor appearance as an end-point.
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PMID:The potential for the use of cell proliferation and oncogene expression as intermediate markers during liver carcinogenesis. 760 May 46

A mutation in the tumor suppressor p53 gene resulting in an Arg-->Ser substitution in position 249 is found frequently in human hepatocellular carcinomas associated with hepatitis B infection and with aflatoxin exposure. To determine the significance of this mutation in an in vivo experimental model using transgenic mice, we introduced a two-nucleotide change in the mouse p53 gene at amino-acid position 246, which is equivalent to position 249 in human p53, by the recombinant polymerase chain reaction mismatched primer method. This p53 mutation resulted in the same change, an Arg-->Ser substitution, as in the human p53 gene at position 249. We now report that the protein product of this mutant mouse p53ser246 had properties similar to those of the wild-type protein when tested by binding to (i) monoclonal antibodies PAb246 and PAb240, ii) simian virus 40 large T antigen, and (iii) heat-shock protein. However, it had mutant-type transforming properties when tested for colony formation with an osteosarcoma cell line. It was not active, as is wild-type p53, in transcription activation of the muscle creatine kinase promoter. These properties are the same as those found in the p53trp248 product of the p53 mutation associated with the Li-Fraumeni syndrome. Although less is known about the human p53ser249 product associated with hepatocellular carcinoma, the mutant murine p53ser246 protein shares the known properties of the human gene product.
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PMID:Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. 760 78

Hepatitis B virus (HBV) infection is closely associated with the development of hepatocellular carcinoma (HCC), but definite mechanisms by which it could play an etiologic role have not yet been identified. Modifications of the function of the RB tumor suppressor gene, which regulates the cell cycle, could provide such a mechanism. In the present study, the expression of the protein product of RB, pRB, was evaluated by immunohistochemical staining in HCC tissues from 25 patients from China and the United States, adjacent nontumorous liver from 19 of those patients, five human HCC cell lines, three human hepatoblastoma cell lines, and five specimens of normal human liver. Representative samples were also evaluated by western blot. Altered expression of RB was detected in eight HCC tissues (pRB undetectable in five HCCs and detected in < 1% of nuclei of HCC cells in three others); all eight had detectable hepatitis B surface or core antigen in the adjacent nontumorous liver, indicating active HBV infection. pRB was detected in 10-95% of nuclei (normal expression) in the remaining 17 HCCs, and in many nuclei in all 19 nontumorous livers, and in the 5 normal livers. No pRB staining was detected in the nuclei of three HCC cell lines, but pRB was detected in > 90% of nuclei of the other HCC and hepatoblastoma cell lines. The relationship of pRB expression to mutations of the p53 tumor suppressor gene was also examined. The absence of detectable nuclear pRB by immunohistochemical staining was associated with the presence of presumed mutant p53 detected by immunohistochemical staining in four out of five HCC cases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:RB tumor suppressor gene expression in hepatocellular carcinomas from patients infected with the hepatitis B virus. 779 88

We have established two cell lines of hepatocellular carcinoma [Hep-KANO, clone 1 (CL-1) and clone 2 (CL-2)] from tissue obtained at autopsy of a hepatitis B virus (HBV) carrier without histological signs of hepatitis or liver cirrhosis. These cell lines differed considerably from each other in morphology, proliferation pattern, alpha-fetoprotein secretion, albumin synthesis, cytokine secretion, modal chromosome number and transplantability to nude mice. Histologic examinations also revealed differences between them. Amplification of N-myc, L-myc, H-ras, K-ras, N-ras, c-erb-B and c-erb-B-2 and rearrangement of p53 were not found in either of the cell lines. However, CL-1 and CL-2 showed an identical HBV-DNA integration pattern. A 4-fold amplification of c-myc was observed in CL-1, but not in CL-2. Hep-KANO cell lines, CL-1 and CL-2 may be useful in clarifying the question of whether hepatocarcinogenesis is directly caused by HBV infection.
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PMID:Characteristics of human hepatocellular carcinoma cell lines (Hep-KANO) derived from a non-hepatitic, non-cirrhotic hepatitis B virus carrier. 782 95

Hepatitis B virus is a major risk factor in human hepatocellular carcinomas. We have used protein affinity chromatography to show that the 17-kDa hepatitis B virus gene product, HBx, binds directly to the human tumor suppressor gene product, p53. Interaction of HBx with p53 did not prevent p53 from specifically binding DNA. Instead, HBx enhanced p53's oligomerization state on a DNA oligonucleotide containing a p53 response element. Optimal binding of HBx to p53 required intact p53, but weaker binding to both the N-terminal activation domain of p53 and a protein fragment containing the C-terminal DNA-binding and oligomerization domains of p53 was observed. In transient transfection experiments with human Calu-6 cells, HBx inhibited transactivation by p53 of a reporter gene containing a p53 response element. Also, HBx inhibited p53-stimulated transcription in vitro even when added to the reaction mixture after the formation of the preinitiation complex. Interaction of HBx with p53 did not prevent the activation domain of p53 from binding two general initiation factors, the TATA-box binding protein subunit of TFIID and the p62 subunit of TFIIH. To explain these results, we propose that localization of HBx to a promoter by interaction with DNA-bound p53 enables a repression domain in HBx to directly contact the basal transcription machinery and thereby repress transcription.
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PMID:Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. 785 26

Wild-type p53 acts as a tumor suppressor gene by protecting cells from deleterious effects of genotoxic agents through the induction of a G1/S arrest or apoptosis as a response to DNA damage. Transforming proteins of several oncogenic DNA viruses inactivate tumor suppressor activity of p53 by blocking this cellular response. To test whether hepatitis B virus displays a similar effect, we studied the p53-mediated cellular response to DNA damage in 2215 hepatoma cells with replicative hepatitis B virus. We demonstrate that hepatitis B virus replication does not interfere with known cellular functions of p53 protein.
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PMID:p53-mediated cellular response to DNA damage in cells with replicative hepatitis B virus. 787 79

Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.
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PMID:Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. 789 76


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