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)

Abnormalities of the tumor-suppressor p53 gene have been discovered in human hepatocellular carcinoma (HCC). It is unclear, however, whether HCC related to chronic viral hepatitis is associated with p53 gene alterations. In this study, we have examined p53 abnormalities in HCC associated with hepatitis C and B virus (HCV and HBV) infections. Tissues from 18 HCC patients from several hospitals throughout the United States were collected (9 were HCV-infected, 5 were HBV-infected, 1 was HCV/HBV-infected, and 3 were non-virus-associated). Immunostaining with monoclonal pAb 1801 revealed expression of p53 protein in tumor-cell nuclei in one HCV-associated HCC, and in no case of HBV-associated HCC, while the nuclei of adjacent hepatocytes were negative. Using Hae III-digestion of chromosomal DNA, mutations at codon 249 were not found in any of 18 HCC tissues studied. Direct sequencing demonstrated a mutated codon 244 and a wild-type codon 249 in the conserved regions (exon 5-8) of p53 gene from the tumor tissue with nuclear p53 expression. By reverse-transcription-polymerase chain reaction (RT-PCR), the expression of p53 mRNA was demonstrated in tumor cells from 10 out of 16 HCC tissues. In conclusion, the specific mutation at codon 249 with G to T transversion was not observed in the HCCs associated with HCV or HBV infections. In HBV or non-virus-associated HCCs studied, no other p53 gene abnormalities were found. A point mutation at codon 244 with G to A transition of p53 gene was detected in only one of 10 HCV-associated HCCs, which suggests that p53 mutations may not play a significant role in HCV- or HBV-associated hepatocarcinogenesis.
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PMID:Tumor-suppressor p53 gene in hepatitis C and B virus-associated human hepatocellular carcinoma. 839 Apr 7

Forty-two patients with hepatocellular carcinoma (HCC) were resected and their tumours were analysed for p53 mutations by GC-clamped denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP) and gene sequencing. All the exons have been analysed in this study. Eight of 12 HCCs with cirrhosis due to viral hepatitis and the two patients with sarcomatoid changes displayed p53 mutations. In contrast, no mutation was observed in the fibrolamellar variant (n = 9), non-cirrhotics (n = 13) and alcoholic cirrhosis (n = 6). The mutations observed were in exons 5-8. Two mutations were observed in codons 136 and 213 as well as a T insertion between residues 156 and 157 (exon 5) and these are reported for the first time in HCC. Likewise, the silent mutation polymorphism in codon 213 was noticed in 3 of the 42 patients. Survival analysis of these patients after surgery showed the mean and median survival in patients with wild-type p53 to be 60 and 43 months respectively. In the group with p53 mutations, the mean and median survival was 15 and 12 months. The difference was statistically significant (P= 0.003).
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PMID:p53 mutation is a poor prognostic indicator for survival in patients with hepatocellular carcinoma undergoing surgical tumour ablation. 951 57

The mechanisms by which the hepatitis B x protein (HBx) contributes to hepatocarcinogenesis remain unclear. However, interaction with the tumor suppressor gene p53 and inhibition of p53-dependent cellular functions, including nucleotide excision repair, could be central to this process. We studied the levels of global repair (removal of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts) and transcription-coupled repair (removal of CPDs in both strands of the dihydrofolate reductase gene) in primary wild-type and p53-null mouse hepatocytes. We show that global repair of CPDs appears to be more efficient in mouse hepatocytes than in other commonly studied rodent cells and approaches the levels of human cells and that p53 is required for global genomic DNA repair of CPDs but not for transcription-coupled repair. We then investigated the effect of HBx expression on hepatocyte nucleotide excision repair. We demonstrate that HBx expression affects DNA repair in a p53-dependent manner. Transient HBx expression reduces global DNA repair in wild-type cells to the level of p53-null hepatocytes and has no effect on the repair of a transfected damaged plasmid. Therefore, in viral hepatitis, the hepatitis B virus could inhibit the p53-dependent component of global repair leading, over time, to accumulation of genetic defects and fostering carcinogenesis.
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PMID:Hepatitis B x protein inhibits p53-dependent DNA repair in primary mouse hepatocytes. 983 6

Expression of the proto-oncogene c-myc has been implicated in liver regeneration and hepatocarcinogenesis. The biologic significance of c-myc gene amplification in human hepatocellular carcinoma, however, is unconfirmed. We correlated c-myc gene amplification with clinicopathologic features, proliferative activity, and p53 expression in 42 resected tumors. c-myc amplification in tumor tissue was determined using a differential polymerase chain reaction, a useful procedure for the evaluation of gene amplification in archival formalin-fixed paraffin-embedded tissues, in comparison with a dopamine D2 receptor gene. Proliferative activity was estimated by numbers of argyrophilic nucleolar organizer regions and immunohistochemical nuclear labeling rates using a monoclonal antibody against Ki-67. The c-myc gene was amplified in 14 of 42 tumors (33.3%). Amplification of c-myc was more frequent in younger patients and in larger tumors, and less differentiated tumors. No correlation was noted with alpha-fetoprotein level or viral hepatitis state. The amplification showed positive correlation with both proliferative activity and p53 overexpression. Disease-free survival in patients showing c-myc amplification was significantly shorter than in those without amplification. These results suggest that c-myc amplification is an indicator of malignant potential and poor prognosis in hepatocellular carcinoma. c-myc amplification and p53 alteration may be coparticipating events in the progression of these tumors.
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PMID:Amplification of c-myc in hepatocellular carcinoma: correlation with clinicopathologic features, proliferative activity and p53 overexpression. 1046 Oct 64

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major risk factors for HCC development are now well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. However, no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Malignant transformation of hepatocytes may occur as a consequence of various etiologies, such as chronic viral hepatitis, alcohol, and metabolic disorders, in the context of increased cellular turnover induced by chronic liver injury, regeneration and cirrhosis. Activation of cellular oncogenes, inactivation of tumor suppressor genes, overexpression of certain growth factors, and possibly telomerase activation and DNA mismatch repair defects may contribute to the development of HCC. Finally, aflatoxins have been shown to induce specific mutations of the p53 tumor suppressor gene, thus pointing to the contribution of environmental factors to tumor development at the molecular level.
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PMID:[Molecular aspects of hepatocellular carcinoma]. 1096 Sep 67

Chronic hepatitis may progress to cirrhosis and hepatocellular carcinoma (HCC). Progressive accumulation of mutations and genomic instability in chronic viral hepatitis might flag an increased risk of HCC development. Genomic instability at dinucleotide microsatellite loci in chromosomes 2, 13, and 17 and at 2 mononucleotide repeat loci was examined in liver tissues from 41 patients, including 30 without HCC (18 patients with chronic hepatitis and 12 with cirrhosis) and 11 with HCC. Genomic instability was detected in 51% of the 41 cases. Allelic imbalance at informative dinucleotide loci occurred in 37% of the cases. In 14 cases (34%), allelic imbalance was detected in chronic hepatitis or cirrhosis without HCC. Allelic imbalance at the chromosome 13 locus was detected in 50% of the cases of chronic hepatitis C. Allelic imbalance at the TP53 chromosome locus and/or at the chromosome 13 locus was significantly more frequent than alterations at the chromosome 2 locus (P =.026). Low-level microsatellite instability was found in 20% of all cases examined and high-level microsatellite instability in 3 patients (7.5%), including 2 cases of chronic hepatitis and 1 case of cirrhosis. Our results show that allelic imbalance occurs frequently in hepatitis-related HCC as well as in chronic hepatitis in patients without HCC. Allelic imbalance at the D13S170 chromosome 13 locus (13q31.2) occurs frequently in chronic hepatitis, suggesting that genomic alterations affecting the long arm of chromosome 13 might be used to monitor the natural progression of chronic hepatitis-associated liver carcinogenesis.
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PMID:Genomic instability in chronic viral hepatitis and hepatocellular carcinoma. 1148 68

Hepatocellular carcinoma (HCC) is a disease that is extremely difficult to manage and is markedly increasing in incidence. Malignant transformation generally occurs in the setting of liver dysfunction related to a number of different diseases, including viral hepatitis, alcoholic liver disease, and aflatoxin exposure. Short of surgical or ablative approaches, no standard therapy exists for HCC and the prognosis is poor. Perhaps our best hope is that further elucidation of the specific molecular features underlying the disease will translate into innovative, and potentially disease-specific strategies to manage this difficult cancer. Exposure to aflatoxin is associated with a specific mutation in the tumor-suppressor gene p53. The exact molecular events underlying hepatocarcinogenesis in the setting of viral infection have yet to be elucidated, although there is evidence to suggest that virus-encoded proteins contribute to malignant transformation. Both hepatitis B X antigen and hepatitis C core protein appear to interact with a variety of cellular proteins leading to alterations in signal transduction and transcriptional activity. These events presumably cooperate to facilitate malignant progression by promoting extended hepatocyte survival, evasion of the immune response, and acquisition of mutations through genomic instability.
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PMID:Molecular mechanisms underlying the development of hepatocellular carcinoma. 1168 45

Hepatocellular carcinoma (HCC) accounts for 80-90% of liver cancers and is one of the most frequent carcinomas throughout the world. The disease is more prevalent in parts of Africa and Asia than in North and South America and Europe, with a strong etiological association with viral hepatitis, hemochromatosis, known liver (hepatic) carcinogens, and toxins (mycotoxins). Clinical and molecular medical analyses have yielded a considerable amount of information about liver carcinogenesis. Many genes undergo somatic aberrations, with a tendency to cluster at genes involved in cell cycle regulation, in the p53 and Wnt/catenin pathways of signal transduction and cellular adhesion, and in the TGF-beta/IGF axis. Since HCC may arise both in liver cirrhosis and in noncirrhotic liver, one may speculate that different hepatocarcinogenetic pathways exist. Recent results of high-output gene analysis using cDNA microarrays support the idea of different genetic alterations in HCC with or without cirrhosis.
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PMID:Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis. 1195 13

The target antigens of anti-nuclear autoantibodies in autoimmune hepatitis (AIH) are poorly characterised. Since antibodies to the p53 nuclear protein have been reported in various autoimmune diseases, we have assessed the prevalence of these antibodies in patients with AIH (n = 45), primary biliary cirrhosis (n = 60), hepatitis B (n = 22), hepatitis C (n = 55), and in a control group of subjects with various non-liver diseases (n = 56). A significant proportion of patients with AIH (31%) had elevated levels of autoantibodies to the p53 protein. In contrast, the prevalence of these antibodies in primary biliary cirrhosis (8%) and viral hepatitis (6%) was similar to that in the control group (4%). The clinical features of the anti-p53 seropositive AIH patients were similar to those of the seronegative ones. Thus, the prevalence of p53 autoantibodies in AIH is higher than in other forms of chronic hepatitis, and may be useful in differential diagnosis.
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PMID:Prevalence of autoantibodies to the p53 protein in autoimmune hepatitis. 1276 74

Selenium is essential to human health, and its deficiency is associated with different diseases including liver necrosis. Selenium is protective against viral hepatitis and hepatocellular carcinoma (HCC). The underlying molecular mechanisms of selenium effects are not well known. In this study, in vitro response of HCC-derived cell lines to selenium deficiency is examined alone or in conjunction with Vitamin E and copper/zinc. Here, we show that in vitro selenium deficiency in a subset of HCC-derived cell lines causes oxidative stress and cytochrome c release with subsequent cell death by apoptosis. The oxidative stress and consequent cell death induced by selenium deficiency on these cells are reverted by the antioxidant effect of Vitamin E. However, most HCC cell lines (10 of 13) tolerate selenium deficiency. Consequently, they escape apoptosis. Moreover, nine of these tolerant cell lines have integrated hepatitis B Virus (HBV) DNA in their genomes, and some display p53-249 mutation, indicating past exposure to HBV or aflatoxins, established factors for oxidative stress and cancer risk in liver. An HBV-transfected clone (2.2.15) of the sensitive HepG2 cell line has gained tolerance to selenium deficiency. Our findings indicate that selenium deficiency induces apoptosis in some "hepatocyte-like" cells. However, most HCC cells, particularly HBV-related ones, tolerate selenium deficiency and escape its deadly consequences. Thus, as demonstrated by the gain of survival capacity of apoptosis-sensitive cell lines with Vitamin E, such malignant cells have acquired a selective survival advantage that is prominent under selenium-deficient and oxidative-stress conditions.
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PMID:Acquired tolerance of hepatocellular carcinoma cells to selenium deficiency: a selective survival mechanism? 1458 65


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