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)

Hepatitis B virus (HBV) is a causative agent of chronic and acute hepatitis, and is associated with the development of hepatocellular carcinoma (HCC). We demonstrate here that the Hepatitis B viral core protein (HBc) functions as a repressor on the promoter activity of the human p53 gene. The functional analyses of the promoter of the p53 gene by serial deletion, site-directed mutagenesis, and the heterologous promoter system revealed that the promoter activity was repressed through the E2F1-binding site (nucleotides -28 to -8) by HBc. An electrophoretic mobility shift assay (EMSA) showed that the HBc reduced the DNA-binding ability of E2F1 to the binding site of the p53 promoter. The interaction of HBc with E2F1 was also observed by glutathione S-transferase (GST) fusion protein binding assay. Furthermore, HBc represses the expression of the p53 gene in the human liver cell line HepG2. Finally, HBc and HBx synergistically repress both the promoter activity and the expression of the p53 gene in HepG2 cells. These results, together with our previous study, strongly suggest that HBc, like HBx, represses the expression of the human p53 tumor suppressor gene.
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PMID:Transcriptional repression of the human p53 gene by hepatitis B viral core protein (HBc) in human liver cells. 1267 12

Hepatitis C virus (HCV) core protein is a structural viral protein that packages the viral genomic RNA. In addition to this function, HCV core also modulates a number of cellular regulatory functions. In fact, HCV core protein has been found to modulate the expression of the cyclin-dependent inhibitor p21(WAF1/CIP1) and to promote both apoptosis and cell proliferation through its physical interaction with p53. Here, we studied the ability of HCV core to bind the p53-related p73 protein, its isoforms and its deletion mutants. We found that HCV core co-immunoprecipitated with p73 in HepG2 and SAOS-2 cells. Deletion mutational analysis of p73 indicates that the domain involved in HCV core binding is located between amino-acid residues 321-353. We also demonstrate that p73/core interaction results in the nuclear translocation of HCV core protein either in the presence of the p73 alpha or p73 beta tumor-suppressor proteins. In addition, the interaction with HCV core protein prevents p73 alpha, but not p73 beta dependent cell growth arrest in a p53-dependent manner. Our findings demonstrate that HCV core protein may directly influence the various p73 functions, thus playing a role in HCV pathogenesis.
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PMID:Physical and functional interaction between HCV core protein and the different p73 isoforms. 1273 Jun 72

Hepatitis B virus (HBV) X protein (HBx) plays an essential role in viral replication and in the development of hepatocellular carcinoma. HBx has the ability to transactivate the expression of all HBV proteins, including the viral core protein HBc. Consistent with its regulatory role, HBx is relatively unstable and is present at low levels in the cell. We report here that the level of HBx was significantly reduced by the coexpression of HBc in cultured human hepatoma cells, whereas the level of HBx mRNA was unaffected. The repression of HBx by HBc was relieved by treating cells with the proteasome inhibitor MG132, indicating that HBc acts by stimulating the proteasome-mediated degradation of HBx. Moreover, the inhibitory effect of HBc was specific to HBx and did not affect other proteins, including p53, a known target of the proteasome. Although no direct physical interaction between HBc and HBx could be demonstrated, mutational analysis indicated that the C-terminal half of HBc is responsible for its inhibitory effect. These results suggest that HBc functions as a novel regulator of the HBV life cycle and of hepatocellular carcinogenesis through control of the HBx level via an inhibitory feedback type of mechanism.
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PMID:Hepatitis B virus core protein stimulates the proteasome-mediated degradation of viral X protein. 1280 15

Mutated p53 acts as a dominant oncogene and alterations in the p53 gene are described in a large number of patients with hepatocellular carcinoma (HCC). It has been demonstrated that hepatitis C virus (HCV)-core protein regulates transcriptionally cellular genes, as well as cell growth and apoptosis. This study was undertaken to evaluate whether p53 may be expressed also in a precocious stage of HCV-related liver damage. We studied p53 expression by immunoluminometric assay on liver samples from 40 patients (M/F 18/ 22, median age 44 years, range 13-64 years) with biopsy-proven HCV-related chronic hepatitis. We considered the following factors: degree of liver damage, liver iron content and HCV-RNA titre. We also evaluated as possible co-factors alcohol and food intake in the last 3 years. p53 was over-expressed in seven of 40 (17.5%) patients. Liver histology documented the presence of unexpected cirrhosis in two patients among the p53 positive subjects. The p53 positive group had a daily ethanol intake significantly higher in respect to that of the p53 negative group (P < 0.05). Alimentary history documented that patients with a p53 over-expression had a lower intake of total calories, monounsaturated fatty acids, vitamin C and riboflavin. Data indicate that p53 over-expression can occur even in initial stages of HCV-related liver disease.
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PMID:Liver p53 expression in patients with HCV-related chronic hepatitis. 1282 92

The mechanisms of immune evasion and the role of the early immune response in chronic infection caused by hepatitis C virus (HCV) are still unclear. Here, we present evidence for a cascade of molecular events that the virus initiates to subvert the innate immune attack. The HCV core protein induced p53-dependent gene expression of TAP1 (transporter associated with antigen processing 1) and consecutive major histocompatibility complex (MHC) class I upregulation. Moreover, in p53-deficient liver cell lines, only reconstitution with wild-type p53, but not mutated p53 lacking DNA binding capacity, showed this effect. As a consequence of increased MHC class I expression, a significantly downregulated cytotoxic activity of natural killer (NK) cells against HCV core-transfected liver cells was observed, whereas lysis by HCV-specific cytotoxic T cells was not affected. These results demonstrate a way in which HCV avoids recognition by NK cells that may contribute to the establishment of a chronic infection.
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PMID:Upregulation of major histocompatibility complex class I on liver cells by hepatitis C virus core protein via p53 and TAP1 impairs natural killer cell cytotoxicity. 1285 99

By using a vaccinia virus-T7 expression system, possible effects of hepatitis C virus (HCV) core protein on synthesis and accumulation of host cellular proteins transiently expressed in cultured cells were analyzed. Immunoblot and immunofluorescence analyses revealed that synthesis and accumulation of certain nuclear proteins, such as p21/Waf1, p53, proliferating cell nuclear antigen and c-Fos, were strongly inhibited by HCV core protein. On the other hand, synthesis and accumulation of cytoplasmic proteins, such as 2'-5'-oligoadenylate synthetase (2'-5'-OAS), RNase L and MEK1, were barely affected by HCV core protein. Northern blot analysis showed that the degrees of mRNA expression for those proteins did not differ between HCV core protein-expressing cells and the control, suggesting that the inhibition occurred at the post-transcription level. Pulse-labeling analysis suggested that HCV core protein strongly inhibited synthesis of p21/Waf1 at the translation level. Once being accumulated in the nucleus, p21/Waf1 stability was not significantly affected by HCV core protein. Mutants of HCV core protein C-terminally deleted by 18 or 41 amino acids (aa), which were localized almost exclusively in the nucleus, lost their ability to inhibit synthesis/accumulation of p21/Waf1 whereas another mutant C-terminally deleted by 8 aa still maintained the same properties (subcellular localization and the inhibitory effect) as the full-length HCV core protein of 191 aa. Taken together, our present results suggest that expression of HCV core protein in the cytoplasm selectively inhibits synthesis of p21/Waf1 and some other nuclear proteins at the translation level.
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PMID:Hepatitis C virus core protein selectively inhibits synthesis and accumulation of p21/Waf1 and certain nuclear proteins. 1290 3

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant tumor of the liver, and ICC is reportedly increasing recently. ICC is usually adenocarcinoma with variable desmoplastic reaction, although there are several special or unusual histological features. ICC may arise at the large intrahepatic bile duct near the hepatic hilus and also from the bile ductules at the border of the hepatic parenchyma. On the anatomical level, the pathology of ICC differs depending on the region from which the ICC arises. At the large intrahepatic bile duct, ICC presents papillary growth and periductal infiltration. Some cases show extensive papillary growth and intraluminal spread with marked gastroenteric metaplasia. Mucus core protein 1 is expressed in aggressive ICC. ICC arising from ductules shares phenotypes of hepatocellular carcinoma. ICC in chronic biliary diseases, particularly arising in hepatolithiasis, presents precancerous lesions that include biliary epithelial dysplasia, as well as in-situ carcinoma. Chronic advanced hepatitis C is one of the background diseases of ICC. Chronic inflammation, with the upregulation of cyclooxygenase-2 and growth factors, and the formation of reactive oxygen species are one of the causative factors in the DNA damage of biliary epithelial cells. K- ras mutation and aberrant expression of p53 are found in one-third of ICCs. The latter may be due to mdm-2 upregulation. Hepatocyte growth factor/met and interleukin 6 (IL6)/IL6 receptor are involved in cell proliferation/mitoinhibition and apoptosis in ICC. Fibrous stroma formation and invasion involve the proliferation of Alpha-smooth muscle antigen-positive stromal cells, and cell-to-cell and cell-to-matrix interactions involving E-cadherin/catenin and CD44 and matrix proteinases may be involved in the invasion of ICC. Evasion of immune surveillance involving the Fas/FasL system is important in the malignant progression of ICC. Further molecular and genetic studies are mandatory to evaluate the pathogenesis and progression of ICC.
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PMID:Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. 1459 45

Hepatitis C virus (HCV) is one of the major causes of chronic liver disease with the potential for development of hepatocellular carcinoma (HCC). The core protein of HCV has been shown to modulate expression of various cellular genes and to influence a number of cellular functions. We investigated the effect of constitutively expressed HCV core protein on cell cycle progression in HepG2 cell line, which is derived from a differentiated human hepatoblastoma and shows biosynthetic features similar to human hepatocytes. The results indicated that stable expression of the core protein in unsynchronized HepG2 cells induced a perturbation of the cell cycle with reduced cell doubling meantime and increased S phase fraction. Increase of c-myc protein above the basal expression level was demonstrated with a significant increase of c-myc stability, as revealed by its prolonged intracellular half-life, in HepG2 expressing HCV core protein. In contrast, p53 and p21 levels were unchanged. These results suggest that HCV core protein may promote cell cycle progression in HepG2 cells possibly through increasing stability of c-myc oncoprotein. These results are in support of important role played by HCV core protein in virus-mediated pathogenesis in persistently infected hosts and in hepatocarcinogenesis.
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PMID:Cell cycle perturbation in a human hepatoblastoma cell line constitutively expressing Hepatitis C virus core protein. 1468 76

Oncogenic virus proteins often target to tumor suppressor p53 during virus life cycle. In the case of hepatitis C virus (HCV) core protein, it has been shown to affect p53-dependent transcription. Here, we further characterized the in vitro and in vivo interactions between HCV core protein and p53 and showed that these two proteins colocalized in subnuclear granular structures and the perinuclear area. By use of a reporter assay, we observed that while low level of HCV core protein enhanced the transactivational activity of p53, high level of HCV core protein inhibited this activity. In both cases, however, HCV core protein increased the p53 DNA-binding affinity in gel retardation analyses, likely due to the hyperacetylation of p53 Lys(373) and Lys(382) residues. Additionally, HCV core protein, depending on its expression level, had differential effects on the Ser(15) phosphorylation of p53. Moreover, HCV core protein could rescue p53-mediated suppressive effects on both RNA polymerase I and III transcriptions. Collectively, our results indicate that HCV core protein targets to p53 pathway via at least three means: physical interaction, modulation of p53 gene regulatory activity and post-translational modification. This feature of HCV core protein, may potentially contribute to the HCV-associated pathogenesis.
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PMID:Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein. 1496 11

The core protein of Hepatitis C virus affects several biological functions of the host cells such as cellular growth and apoptosis. The core was shown to interact with 53BP2/Bbp/ASPP2, a p53-binding protein, in a yeast two-hybrid assay. The core competed with p53 in binding to ASPP2 in vitro. In an apoptosis assay using human osteosarcoma Saos-2 cells or hepatocellular carcinoma HepG2 cells, ectopic expression of p53 induced apoptosis and ASPP2 enhanced this p53-induced apoptosis. However, coexpression of the core with p53 and ASPP2 increased the number of surviving cells. In a reporter assay, neither ASPP2 nor the core with ASPP2 affected the transcriptional activity of p53 on the promoters of Bax and p21, major p53 target genes. These findings suggest that the core inhibits p53-mediated apoptosis by blocking the interaction between p53 and ASPP2, without modulating the transcriptional activity of p53, which plays a role in oncogenesis of hepatocellular carcinoma.
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PMID:Hepatitis C virus core protein interacts with p53-binding protein, 53BP2/Bbp/ASPP2, and inhibits p53-mediated apoptosis. 1498 81


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