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

Recent studies have revealed that a point mutation at codon 249 in the p53 gene predominates in hepatocellular carcinoma (HCC) cases from Southern Africa and China, where infection with hepatitis B virus (HBV) and contamination of aflatoxin B1 in food are risk factors for HCC. This unique mutation from G to T at the third base in codon 249 observed in human HCC cases is suggested to be linked to aflatoxin exposure. Six ducks with HCC, five of which were fed a diet containing aflatoxin B1 for 1-2 years, were analysed for the presence of point mutations at this codon of the p53 gene by polymerase chain reaction and direct nucleotide sequencing. None of the six ducks with HCC showed the change at this codon regardless of duck hepatitis B virus infection. This suggests that aflatoxin B1 itself might not be involved in the unique mutation at codon 249 in hepatocarcinogenesis, or that other factors coincident with aflatoxin may be responsible for this unique mutation.
 ...
PMID:Aflatoxin and p53 abnormality in duck hepatocellular carcinoma. 858 Apr 7

Carcinogenesis is a multistage process involving activation of protooncogenes, e.g., ras, and inactivation of tumor suppressor genes, e.g., p53 and p16INK4.p53 is a prototype tumor suppressor gene that is well suited for analysis of mutational spectrum in human cancers; it is the most common genetic lesion in human cancers, it is a reasonable size for a molecular target, and it may indicate selection of mutations with pathobiological significance. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain and lymphoid malignancies. Mutational hotspots at CpG dinucleotides in codons 175, 245, 248, 273 and 282 may reflect endogenous mutagenic mechanisms, e.g., deamination of 5-methylcytosine to thymidine. Oxy-radicals including nitric oxide may enhance the rate of deamination. G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung, breast, esophagus and liver, and are more likely to be due to bulky carcinogen-DNA adducts. G to T transversion is more common in lung cancers from smokers when compared to never smokers. The high frequency of p53 mutations in the nontranscribed DNA strand is a reflection of strand specific repair, p53 mutation and/or accumulation of p53 protein can be preinvasive events in bronchial or esophageal carcinogenesis, p53 mutations also generally indicate a poor prognosis. In geographic areas where hepatitis B virus (HBV) and aflatoxin B1 are cancer risk factors, most mutations are at the third nucleotide pair of codon 249. In geographic areas where hepatitis B and C virus--but not aflatoxin B1--are risk factors, the p53 mutations are distributed in numerous codons. HBV X protein complexes with the p53 protein and inhibits its sequence specific DNA binding, transactivating and apoptotic capacity. The mutation load of 249ser mutant cells in nontumorous liver is positively correlated with dietary aflatoxin B1 exposure. The induction of skin carcinoma by ultraviolet light is indicated by the occurrence of p53 mutations at dipyrimidine sites including CC to TT double base changes. In summary, these differences in mutational frequency and spectrum among human cancer types suggest the etiological contributions in both exogenous and endogenous factors to human carcinogenesis and have implications for human cancer risk assessment.
 ...
PMID:1995 Deichmann Lecture--p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology and cancer risk assessment. 859 35

Hepatitis B virus (HBV) X gene is known to exhibit a transcriptional activation function and is considered to play a major role in hepatocarcinogenesis. We determined a 20-bp promoter element for the HBV X gene transcription and found a binding protein to this promoter element, designated as an X-PBP. We then examined the effects of HBV X protein and p53 tumor suppressor gene product on X gene transcription from the 20-bp promoter element using the transient expression technique. Activity of the X gene promoter was stimulated by X protein expression, but, in contrast, was repressed by transfected normal p53 gene. On the other hand, mutant p53 gene product exhibited no repression. Moreover, the p53 repression of X gene transcription was canceled by X protein coexpression. Thus, the effects of X protein and normal p53 product appear to be mutually antagonistic in the regulation of X gene expression. However, mutated promoter elements which failed to bind to X-PBP still responded to X protein or p53, indicating that the process of X transactivation or p53 repression may be independent of X-PBP binding to the promoter element. Our data suggest that X protein could disrupt function of normal p53 protein in X gene-transfected cells.
 ...
PMID:Hepatitis B virus X gene expression is activated by X protein but repressed by p53 tumor suppressor gene product in the transient expression system. 861 9

The role of the hepatitis B virus (HBV) X protein in liver tumorigenesis is unresolved. Transgenic mice harboring the X gene (nt 1376-1840 under the control of the human alpha-1-antitrypsin regulatory elements) (ATX mice) display only minor histopathologic alterations of the liver. To determine if ATX mice are more susceptible to the effects of hepatocarcinogens, 12- to 15-d-old male ATX and control littermate mice were injected with a single dose (2 microgram/g body weight) of diethylnitrosamine (DEN). The animals were killed 6-10 mo after exposure and were analyzed for histological changes in the liver. One hundred percent of the DEN-treated AXT mice developed abnormal liver lesions. Then their liver tissues were compared by stereological analysis with those of non-transgenic animals, the ATX mice had a relative twofold increase in the total number of focal lesion and a twofold increase in the incidence of hepatocellular carcinoma. Elevated levels of X protein and p53 protein were not detected in carcinogen-induced nodules or tumors. These results are consistent with a model in which the expression of the HBV X protein potentiates the induction of DEN-mediated liver disease.
 ...
PMID:Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene. 863 84

The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum antibodies recognizing p53 protein were found in one of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.
 ...
PMID:An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor suppressor gene occurs in hepatocellular carcinomas from Mexico. 864 Sep 5

Hepatitis B virus X gene codes for a small basic cytoplasmic protein and is able to transactivate viral and cellular genes, although X protein exhibits no DNA-binding activity. The mechanism of transactivation by X protein has been suggested to be via protein-protein interaction(s). X protein had amino acid sequences homologous to the functionally essential domain of Kunitz-type serine protease inhibitors, and these sequences were indispensable for transactivation function. X protein activated X-gene transcription itself and an X-responsive element were localized in their minimal promoter. Furthermore, tumor suppressor gene product p53, but not mutant p53, repressed X-gene transcription from the minimal promoter, indicating that X protein disrupts the function of normal p53, which represses transcription of X gene or cellular gene. Data suggest that inhibition of a hepatic serine protease by X protein leads to eliminate the suppressor effect of p53 on the basic transcription machinery in nucleus.
 ...
PMID:Biochemistry and functions of hepatitis B virus X protein. 866 28

Aberrations of the p53 and Rb tumour suppressor genes were examined in 12 human hepatocellular carcinoma (HCC)-derived cell lines from different geographic areas and 9 local HCCs by restriction fragment length polymorphisms (RFLP), polymerase chain reaction-single-strand conformation polymorphisms (PCR-SSCP) and DNA sequencing. The relationships between genetic changes and hepatitis B virus (HBV) DNA integration in samples were compared. None of the cell lines and tumours showed structural changes in the Rb gene, while 6 cell lines and 2 tumours had mutation or deletion in exons 5 to 8 of p53. Mutations include an AGG --> AGT (Arg --> Ser) transversion at codon 249 in PLC/PRF/5 and Mahlavu, an AAT --> AAA (Asn --> Cys) transversion at codon 200 in TONG/HCC, an AAG --> GAG (Lys --> Glu) transition at codon 139 in HCC-T, a CAT --> CGT (His --> Arg) transition at codon 214 in SC4, and a CCC --> CTC (Pro --> Leu) transition at codon 250 in SC8. In Huh4, an 18-bp deletion from codon 264 to 270 resulted in loss of Leu-Gly-Arg-Asn-Ser-Phe from the amino acid sequences 265 to 270, whereas Hep3B had a 7-kb deletion after exon 7 of p53. Our data indicate that whereas Rb may not have pleiotropic effects on HCC, p53 aberrations are frequently involved in hepatocarcinogenesis. Further, HBV infection appears to be unrelated to the micro-genetic changes of p53. The G to T codon-249-mutation is consistent with HCCs arising from areas at high risk for both aflatoxin B1 (AFB1) exposure and HBV infection.
 ...
PMID:Tumour suppressor p53 and Rb genes in human hepatocellular carcinoma. 877 41

Carcinogenesis is a multistage process involving the inappropriate activation of normal cellular genes to become oncogenes, e.g., ras, and the inactivation of other cellular genes called tumor suppressor genes. p53 is the prototypic tumor suppressor gene that is well suited as a molecular link between the causes of cancer, i.e., carcinogenic chemical and physical agents and certain viruses, and the development of clinical cancer. The p53 tumor suppressor gene is mutated in the majority of human cancers. Genetic analysis of human cancer is providing clues to the etiology of these diverse tumors and to the functions of the p53 gene. Some of the mutations in the p53 gene reflect endogenous causes of cancer, whereas others are characteristic of carcinogens found in our environment. In geographic areas where hepatitis B virus and a dietary chemical carcinogen, aflatoxin B1, are risk factors of liver cancer, a molecular signature of the chemical carcinogen is found in the mutated p53 gene. A different molecular signature in the p53 gene is found in skin cancer caused by sunlight. Because mutations in the p53 gene can occur in precancerous lesions in the lung, breast, esophagus, and colon, molecular analysis of the p53 gene in exfoliated cells found in either body fluids or tissue biopsies may identify individuals at increased cancer risk. p53 mutations in tumors generally indicate a poorer prognosis. In summary, the recent history of p53 investigations is a paradigm in cancer research, illustrating both the convergence of previously parallel lines of basic, clinical, and epidemiologic investigation and the rapid translation of research findings from the laboratory to the clinic.
 ...
PMID:p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and cancer risk assessment. 878 59

Some of the multiple factors involved in the molecular pathogenesis of hepatocellular carcinoma have been elucidated in recent years but no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Transformation of hepatocytes to the malignant phenotype may occur irrespective of the aetiological agent through a pathway of chronic liver injury, regeneration and cirrhosis. The activation of cellular oncogenes, the inactivation of tumour suppressor genes and overexpression of certain growth factors contribute to the development of HCC. There is increasing evidence that the hepatitis B virus may play a direct role in the molecular pathogenesis of HCC. Aflatoxins have been shown to induce specific mutations of the p53 tumour suppressor gene thus providing a clue to how an environmental factor may contribute to tumour development at the molecular level.
 ...
PMID:The molecular pathogenesis of hepatocellular carcinoma. 879 May 56

The hepatitis B virus-encoded protein, HBx, may contribute to carcinogenesis by perturbing cell growth and differentiation. There is some evidence indicating that HBx represses the nuclear import of the tumour repressor p53 and p53-dependent trans-activation and that HBx activates members of the basic region-leucine zipper (bZIP) family.
 ...
PMID:Hepatitis B virus-induced hepatocellular carcinoma: possible roles for HBx. 882 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>