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)

The p53 gene is the most frequently mutated gene in many human cancers, including those of the colon, breast, lung, esophagus, liver and brain. Such genetically mutated tumours are generally associated with progression of the disease and poor clinical outcome. One hundred cases of documented gallbladder carcinomas were reviewed. Twenty-eight cases were randomly selected to evaluate the expression of P53, Bcl-2, carcinoembryonic antigen (CEA) and alpha-fetoprotein, in both the in situ (19 cases) and invasive components (28 cases) of the tumour by the avidin-biotin complex method of immunohistochemistry. These results were correlated with the mean survival intervals in an effort to clarify the progression of the disease and evaluate their role as prognostic markers. Staining to alpha-fetoprotein and Bcl-2 remained consistently negative to weak insignificant staining in both the in situ and invasive components of the tumour in all cases. P53 staining of the invasive part of the tumour was seen in 24 (86%) of the cases and in 17 (89%) of the in situ component. The in situ staining patterns of P53 were not statistically significant in relation to the mean survival. However, in the invasive component, moderate to strong staining tumours, as seen in 15 (54%) cases, were associated with a mean survival of 8.8 months. A similar trend was also observed with staining patterns to CEA. Eighty-nine per cent of the invasive and 84% of the in situ components of the tumour stained positive to CEA. Moderate to strong staining of both the in situ and the invasive components of the tumours was associated with a mean survival of 10.6 months in 76% of cases. This study shows that altered expressions of P53 and CEA are detectable by immunohistochemistry in gallbladder carcinomas. Tumours with increased expression of P53 and CEA of a strong to moderate staining were associated with poor clinical outcomes as evidenced by their mean survival. A stepwise progression of altered CEA and P53 expression may reflect ongoing progression of the disease from the in situ to the invasive phase. However, such trends need to be evaluated in larger numbers and are thus not considered to be true independent prognostic markers.
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PMID:Gallbladder carcinomas: an immunoprognostic evaluation of P53, Bcl-2, CEA and alpha-fetoprotein. 1075 14

Chronic infection with hepatitis B virus (HBV) is associated with development of hepatocellular carcinoma (HCC). The exact mechanism by which chronic infection with HBV contributes to onset of HCC is unknown. However, previous studies have implicated the HBV transactivator protein, HBx, in progression of HCC through its ability to bind the human tumor suppressor protein, p53. In this study, we have examined the ability of HBx to modify p53 regulation of the HCC tumor marker gene, alpha-fetoprotein (AFP). By utilizing in vitro chromatin assembly of DNA templates prior to transcription analysis, we have demonstrated that HBx functionally disrupts p53-mediated repression of AFP transcription through protein-protein interaction. HBx modification of p53 gene regulation is both tissue-specific and dependent upon the p53 binding element. Our data suggest that the mechanism by which HBx alleviates p53 repression of AFP transcription is through an association with DNA-bound p53, resulting in a loss of p53 interaction with liver-specific transcriptional co-repressors.
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PMID:Hepatitis B viral transactivator HBx alleviates p53-mediated repression of alpha-fetoprotein gene expression. 1084 85

A continuously growing human hepatocellular carcinoma (HCC) cell line was established from a Chinese male, carrier of the hepatitis B virus (HBV). This cell line, designated HKCI-1, grows as an adhering monolayer of polygonal epithelial cells that embody one or more nuclei. HKCI-1 secretes alpha-fetoprotein but shows no evidence of HBV carriage. Conventional banding analysis of the short-term cultured primary tumor and the propagated HKCI-1 revealed a chromosome modal number of near-triploidy. It was, however, impossible to derive their complete karyotype due to the complex nature of chromosomal rearrangements and many marker chromosomes of uncertain origin. Spectral karyotyping (SKY) is a newly developed molecular cytogenetic technique that allows the unprecedented discernment of chromosomal abnormalities. Spectral karyotyping analysis on HKCI-1 and the primary tumor elucidated all aberrant chromosomes and revealed complex karyograms. Recurring aberrations detected in both primary tumor and HKCI-1 included der(X)t(X;11)(q10;p10), der(1)t(1;10)(q10;?pq), der(4)t(4;16)(p10;q10), i(5p), del(5)(q13), der(7)t(7;21)(q32q10::q10), der(8)t(8;17)(q10;p10), and der(9)t(9;22)(q34;?pq). Comparative genomic hybridization (CGH) was employed to monitor the culture evolution in vitro. Genomic imbalances in HKCI-1 involved chromosomal losses on 4q, 5q13-qter, 8p, 9pter-q33, 10q, 11q, 13q, 16q, 17q12-qter, and 22, and low-level gains on 6pter-q22, 7p, 8q, 9q34, 10p, 11p, 12, 17pter-q11.2, 18, 19, 20, 21, and Y. High-level amplifications were also detected on 5pter-q12, 7q11.2-qter, and Xq. The corresponding CGH finding on the primary tumor indicated similar imbalances. TP53 mutational analysis showed that both HKCI-1 and the primary tumor had the aflatoxin-associated mutation in codon 249 and an additional TP53 polymorphism in codon 72. Our present study demonstrates the value of combined SKY and CGH study in defining complex rearrangements and identifying cryptic translocations, and provides a comprehensive analysis on the chromosomal abnormalities in HKCI-1.
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PMID:A comprehensive karyotypic analysis on a newly developed hepatocellular carcinoma cell line, HKCI-1, by spectral karyotyping and comparative genomic hybridization. 1095 34

10-Hydroxycamptothecin (HCPT), a DNA topoisomerase I (Topo I) inhibitor, exhibited a remarkable apoptosis-inducing effect on human hepatoma Hep G2 cells. We studied the effect of HCPT upon the expression of P53, c-Myc, Bcl-2, Bax and alpha-fetoprotein (AFP) proteins, and caspase (caspase-1 and caspase-3) activity of Hep G2 cells. It showed that HCPT at a dose of 0.1 microg/ml increased the expression of P53, c-Myc and Bax protein, and decreased the expression of Bcl-2 and AFP. The increase of P53, which was remarkable after only 3 h incubation with HCPT, occurred much earlier than the changes of other proteins, suggesting that the increase of P53 expression may be the upstream event in the apoptosis of Hep G2 cells induced by HCPT. Both caspase-1 and caspase-3 were activated in Hep G2 cells by HCPT treatment, suggesting that caspase-1 and caspase-3 are involved in the process of apoptosis in Hep G2 cells, and may be the main effectors of the apoptosis.
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PMID:Differential regulation of P53, c-Myc, Bcl-2, Bax and AFP protein expression, and caspase activity during 10-hydroxycamptothecin-induced apoptosis in Hep G2 cells. 1112 38

Although p53 regulates the cell cycle and apoptosis, gross embryonic development is normal in the p53 knockout (-/-) mouse. In this study, we comprehensively assessed liver development in p53 -/- mice (from embryonic day 15 to adult) for evidence of a cell cycle-induced perturbation in differentiation. Liver cell proliferation in the embryo and newborn is similar in p53 -/- and +/+ mice; in contrast, -/- adult hepatocytes divide at twice the rate of wild types. Developmental expression patterns of liver-specific markers that are up-regulated (e.g., phosphoenolpyruvate carboxykinase and aldolase B) and down-regulated (e.g., alpha-fetoprotein) are similar. Therefore, embryonic and perinatal liver development is normal in the absence of p53. However, the p53 -/- adult liver displays small blast-like cells, the majority being hepatic and some lymphoid. These cells appear in periportal regions and can infiltrate the parenchyma. The hepatic blast-like cells express both mature and immature liver markers, suggesting that differentiation of the liver stem cell compartment is blocked.
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PMID:Hepatoblast-like cells populate the adult p53 knockout mouse liver: evidence for a hyperproliferative maturation-arrested stem cell compartment. 1137 69

Gene therapy using replication-competent adenovirus that selectively propagates in tumor cells may be an effective treatment for cancer. We developed an adenovirus that would be replication specific for hepatocellular carcinoma (HCC). Based on our finding that the E1B55k-deficient adenovirus was able to replicate in human primary hepatocytes, we therefore designed an adenovirus carrying E1A and attenuated E1B gene driven by the alpha-fetoprotein promoter (Adv-AFP-E1AdB), thus restricting the replication specificity in AFP-producing HCC. Replication of Adv-AFP-E1AdB in primary hepatocytes was practically negligible 4 days after infection. Although Adv-AFP-E1AdB replicated slowly in AFP-producing HCC, it efficiently destroyed HCC cells independent of their p53 status. Experiments were conducted in vivo using systemic administration of Adv-AFP-E1AdB and we observed tumor size reduction in nude mice having liver cancer. The use of replication-competent adenovirus deficient of the E1B gene coupled to an AFP-targeting strategy may be a safe and efficacious treatment for HCC.
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PMID:Target gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by E1B55k-attenuated adenovirus. 1140 92

Mutations of p53 as a tumor suppressor gene in hepatocellular carcinoma (HCC) have been reported to occur with varying frequency in different geographic regions, which might be different etiology for HCC. Overexpressions of p53 (well known for its implications in mutations of the p53 gene), PCNA and alpha-fetoprotein (AFP) have been reported to be associated with carcinogenesis and/or tumor progression and poor prognosis in various types of cancer. To estimate the geographical difference of the p53 gene, PCNA and AFP in HCC, we examined 14 Japanese HCC cases, 8 Indonesian HCC cases, and 27 Indonesian chronic active hepatitis (CAH) or liver cirrhosis cases, using immunohistochemical approaches. Overexpression of p53 was identified in 37.5% of Japanese HCC, in 62.5% of Indonesian HCC and none in CAH. The mean PCNA Labeling Index of Japanese HCC, Indonesian HCC and CAH was detected in 48.6%, 30.4%, and 43.5%, respectively. AFP was detected in 35.7% of Japanese and 25% of Indonesian HCC. The rate of p53 overexpression in Indonesian HCC was as high as in HCC of southern part of China, which might share the similar etiology in both regions.
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PMID:Immunohistochemical study of P53, PCNA and AFP in hepatocellular carcinoma, a comparison between Indonesian and Japanese cases. 1141 97

Identification of the basic genetic changes in human hepatocellular carcinoma (HCC) is very important for the understanding of this cancer. In this study, genomic DNA from 29 pairs of HCC and corresponding non-tumour tissues infected with hepatitis B virus (HBV) was prepared. Five CA-repeated microsatellite markers, including D8S277, D3S1029, D5S409, D2S123, and TP53, were used to analyse microsatellite alterations and their subtypes in these patients by polymerase chain reaction (PCR) amplification and denatured polyacrylamide gel electrophoresis. Microsatellite alterations were found in 15 of the 29 HCC patients (51.72%), implying that microsatellites are unstable in genomic DNA of HBV-infected HCC. It was found that frequency of microsatellite alterations in these HCC patients was not associated with patients' age, sex, status of tumour differentiation, and tumour size. Frequency of microsatellite alterations in HCC patients with cirrhosis tended to be less than that in patients without cirrhosis, but Fisher's exact test, 2-tailed, showed that this difference was not significant. Significantly more microsatellite alterations in serum alpha-fetoprotein (AFP)-positive cases were observed than those in serum AFP-negative ones, implying that the elevation of AFP in HBV-infected HCC may be associated with microsatellite stability.
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PMID:Microsatellite alterations in human hepatocellular carcinoma infected with hepatitis B virus: associated with the elevation of serum alpha-fetoprotein. 1149 29

Many of the functions ascribed to p53 tumor suppressor protein are mediated through transcription regulation. We have shown that p53 represses hepatic-specific alpha-fetoprotein (AFP) gene expression by direct interaction with a composite HNF-3/p53 DNA binding element. Using solid-phase, chromatin-assembled AFP DNA templates and analysis of chromatin structure and transcription in vitro, we find that p53 binds DNA and alters chromatin structure at the AFP core promoter to regulate transcription. Chromatin assembled in the presence of hepatoma extracts is activated for AFP transcription with an open, accessible core promoter structure. Distal (-850) binding of p53 during chromatin assembly, but not post-assembly, reverses transcription activation concomitant with promoter inaccessibility to restriction enzyme digestion. Inhibition of histone deacetylase activity by trichostatin-A (TSA) addition, prior to and during chromatin assembly, activated chromatin transcription in parallel with increased core promoter accessibility. Chromatin immunoprecipitation analyses showed increased H3 and H4 acetylated histones at the core promoter in the presence of TSA, while histone acetylation remained unchanged at the site of distal p53 binding. Our data reveal that p53 targets chromatin structure alteration at the core promoter, independently of effects on histone acetylation, to establish repressed AFP gene expression.
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PMID:p53 targets chromatin structure alteration to repress alpha-fetoprotein gene expression. 1157 52

A pleomorphic undifferentiated tumor primarily located in the retroperitoneum with a phenotype compatible with an extraosseous Ewing tumor/peripheral primitive neuroectodermal tumor (ET/pPNET) pattern and unusual molecular features is described. Immunohistochemically, HBA-71 (CD99/mic2) and several neural markers were intensively expressed together with scattered cells expressing carcinoembryonic antigen (CEA). Short-term culture showed biphasic neuroblastic and epithelioid cell populations, with the latter expressing germ cell markers (CEA, alpha-fetoprotein, and the beta-subunit of chorionic gonadotrophin). Conventional cytogenetics displayed several chromosomic rearrangements, especially a complex translocation t(17,2,22,13) (q21::q11-->q33::q12-->q13::q14). These structural abnormalities were confirmed using fluorescence in situ hybridization analysis. Molecular studies revealed EWS-FEV fusion transcripts (exon 7 of the EWS gene and exon 2 of the FEV gene). In addition, a new p53 mutation not previously reported in ET/pPNET involving exon 5 codon 138: GCC to GAC (Ala/Asp) was detected. In our case, we emphasize the presence of atypical features not only from the phenotypic point of view but also at the genetic level as well as the value of detecting such markers in the differential diagnosis with other abdominal pleomorphic tumors.
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PMID:Atypical pleomorphic extraosseous ewing tumor/peripheral primitive neuroectodermal tumor with unusual phenotypic/genotypic profile. 1185 96


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