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)

TIP30 (Tat-interacting protein 30), a newly found proapoptotic factor, appears to be involved in multiple functions including metabolic suppression, apoptosis induction, and diminishing angiogenic properties. In the present study, we reported that mitochondrial events were required for apoptosis induced by TIP30 in hepatocellular carcinoma cells (HCC cells). Translocation of Bax was essential for TIP30-induced apoptosis, whereas overexpression of the anti-apoptotic protein Bcl-xL delayed both second mitochondria-derived activator of caspases (Smac/DIABLO) release and onset of apoptosis. Furthermore, TIP30-induced apoptosis was dependent on caspase activity because the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (z-VAD-fmk) blocked DNA fragmentation. Release of Smac/DIABLO from the mitochondria through the TIP30-P53-Bax cascade was required to remove the inhibitory effect of XIAP (X-linked Inhibitor of Apoptosis) and allowed apoptosis to proceed. Our results showed for the first time that Bax-dependent release of Smac/DIABLO, cytochrome c and AIF from the mitochondria mediated the contribution of the mitochondrial pathway to TIP30-mediated apoptosis. Our data suggested that adenovirus-mediated overexpression of TIP30 was capable of inducing therapeutic programmed cell death in vitro by activating the mitochondrial pathway of apoptosis. On the basis of these studies, elucidating the mechanism by which TIP30 induces cell death might establish it as an anticancer approach.
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PMID:Tip30-induced apoptosis requires translocation of Bax and involves mitochondrial release of cytochrome c and Smac/DIABLO in hepatocellular carcinoma cells. 1799 90

The neurite outgrowth inhibitor Nogo has attracted great interest, but its relevance with hepatocellular carcinoma has not been reported. This paper first found mutations of Nogo-C in HCC patients from Qidong in China: A172G (Thr58Ala), A340G (Arg114Gly), A571G (Ile191Val). In six examined patient cases from Qidong, the mutations occurred in five cases. The mutation Arg114Gly was predicted bioinformatically to affect Nogo-66 dimensional structure of Nogo-C. Our previous works also had indicated that mutant Nogo-C promoted liver cancer cell line apoptosis and resulted in molecular marker of HCC p53 gene transfer from nucleus to cytoplast. Above results revealed a new physiological role and clinical implications of Nogo-C on HCC.
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PMID:New mutations of Nogo-C in hepatocellular carcinoma. 1808 Jul 85

Circulating free DNA (CFDNA) has been shown to be a good source of liver tissue-derived DNA in African and Asian patients with chronic liver disease or HCC. In Egypt, HCC is a frequent carcinoma and mostly occur in the context of chronic infection by HCV, a widespread infection in the Egyptian population. Here we have examined the presence of mutations in TP53 at codon 249 (Ser-249, considered as a hallmark of mutagenesis by aflatoxin) and in CTNNB1 (gene encoding beta-catenin) in CFDNA of patients with HCC or chronic liver disease, from Alexandria, Egypt. The DNA concentrations were significantly higher in HCC patients compared to HBV and HCV carriers without cancer, and to sero-negative individuals. Ser-249 TP53 mutations were determined using PCR-restriction digestion (RFLP) in CFDNA of 255 subjects, and confirmed by sequencing. Ser-249 was found in CFDNA of 12 subjects (4.8%), with the highest prevalence in subjects with chronic liver disease and infection by HBV (6/36; 16.7%) Mutations in CTNNB1 were examined using PCR combined to DHPLC and followed by sequencing. No mutations were found in CTNNB1 neither in CFDNA or in tumour tissue. In parallel, studies on DNA extracted from 20 HCC biopsies showed the presence of ser-249 mutation in two cases (10%). These results indicate that mutagenesis by aflatoxin may play a role in hepatocarcinogenesis in Egypt, and CFDNA may serve as a convenient source of material in monitoring the effects of aflatoxin exposure and viral infections in chronic liver disease and cancer.
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PMID:Ser-249 TP53 and CTNNB1 mutations in circulating free DNA of Egyptian patients with hepatocellular carcinoma versus chronic liver diseases. 1831 40

The aim of this study is to clarify the existence and the form of HCV RNA and HBV DNA genome integration and genetic instability in liver tissue with HBsAg-negative and anti-HCV-positive HCC. We investigated 16 Japanese patients with HBsAg-negative and anti-HCV-positive HCC. HBV genome integration into host cell genome by Southern hybridization and PCR was examined. Moreover, we analyzed loss of heterozygosity (LOH) and replication errors (RER) of chromosomes 2p, 3p and 17p using the PCR and an autosequencer to determine the three microsatellite regions D2S123, D3S1067, TP53. Eight (50.0%) of 16 were found to have integrated genome of HBV in tumor tissue (T) by PCR. In even the non-tumor regions (NT), seven patients (43.8%) were found to have HBV genome integration. The coincidence between T and NT was found in 4 (25%). Integration of HBV-X gene in T was revealed in three (18.7%), and HBV-integration was confirmed in all NT. No integration of the X gene alone was found in the liver tissue. Five (37.5%) of eight HBV DNA integrated cases simultaneously had HCV RNA minus strand. Concerning the genetic instability, RER were detected in two of 16 (12.5%). RER at 2p; D2S123 was observed in one of 16 (6.2%) and at 3p; D3S1067 was observed in one (6.2%). LOH at the D2S123 locus was observed in one of 12 tumors with heterozygosity (8.3%). There was no genetic instability (LOH or RER) of TP53 which was p53 locus on 17p in T. There was only one case of eight HBV DNA integrated cases (6.2%) with genetic instability of RER of 3p simultaneously in T. In conclusion, the majority of HBsAg-negative and anti-HCV-positive HCC liver tissue was found to have HCV-RNA and HBV DNA integration, and in some samples, HBV DNA integration and genetic instability were concurrently confirmed. It is speculated that multistep carcinogenesis may have been proposed for HCC oncogenetic progression.
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PMID:HBV genome integration and genetic instability in HBsAg-negative and anti-HCV-positive hepatocellular carcinoma in Japan. 1837 22

Bid has multiple functions in apoptosis, survival, and proliferation. The role of Bid in etoposide-induced-DNA damage in HCC has not been investigated. Here, we report that p53-overexpression led to the notable up-regulation of the expression of Bid protein, whereas the acquired expression of Bid by PLC/PRF/5 cells dramatically decreased the p53 level. Upon the administration of a high dose of etoposide (causing irreparable damage), Bid sensitized cells to apoptosis. However, at a low dose of etoposide (repairable damage), Bid activated the S phase checkpoint through the up-regulation of p21 and p27, which are both p53-independent. While the unrepairable damage was being carried out, Bid was quickly translocated to the mitochondria to release cytochrome c into the cytosol, which activated caspases 9 and 3 and led to cell death. In conclusion, our study demonstrates that Bid both exhibits S phase checkpoint activation and plays a pro-apoptotic role in response to different degrees of etoposide-induced DNA damage in HCC cells. The elucidation of these intricate mechanisms of Bid points to the development of a possible therapeutic option that combines cytotoxic therapies to treat HCC.
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PMID:Bid exhibits S phase checkpoint activation and plays a pro-apoptotic role in response to etoposide-induced DNA damage in hepatocellular carcinoma cells. 1837 75

CpG island methylator phenotype (CIMP) involves the targeting of multiple genes by promoter hypermethylation. Telomerase plays an important role in the development of cellular immortality and oncogenesis. To gain insight into the role of epigenetic aberration of telomerase-related genes in hepatocarcinogenesis, we determined a hypermethylation profile in HCC. We examined the promoter methylation status of 9 genes associated with telomerase activity in 120 HCC, 120 cirrhosis tissues and 10 normal liver tissues by methylation-specific PCR. Assay of telomerase activity was by TRAP-ELISA. The frequency of promoter methylation of each gene was P21 63.3%, P15 42.5%, P16 62.5%, P53 14.2%, RB 32.5%, P27 48.3%, WTI 54.2%, E2F-1 70.8% and P300 65.8% of 120 HCC. Methylation status of P21, P15, P16, WTI and E2F-1 was significantly associated with HCC and nontumor tissues (p < 0.05). CIMP+ was detected in 61.7% (74/120) HCC and 15% (18/120) cirrhosis tissues, no CIMP+ was present in normal liver tissues (p < 0.001). A significant difference between CIMP status and metastasis was been found in HCC (p < 0.001). Results showed that 94.6% (70/74) HCC and 55.6% (10/18) cirrhosis patients with CIMP+ show expression of high telomerase activity than 45.5% (10/22) HCC and 6.25% (1/16) cirrhosis patients with CIMP- (p < 0.001). CIMP lead to high levels of expression of telomerase activity through the simultaneous inactivation of multiple genes associated with telomerase activity by concordant methylation.
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PMID:CpG island methylator phenotype association with upregulated telomerase activity in hepatocellular carcinoma. 1854 60

Various molecular changes characterizing organ-specific carcinogenesis have been identified in human tumors; however, the molecular mechanisms of the genomic changes specific for each cancer are not well defined. A transgenic (Tg) mouse model with constitutive expression of the nucleotide-editing enzyme, activation-induced cytidine deaminase (AID), develops tumors in various organs as a result of the mutagenic activities of AID. This phenotypic character of AID Tg mice allowed us to analyze the organ-specific genetic changes in tumor-related genes commonly triggered by AID-mediated mutagenesis. Among the 80 AID Tg mice analyzed, 11 mice developed hepatocellular carcinomas, and 7 developed lung cancers. In addition, 1 developed the gastric cancer and 3 developed gastric adenomas. Organ-specific preferences for nucleotide changes were observed in some of the tumor-related genes in each epithelial tissue of the AID Tg mice. Of note, the c-myc and K-ras genes were the preferential targets of the mutagenic activity of AID in lung and stomach cancers, respectively, whereas mutations in the p53 and beta-catenin genes were commonly observed in all 3 organs. Quantitative RT-PCR analyses revealed that alpha-fetoprotein, insulin-like growth factor-2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase-7 gene was more marked in lung cancer. Our findings suggest that AID, a DNA mutator that plays a critical role linking inflammation to human cancers, might be involved in the generation of organ-specific genetic diversity in oncogenic pathways during cancer development.
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PMID:Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. 1878 63

The present study investigated the effect of mammalian target of rapamycin (mTOR) inhibition on HCC cells in vitro and in vivo, either alone or in combination with cytotoxic agents. In vitro, HCC cell lines were exposed to RAD001, an mTOR inhibitor, either alone or in combination with cisplatin. Alone, RAD001 suppressed cell proliferation in all cell lines tested, but did not induce apoptosis. RAD001 in combination with cisplatin induced a significant increase in the number of apoptotic cells, downregulated the expression of pro-survival molecules, Bcl-2, survivin and cyclinD1, and increased the cleavage of PARP, compared to RAD001 or cisplatin alone. Transfection of p53 into the Hep3B cell line increased the sensitivity of tumor cells to cisplatin. The suppression of HCC tumor growth in vivo was enhanced by RAD001 combined with cisplatin, accompanied by a significant increase in the number of apoptotic cells in tumor tissues. This study demonstrates that inhibition of mTOR suppresses tumor growth and sensitizes tumor cells to chemocytotoxic agents.
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PMID:Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma. 1882 93

Mouse monoclonal antibodies (MAb) were generated against p33ING1b tumor suppressor protein. 15B9 MAb was highly specific in recognizing a single protein band of approximately 33 kDa endogenous p33ING1b protein from HCC cell lines and normal liver tissue by Western blot analysis and by immunoprecipitation. Although p33ING1b mutations are rarely observed in cancer, differential subcellular distribution and nuclear exclusion of p33ING1b were reported in different cancer types. Therefore we analyzed the expression and subcellular localization of p33ING1b in HCC cell lines using 15B9 MAb. So far, p33ING1b mutations or differential subcellular localization are not reported in HCC. In this study, by indirect immunofluorescence using MAb 15B9, we demonstrate that nuclear localization of p33ING1b was highly correlated with well-differentiated HCC cell lines whereas poorly differentiated HCC cells have nuclear exclusion of the protein. Moreover no association was observed between differential subcellular localization of p33ING1b and p53 mutation status of HCC cell lines. Hence our newly produced MAb 15B9 can be used for studying cellular activities of p33ING1b under normal and cancerous conditions.
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PMID:Nuclear exclusion of p33ING1b tumor suppressor protein: explored in HCC cells using a new highly specific antibody. 1913 96

This study investigated the effect of baicalein, silymarin, and their combination, on two human liver-derived cell lines, HepG2 (hepatocellular carcinoma) and Chang liver (non-tumor liver cells). It was found that 6.75 microg/ml baicalein or 100 microg/ml silymarin alone significantly inhibited the growth of HepG2. When baicalein was used in combination with silymarin on HepG2, an additive effect at 24 h and a synergistic effect at 48 h were observed. The viability at 48 h was 85.62% from 6.75 microg/ml baicalein treatment; but the viability reduced to 49.67%, 38.56%, and 19.61% when 25, 50, and 100 microg/ml silymarin respectively, was added to the treatment. By contrast, each treatment had little or no effect on Chang liver. Compared to treatment of baicalein or silymarin alone on HepG2, combination of both drugs synergistically increased the percentages of cells in G0/G1 phase and decreased those in S-phase, which were associated with up-regulation of Rb, p53, p21(Cip1) and p27(Kip1) and down-regulation of cyclin D1, cyclin E, CDK4 and phospho-Rb. The results indicate that the combination of baicalein and silymarin eradicates tumor cells efficiently, has minimal deleterious effects to the surrounding normal cells, and offers mechanistic insight for further exploitation of HCC treatment.
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PMID:Synergistic anti-cancer effect of baicalein and silymarin on human hepatoma HepG2 Cells. 1915 Mar 84


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