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)

There is little information regarding the molecular mechanisms of hepatocarcinogenesis. We studied the p53 gene at the DNA, RNA, and protein level in seven human hepatocellular carcinoma (HCC)-derived cell lines; six of seven showed p53 abnormalities. By Southern blotting, the p53 gene was found to be partially deleted in Hep 3B and rearranged in SK-HEP-1 cells. Transcripts of the p53 gene were undetectable in Hep 3B as well as in FOCUS cells that had no apparent deletion or rearrangement of the p53 gene. Immunoprecipitation after [35S]methionine labeling of HCC cells demonstrated that p53 protein was absent in Hep 3B and FOCUS and reduced in concentration in PLC/PRF/5 cells. p53 synthesized by Mahlavu cells showed a slower migration on SDS/polyacrylamide gels suggesting it was an abnormal protein. In Huh7 cells, p53 protein had a prolonged half-life leading to its accumulation in the nuclei; increased levels of p53 protein were also found by immunoblotting. The p53 gene and its expression appeared to be unaltered in the hepatoblastoma-derived Hep G2 cell line. We found that the loss of p53 expression did not occur as a late in vitro event in the FOCUS cell line because p53 protein was also nondetectable at an early passage. We conclude that the loss of p53 expression or the presence of abnormal forms of the protein are frequently associated with HCC cell lines. These observations suggest that alterations in p53 may be important events in the transformation of hepatocytes to the malignant phenotype.
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PMID:Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. 215 27

Human hepatocarcinoma cells (SK-HEP-1) were induced to die through apoptosis by treatment with delta 12-prostaglandin (PG)J2, as characterized by the appearance of a typical DNA ladder. The induction of apoptosis by delta 12-PGJ2 was specifically blocked by cycloheximide (CHX). Western analysis using anti-p53 or anti-WAF1 monoclonal antibodies demonstrated that these two protein levels were increased 3 h after delta 12-PGJ2 treatment, and accumulated for up to 12 h. The induction of p53 protein seemed to be dependent on the increase of p53 mRNA level, which was inhibited by CHX treatment. However, delayed addition of CHX after delta 12-PGJ2 treatment failed to affect both p53 mRNA levels and DNA fragmentation following delta 12-PGJ2 treatment, indicating that the inhibition of p53 synthesis may contribute to the protective effect of CHX against delta 12-PGJ2-mediated cytotoxicity. Therefore, our results suggest that the initial events caused by delta 12-PGJ2, leading ultimately to SK-HEP-1 cell death, involve a certain process required for p53 induction. However, the finding that delta 12-PGJ2 is also active against Hep 3B cells which are devoid of a functional p53 indicates that p53 may not be the critical requirement for inducing apoptosis by delta 12-PGJ2.
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PMID:Induction of p53 and apoptosis by delta 12-PGJ2 in human hepatocarcinoma SK-HEP-1 cells. 762 35

Hepatocellular carcinoma (HCC) is a heterogeneous disease. HCC derived from different stages of cellular differentiation may have different clinical and pathobiological behavior. To test the hypothesis that HCC can be classified into two types based on its phenotypic markers (hepatocellular and biliary differentiation), liver tissues from 290 Chinese patients with HCC were studied. Expression of hepatocytic differentiation marker (HEP-PAR-reactive antigen), biliary differentiation markers (AE1-AE3, cytokeratin-19), proliferation markers (Ki-67, proliferating cell nuclear antigen), alpha-fetoprotein, p53, and transforming growth factor-alpha in the tumor tissue were assessed by immunohistochemistry. Hepatocytic differentiation marker was detected in 99.7% and biliary differentiation markers were detected in 29.3% of these tumors. Clinically, no patient with HCC with biliary markers survived for more than 27 weeks compared with a 22.6% survival rate in patients with HCC negative for biliary markers. HCCs positive for the biliary differentiation markers showed features of more aggressive disease in terms of poorer cellular differentiation (P < 0.001) and high-level expression of proliferation markers (Ki-67, P < 0.001; proliferating cell nuclear antigen, P = 0.0114) compared with HCCs without biliary markers. HCCs with biliary markers also had a higher level of expression of alpha-fetoprotein (P < 0.001) and p53 (P = 0.0077). Classification of HCCs based on its phenotypic (differentiation) markers has both clinical and pathobiological implications.
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PMID:Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. 886 66

Ceramide acts as a mediator of programmed cell death in various cell types, but its molecular mechanisms linked to the cell cycle are poorly understood. In this study, we investigated the expression of the p21 gene and its relationship to apoptosis induced by ceramide. In SK-HEP-1 cells, the addition of C6-ceramide resulted in a dose- and time-dependent growth suppression and DNA fragmentation characteristics of apoptosis. p21 protein was induced during that process, while the protein level of p53, known as a transcriptional activator of p21, was not elevated under the same condition. This apoptotic cell death with p21 induction was also observed in the Hep 3B cells lacking functional p53 after exposure to C6-ceramide. These findings suggest that ceramide-induced apoptosis is associated with the upregulation of p21 mRNA and protein in a p53-independent pathway.
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PMID:Induction of p21 during ceramide-mediated apoptosis in human hepatocarcinoma cells. 971 64

In this paper, we present evidence that Ginsenoside-Rs3 (G-Rs3), a new diol-type ginseng saponin isolated from the roots of Panax ginseng C.A. Meyer, efficiently arrests the cell cycle at the G1/S boundary at lower doses, 0.1-5 microM, but induces apoptosis at higher doses, 10-25 microM, the effects of which were associated with selectively elevating protein levels of p53 and p21WAF1 in SK-HEP-1 cells. The cell growth suppressive and apoptosis inducing effects were confirmed by MTT assays together with flow cytometric analyses, morphological changes and DNA fragmentation. Immunoblotting showed that G-Rs3 significantly elevated protein levels of p53 and p21WAF1 prior to inducing apoptosis, while it did not elevate those of cyclin E, cyclin A, p27Kip1, and PCNA. Immune complex kinase assays showed that G-Rs3 downregulated the activities of both cyclins E- and A-associated kinases. Collectively, we suggest that G-Rs3 selectively elevates protein levels of p53 and p21WAF1 and hence downregulates the activities of the cyclin-dependent kinases, resulting in cell cycle arrest at the G1/S boundary. We also propose that apoptosis induced by G-Rs3 is related to the elevations of p53 and p21WAF1 in the cells.
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PMID:Ginsenoside-Rs3, a new diol-type ginseng saponin, selectively elevates protein levels of p53 and p21WAF1 leading to induction of apoptosis in SK-HEP-1 cells. 1022 87

In this paper, we present evidence that ginsenoside-Rs4 (G-Rs4; an acetylated analogue of ginsenoside-Rg5), a new ginseng saponin isolated from Panax ginseng C. A. Meyer, elevates protein levels of p53 and p21WAF1, which are associated with the induction of apoptosis in SK-HEP-1 cells. Flow cytometric analyses showed that G-Rs4 initially arrested the cell cycle at the G1/S boundary, but consequently induced apoptosis as evidenced by generating an apoptotic peak. The induction of apoptosis was confirmed by the results of DNA fragmentation assays and alterations in cell morphology after treatment of the cells with G-Rs4. Immunoblot assays showed that G-Rs4 significantly elevated protein levels of p53 and p21WAF1, concurrently with the downregulation of both cyclins E- and A-dependent kinase activities and induction of apoptosis. We suggest that G-Rs4 induces apoptosis, the effect of which is closely related to the downregulation of both cyclins E- and A-dependent kinase activity as a consequence of selectively elevating protein levels of p53 and p21WAF1 in SK-HEP-1 cells.
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PMID:Ginsenoside-Rs4, a new type of ginseng saponin concurrently induces apoptosis and selectively elevates protein levels of p53 and p21WAF1 in human hepatoma SK-HEP-1 cells. 1044 8

Wogonin and fisetin are flavonoids, which are widely distributed in plants. Our recent study demonstrated that, among seven structurally related flavonoids, wogonin and fisetin showed the most potent apoptosis-inducing activities in human promyeloleukemic cells HL-60. In the present investigation, we performed molecular studies to assess the apoptotic effects of wogonin and fisetin on hepatocellular carcinoma cells SK-HEP-1. Both wogonin and fisetin showed dose-dependent cytotoxic effects on SK-HEP-1 cells, accompanied by DNA fragmentation. Microscopic observation under Giemsa staining showed that wogonin and fisetin, at the dose of 80 microM, induced cellular swelling and the appearance of apoptotic bodies, characteristics of apoptosis, in SK-HEP-1 cells. Furthermore, flow cytometry analysis showed an increase of hypodiploid cells in wogonin- and fisetin-treated SK-HEP-1 cells. These data demonstrated that wogonin and fisetin were effective inducers of apoptosis in SK-HEP-1 cells. Treatment with an apoptosis-inducing concentration of wogonin or fisetin caused induction of caspase 3/CPP32 activity, but not of caspase 1 activity. In addition, a caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor Ac-YVAD-CHO, reversed the cytotoxic effects of wogonin and fisetin on SK-HEP-1 cells. Further, cleavage of caspase 3 substrates including poly(ADP-ribose) polymerase (PARP) and D4-GDI protein, and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated SK-HEP-1 cells. Increase of p53 protein was associated with wogonin- and fisetin-induced apoptosis; however, a p53-controlled gene, p21(Waf/Cip-1), was only induced in wogonin- (not fisetin-) treated SK-HEP-1 cells. Serum starvation elevated p21(Waf/Cip-1) protein expression, and enhanced the apoptotic induction activity of wogonin (not fiseitn) in SK-HEP-1 cells. Our study has provided molecular evidence to demonstrate that wogonin and fisetin had effective cytotoxic effects through apoptosis induction in hepatocellular carcinoma cells SK-HEP-1; activation of caspase 3 cascade, induction of p53 protein and alternative expression of p21(Waf/Cip-1) protein were involved.
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PMID:Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. 1210 53

Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible cells. However, the signaling pathway of their apoptotic effects remains undefined. In this study, the cytotoxic effect of emodin on various human hepatoma cell lines was investigated. Results demonstrated that emodin exhibited strongly suppressing effect on HepG2/C3A, PLC/PRF/5, and SK-HEP-1 cells, with the IC(50) value of 42.5, 46.6, and 53.1 microM, respectively. Furthermore, emodin induced apoptosis in HepG2/C3A cells was clearly verified by the appearance of DNA fragmentation and sub-G(1) accumulation. Besides, HepG2/C3A cells were found to be arrested in G(2)/M phase after the cells were treated with 60 microM emodin for 48 h. Moreover, significant increase in the levels of apoptosis-related signals such as p53 (419.3 pg/ml), p21 (437.4 units/ml), Fas (6.6 units/ml), and caspase-3 (35.4 pmol/min) were observed in emodin treated HepG2/C3A cells. Taken together, emodin displays effective inhibitory effects on the growth of various human hepatoma cell lines and stimulates the expression of p53 and p21 that resulted in the cell cycle arrest of HepG2/C3A cells at G(2)/M phase. Results also suggest that emodin-induced apoptosis in HepG2/C3A cells were mediated through the activation of p53, p21, Fas/APO-1, and caspase-3. It implies that emodin could be a useful chemotherapeutical agent for treatment of hepatocellular carcinoma (HCC).
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PMID:Emodin-induced apoptosis through p53-dependent pathway in human hepatoma cells. 1498 52

Recently, indole-3-acetic acid (IAA) has been introduced as a new cancer therapeutic agent through oxidative decarboxylation by horseradish peroxidase (HRP). The purpose of this study was to determine the therapeutic feasibility of IAA/light combination against liver cancer. SK-HEP-1 cells were irradiated with UVB or visible light (518 nm) in the presence of IAA. Cell viability was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Then, IAA was injected in SK-HEP-1 liver cancer cell-implanted nude mice, and the tumor area was irradiated with intense pulsed light (IPL). Then, tissue was taken for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and immunohistochemical staining for 8-hydroxy-deoxyguanosine (8-OHdG), p53, caspase-3, and proliferating cell nuclear antigen (PCNA). In vitro experiments demonstrated that IAA alone was not cytotoxic, but activated IAA by HRP or light caused cell death. In vivo experiments showed that IAA/IPL treatment caused regression of tumor cells in SK-HEP-1-implanted nude mice. The TUNEL assay showed that IAA/IPL induced cancer cell apoptosis, and this was confirmed by increases in 8-OHdG, p53, and caspase-3 in IAA/IPL-treated mice. In contrast, IPL alone did not induce apoptosis, indicating that the apoptotic effect resulted from activated IAA by light. In summary, we showed that IAA/light induced tumor regression in SK-HEP-1-implanted nude mice. These results suggest the potential use of IAA/light combination in liver cancer.
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PMID:Experimental photodynamic therapy for liver cancer cell-implanted nude mice by an indole-3-acetic acid and intense pulsed light combination. 1972 Dec 41

The homeobox transcription factor Prox1 is highly expressed in adult hepatocytes and is involved in the regulation of bile acid synthesis and gluconeogenesis in the liver by interacting with other transcriptional activators or repressors. Recent studies showed that Prox1 could inhibit proliferation of hepatocellular carcinoma (HCC) cells and reduced Prox1 expression was associated with poor prognosis of HCC patients. However, the underlying mechanism by which Prox1 attenuates HCC growth is still unclear. In this study, we demonstrated that Prox1 induced senescence-like phenotype of HCC cells to reduce cell proliferation. Our results indicated that the tumor suppressor p53 is a key mediator of Prox1-induced growth suppression because Prox1 only induced senescence-like phenotype in HCC cells harboring wild type p53. In addition, knockdown of p53 by shRNA reversed the effect of Prox1. However, chromatin immunoprecipitation assay did not demonstrate the direct binding of Prox1 to proximal promoter of human p53 gene suggesting Prox1 might not directly activate p53 transcription. We found that Prox1 suppressed Twist expression in HCC cells and subsequently relieved its inhibition on p53 gene transcription. The involvement of Twist in the regulation of p53 by Prox1 was supported by the following evidence: (1) Prox1 inhibited Twist expression and promoter activity; (2) knockdown of Twist in SK-HEP-1 cells upregulated p53 expression and (3) ectopic expression of Twist counteracted Prox1-induced p53 transcription and senescence-like phenotype. We also indentified an E-box located at p53 promoter which is required for Twist to inhibit p53 expression. Finally, our animal experiment confirmed that Prox1 suppressed HCC growth in vivo. Collectively, we conclude that Prox1 suppresses proliferation of HCC cells via inhibiting Twist to trigger p53-dependent senescence-like phenotype.
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PMID:The homeobox transcription factor Prox1 inhibits proliferation of hepatocellular carcinoma cells by inducing p53-dependent senescence-like phenotype. 2329 86


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