UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deferoxamine (DFO)-induced iron deprivation caused an increase in p53 expression in ML-1 and Raji cells. In ML-1 cells, with express wild type p53, p53 protein levels were transiently increased 6 h after addition of 10(-4)M DFO. In Raji cells, which carry a mutant p53 allele, p53 increased 6 h after addition of 10(-4)M DFO and remained elevated for 24 h. Growth inhibition was observed in both cell types 6 h after addition of 10(-4)M DFO. In both cells, p53 mRNA levels did not increase following incubation with DFO, suggesting that increased p53 expression is the result of a post-transcriptional mechanism. Although increases in wild type p53 protein in ML-1 cells resulted in increases in a p53 target gene, p21cipl/wafl/sdil, this effect was not observed in Raji cells which express a mutant p53 protein.
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PMID:Iron deprivation results in an increase in p53 expression. 859 Jun 32

We examined the effects of a cell-permeable ceramide analog, C2-ceramide, on the growth of TNF-alpha-resistant B lymphoma Raji cells lacking TNF-alpha-receptors (TNF-R). C2-ceramide inhibited the clonal growth of not only TNF-alpha-sensitive myeloid leukemia cells (HL60 and U937) but also Raji cells. Following stimulation with C2-ceramide, HL60 and U937 cells showed apoptotic cell death, whereas Raji cells did not show a detectable level of apoptosis. However, a cell-cycle arrest in G0/G1 phase was observed in Raji cells after the treatment with C2-ceramide, which was accompanied by the dephosphorylation of retinoblastoma (RB) gene products and decreased expression of p53 proteins. Failure of C2-ceramide to induce apoptosis in Raji cells might be explained by the lack or low expression of apoptosis-inducing proteins by two lines of evidence: (1) Raji cells were resistant to apoptosis induced by ceramide even in the presence of transcription/translation inhibitors; (2) Bax protein expression was not detectable in Raji cells, although Bcl-2 protein expression in Raji cells was even less than that in HL60 and U937 cells. Moreover, protein kinase C (PKC), whose activation has been described to inhibit ceramide-induced apoptosis, inhibitor H-7 did not induce apoptotic cell death in Raji cells, suggesting that an imbalance between PKC and ceramide pathways is not the reason for the resistance of Raji cells against ceramide-induced apoptosis. Finally, ceramide-induced activation of nuclear factor kappaB (NF-kappaB) was observed in Raji cells as well as HL60 cells, indicating that activation of this molecule may not be specific for apoptosis. By using the present model, one can dissect cell-cycle arrest and apoptosis induced by ceramide.
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PMID:Cell-permeable ceramide inhibits the growth of B lymphoma Raji cells lacking TNF-alpha-receptors by inducing G0/G1 arrest but not apoptosis: a new model for dissecting cell-cycle arrest and apoptosis. 894 36

Methylprednisolone (MP) and related corticosteroids are a fundamental part of regimens used to treat lymphoma and leukemia. In many of these malignancies, oncogenic activation of C-MYC and BCL2 is seen. Abnormalities of the tumor suppressor p53, which exerts growth-suppressing and apoptosis-enhancing functions through the transcriptional regulation of downstream genes including CDKN1, GADD45, and BCL2, are also often found. The goal was to determine the modulation of expression of the oncogenes (C-MYC and BCL2), the p53 pathway described above, and the apoptosis marker TGF-beta 1 in the human Raji lymphoma following MP treatment. Raji xenografts were grown in nude mice and growth curves characterized by sequential measurement. Mice were treated daily for 8 days with MP. Tumors were harvested untreated, or at 1 or 8 days after cessation of MP treatment, and the RNA was extracted. RT-PCR was used to determine the level of mRNA expression of the genes. Tumor growth was greatly reduced in the MP-treated mice. Gene expression levels for C-MYC and BCL2 were reduced at 1 day following MP and approached control levels 8 days after MP treatment. Expression levels of p53, CDKN1, and GADD45 were moderately and coordinately decreased at 1 day after cessation of MP treatment and remained repressed a week later. TGF-beta 1 exhibited no change in expression levels. These results suggest that decreased expression of C-MYC and BCL2 may play a role in the molecular events that initiate and are responsible for the growth inhibition of Raji lymphoma xenografts by MP.
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PMID:Decreased C-MYC and BCL2 expression correlates with methylprednisolone-mediated inhibition of Raji lymphoma growth. 916 90

Following our demonstration of cytochrome P450-independent DNA damage induced by aqueous solutions of cigarette smoke in human mucosal cells in vivo, and in a lymphoblastoid cell line, we have developed a new technique to demonstrate gene-region specific DNA damage, with the EBNA-1 gene present in multiple nuclear matrix-attached episomes in Raji cells serving as an amplified target. DNA was extracted from Raji cells treated by gamma-irradiation or aqueous solutions of cigarette smoke; adducted bases or other damage were removed chemically by depurination/alkali treatment. Single-strand breaks induced directly by cigarette smoke as well as DNA cleaved at the site of former adducts were end-labelled either with alpha-[32P]dCTP or with biotin-16-dUTP. With 32P-labelling, a dose-dependent increase in DNA labelling was seen for different concentrations of cigarette smoke; undiluted smoke produced a similar amount of damage as 22.4 Gy of gamma-irradiation. For isolation of DNA regions that contained biotin label at the sites of former damage, DNA was cut by restriction endonucleases and 3-kb-fragments including the target gene, EBV-EBNA-1, were isolated by agarose-gel electrophoresis. Those containing biotin were selected on streptavidin-coated magnetic beads. PCR amplification of the bound DNA revealed EBNA-1 DNA only when cells were pretreated with either cigarette smoke or gamma-irradiation. The presented method thus provides a new approach for detecting gene-specific damage in a readily accessible target, EBV episomes. The method is also potentially applicable for studying single-copy genes such as p53, the types of adducts involved, and quantitative aspects of DNA damage and its repair.
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PMID:Epstein-Barr virus episomes as targets for cigarette smoke- and gamma-irradiation-induced DNA damage: studies on the EBNA-1 region by a new gene-specific technique. 923 Feb 87

DNA-dependent protein kinase (DNA-PK) has been known to catalyze phosphorylation of a number of regulatory factors involved in DNA replication and transcription such as simian virus 40 T antigen, p53, c-Myc, Sp1, and RNA polymerase II (Pol II). We examined the possibility that DNA-PK phosphorylates the general transcription factors TATA-binding protein (TBP) and transcription factor (TF) IIB, which play key roles in the formation of transcription initiation complex with Pol II. By using a highly purified preparation of DNA-PK from Raji cells, both TBP and TFIIB were shown to be phosphorylated in vitro by DNA-PK. We then investigated the effect of the phosphorylation of these factors on Pol II basal transcription. Stepwise analysis of preinitiation complex formation by electrophoretic mobility shift assay revealed that the phosphorylation of TBP and TFIIB by DNA-PK did not affect the formation of promoter (P)-TBP and P-TBP-TFIIB complexes but synergistically stimulated the formation of P-TBP-TFIIB-TFIIF-Pol II complex. Similarly, combination of the phosphorylated TBP and TFIIB synergistically stimulated Pol II basal transcription from adenovirus major late promoter. These observations suggest that DNA-PK could positively regulate the Pol II basal transcription by phosphorylating TBP and TFIIB.
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PMID:Phosphorylation of human general transcription factors TATA-binding protein and transcription factor IIB by DNA-dependent protein kinase--synergistic stimulation of RNA polymerase II basal transcription in vitro. 928 44

Mitoguazone (methylglyoxal bisguanylhydrazone, methyl-GAG or MGBG) is a synthetic polycarbonyl derivative with activity in patients with Hodgkin's and non-Hodgkin's lymphoma, head and neck cancer, prostate cancer, and esophageal cancer. Mitoguazone has also recently been documented to have activity in patients with AIDS-related lymphoma. Among anticancer drugs, mitoguazone has a unique mechanism of action via interference with the polyamine biosynthetic pathway. Polyamines stabilize DNA structure by non-covalent cross-bridging between phosphate groups on opposite strands. In addition, mitoguazone causes uncoupling of oxidative phosphorylation. In this study, the ability of mitoguazone to induce apoptosis by inhibiting the polyamine pathway was assessed in three Burkitt's lymphoma cell lines (Raji, Ramos and Daudi) and one prostate carcinoma cell line (MPC 3). Additional evaluations were performed in two human breast cancer cell lines (MCF7 with wild-type p53 and VM4K with mutated p53) to determine whether the p53 tumor suppressor gene was required for efficient apoptosis induction. The present study demonstrated that mitoguazone induces apoptosis in all the different human cancer cell lines tested in a concentration- and time-dependent way, and triggers a p53-independent programmed cell death in the human breast cancer MCF7 cell line.
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PMID:Mitoguazone induces apoptosis via a p53-independent mechanism. 977 8

Overexpressed MDM2 inactivates wild-type (wt) p53 in various human tumors. However, whether and how the wild-type p53 can be activated by anticancer drug treatment in the presence of excess MDM2 is still unclear. In the present study, we showed that the topoisomerase II inhibitor of widely used anticancer drugs etoposide and doxorubicin activated wt p53 in BL2, a Burkitt's lymphoma cell line which overexpressed MDM2. Activation of p53 was followed by apoptosis in BL2 cells, while the same drug treatment did not induce apoptosis in Raji cells, another Burkitt's lymphoma cell line which carried mutant p53. Activation of p53 was accompanied by phosphorylation of p53 at Ser-15 and elevated p21 and MDM2, both of which were at least partly blocked by wortmannin, a kinase inhibitor against proteins with a PI3 kinase domain. Although MDM2 protein was rapidly cleaved and degraded after anticancer drug treatment, cotreatment with caspase inhibitor Z-VAD blocked degradation, while wt p53 remained activated, suggesting MDM2 degradation not to be essential for the activation of p53. Treatment with proteasome inhibitor stabilized p53 without being further phosphorylated. This p53 was co-immunoprecipitated with MDM2, but p53 activated by etoposide or doxorubicin barely complexed with MDM2. These results suggest that the wild-type p53 in MDM2-overexpressing cells can be activated by anticancer drugs through phosphorylation of p53, alleviating inhibitory action by MDM2, and activating caspases which in turn downregulates MDM2. The activation of p53 in MDM2-overexpressing tumor cells, which does not require the downregulation of MDM2, may have important implications in cancer therapy.
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PMID:Activation of p53 in MDM2-overexpressing cells through phosphorylation. 1054 21

Despite low radiation dose rates, radioimmunotherapy (RIT) has proven particularly effective in the treatment of malignancies, such as lymphoma. Apoptosis has been suggested to be a major mechanism for cell death from continuous low-dose rate radiation from radioimmunotherapy. The goal of this study was to examine Raji lymphoma xenografts for induction of apoptosis and modulation of apoptosis-related gene and protein expression in response to 67Cu-2IT-BAT-Lym-1 RIT. In preclinical and clinical trials, 67Cu-2IT-BAT-Lym-1 has shown an exceptionally long tumor residence time associated with substantial cumulated radiation doses. The Raji model mirrors human lymphomas that have mutant p53 and increased BCL2 expression. Untreated athymic BALB/c nu/nu mice and mice treated with 400 micrograms Lym-1, or 335-500 microCi 67Cu on less than 400 micrograms Lym-1 antibody, were observed for toxicity and response over 84 days. Subgroups of 4-5 mice were sacrificed at 3, 6 and 24 h after therapy so that tumors could be examined for poly(ADP-ribose) polymerase (PARP) and DNA ladder evidence for apoptosis and for BCL2, p53, p21, GADD45, TGF-beta 1 and c-MYC gene and protein expression. Untreated tumors had little evidence of apoptosis and Lym-1 had no effect on apoptosis or gene expression. 67Cu-2IT-BAT-Lym-1 RIT induced an overall response rate of 50% with tolerable toxicity, and 29% of the tumors were cured at cumulated tumor radiation doses of about 1800 cGy. Apoptosis was greatly increased in the RIT treated Raji xenografts as evidenced by cleavage of PARP to the characteristic 85 kD fragment at 3 and 6 h and by the DNA cleavage pattern. BCL2 gene and protein expression were substantially decreased at 3 and 24 h, respectively, after 67Cu-2IT-BAT-Lym-1 RIT despite only modest cumulated radiation doses (56 cGy at 3 h). Evidence for apoptosis preceded tumor regression by 4-6 days. In these therapy-resistant, human lymphoma tumors treated with 67Cu-2IT-BAT-Lym-1, apoptosis was convincingly demonstrated to be a major mechanism for the effectiveness of RIT and occurred by p53-independent mechanisms.
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PMID:Apoptosis-related gene and protein expression in human lymphoma xenografts (Raji) after low dose rate radiation using 67Cu-2IT-BAT-Lym-1 radioimmunotherapy. 1147 86

The effects of radiation and cytotoxic agents on telomerase activity in lymphoma cells were analyzed by a polymerase chain reaction-based telomeric repeat amplification protocol coupled with an enzyme-linked immunosorbent assay, reverse transcriptase-polymerase chain reaction for the expression of the catalytic subunit of telomerase (hTERT), and by Western blot analysis in three lymphoma cell lines (Jurkat, Raji, CEM-6). Telomeric repeat amplification protocol-enzyme-linked immunosorbent assay demonstrated high basal levels of telomerase activity in all cell lines compared to normal and activated peripheral blood lymphocytes. A significant decrease in telomerase activity was observed in all cell lines after exposure to vincristine for 24 hours. The decrease in telomerase activity paralleled the decrease in cell viability in Jurkat and CEM-6 cells but not in Raji cells. Radiation exposure inhibited the telomerase activity of Jurkat and CEM-6 cells whereas Raji cells were unaffected. Cell cycle analysis demonstrated a significant G(2)/M arrest by cisplatin, VP-16, and vincristine. In contrast to the decline in telomerase activity, the level of hTERT RNA and protein increased. Furthermore, the induction of hTERT was preceded by increased expression of the cyclin-dependent kinase inhibitor, p27/Kip1 protein, and p53. These results indicate that telomerase activity is down-regulated by anti-neoplastic agents in lymphoma cells, however expression of hTERT may not be correlated with telomerase activity. We also show that p27/Kip1 may be involved in the G(2)/M growth arrest induced by anti-neoplastic agents.
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PMID:Down-regulation of telomerase activity in malignant lymphomas by radiation and chemotherapeutic agents. 1148 97

The present study assessed the role of adenoviral vector-mediated wild-type p53 gene transfer in B lymphoma cells. Deficiency of p53-mediated cell death is common in human cancer contributing to both tumorigenesis and chemoresistance. Lymphoma cells are being considered as suitable targets for gene therapy protocols. Recently, we reported an adenoviral protocol leading to highly efficient gene transfer to B lymphoma cells. All lymphoma cell lines (n=5) tested here showed mutations in the p53 gene locus. The aim of this work was to transduce lymphoma cells with the wild-type p53 gene. Using this protocol, 88% of Raji, 75% of Daudi, and 45% of OCI-Ly8-LAM53 cells were transfected with the reporter gene green fluorescent protein at a multiplicity of infection of 200. The expression of green fluorescent protein in CA46 and BL41 cells was 27% and 42%, respectively. At this multiplicity of infection, growth characteristics of lymphoma cell lines were not changed significantly. In contrast, cells transduced with wild-type p53 gene showed an inhibition of proliferation as well as an increase in apoptosis. Cell loss by apoptosis after p53 gene transfer was up to 40% as compared to transduction with an irrelevant vector. In addition, we determined the effects of DNA damage produced by the DNA topoisomerase II inhibitor etoposide on wild-type p53 transfected lymphoma cells. In Ad-p53-transfected Raji cells, treatment with the drug resulted in a marked increase of cell loss in comparison to Ad-beta-Gal-transfected cells (45% vs. 77%). Interestingly, performing cytotoxicity studies, we could show an increased sensitivity of Raji and Daudi cells against immunological effector cells. In conclusion, transduction of wild-type p53 into lymphoma cells expressing mutated p53 was efficient and led to inhibition of proliferation and increase in apoptotic rate in some cell lines dependent on p53 mutation. This protocol should have an impact on the use of lymphoma cells in cancer gene therapy protocols.
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PMID:Effects of adenoviral wild-type p53 gene transfer in p53-mutated lymphoma cells. 1149 63

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