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 p53R2 gene encodes the ribonucleotide reductase (RR) small subunit 2 homologue, and is induced by several stress signals activating p53, such as DNA-damaging agents. The p53R2 gene product causes an increase in the deoxynucleotide triphosphate (dNTP) pool in the nucleus, which facilitates DNA repair and synthesis. We hypothesized that p53R2 would be a good molecular target for cancer gene therapy. In this study, three human oral cancer cell lines (SAS, HSC-4 and Ca9-22), a human breast cancer cell line MCF-7, and a normal human fibroblast cell line NHDF were tested. We silenced the expression of p53R2 with the highly specific post-transcriptional suppression of RNA interference (RNAi). We investigated p53R2 expression with the reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The sensitivity to anticancer agents was evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of p53R2 showed no association with the mutational status of p53. The cancer cell lines with higher p53R2 expression were more resistant to 5-FU. RNAi-mediated p53R2 reduction selectivity inhibited growth and enhanced chemosensitivity in cancer cell lines but not in normal fibroblasts. These results suggest that basal transcription of p53R2 could be associated with the sensitivity to anticancer agents. Moreover, we assessed the possibility that p53R2 would be a good molecular target, and report that RNAi targeting of p53R2 could be useful for oral cancer gene therapy.
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PMID:Silencing of the p53R2 gene by RNA interference inhibits growth and enhances 5-fluorouracil sensitivity of oral cancer cells. 1589 Feb 38

Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells, but the underlying mechanism has not been fully elucidated. The present study aimed to evaluate the in vitro anti-tumor activity of a standardized aqueous ethanol extract prepared from CV on four breast cancer cell lines using MTT assay, and test whether the mechanism involves apoptosis induction and modulation of p53 and Bcl-2 protein expressions using cell death detection ELISA, p53 and Bcl-2 ELISAs respectively. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of three breast tumor cell lines, with ascending order of IC50 values: T-47D, MCF-7, MDA-MB-231, while BT-20 cells were not significantly affected. Tumoricidal activity of the CV extract was found to be comparable to a chemotherapeutic anti-cancer drug, mitomycin C. Nucleosome productions in apoptotic MDA-MB-231, MCF-7 and T-47D cells were significantly augmented in a time-dependent manner and paralleled the anti-proliferative activity of CV extract. Expression of p53 protein was significantly upregulated only in T-47D cells treated with the CV extract in a dose- and time-dependent fashion, but not in MCF-7 (except at 400 mug/ml after 16 h) and MDA-MB-231 cells. The CV extract significantly induced a dose-dependent downregulation of Bcl-2 protein expression in MCF-7 and T-47D cells, but not in MDA-MB-231 cells. These results suggested that apoptosis induction, differentially dependent of p53 and Bcl-2 expressions, might be the possible mechanism of CV extract-mediated cytotoxicity in human breast cancer cells in vitro.
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PMID:Differential anti-tumor activity of coriolus versicolor (Yunzhi) extract through p53- and/or Bcl-2-dependent apoptotic pathway in human breast cancer cells. 1590 82

Vitamin D analogs 12 and 13 having a spiro ring in the side chain, various spirostanols 18-21, 26, 27, 29 and 37, and furostanols 34-36 having SCN and SeCN groups at the 26 position were prepared from diosgenin 1 via (20S,22R,25R)-spirost-1alpha,2alpha-epoxy-4,6-dien-3-one 19 as a key intermediate. The cytotoxic activities of these derivatives as well as 1 on scarcely P-gp-expressed HCT 116 cells and P-gp-overexpressed Hep G2 cells were examined by MTT assay. Furostanols 34 (IC(50) value: 4.9+/-0.3 microM) and 36 (IC(50) value: 1.3+/-0.2 microM) exhibited marked cytotoxic effects on HCT 116 cells, and spirostanol 29 (IC(50) value: 2.4+/-0.8 microM) and furostanol 36 (IC(50) value: 2.8+/-0.4 microM) on Hep G2 cells. Furthermore, the effects of vitamin D analog 12, spirostanol 26 and furostanol 36 on apoptosis-signaling pathways were investigated. Compounds 12 and 26 overexpressed p53 and Bax mRNAs, while compound 36 overexpressed only Bax mRNA.
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PMID:Preparations of vitamin D analogs, spirostanols and furostanols from diosgenin and their cytotoxic activities. 1593 1

Polyamines are powerful modulators of both growth and survival in mammalian cells. In this study, we investigated the possibility of attenuating the process of apoptosis in bone marrow stromal cells (BMSCs), which comprise mesenchymal stem cells, by reducing the intracellular levels of polyamines. BMSCs were isolated from rat femurs and expanded for 12 days. At this time, BMSCs were CD34neg, CD45neg, and mostly CD90pos. BMSCs were grown for an additional 2 days in the presence of 1 mM alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, which reduced the content of both putrescine and spermidine by nearly 90%. DFMO treatment progressively slowed down BMSC proliferation, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, without arresting their growth completely. The effect of polyamine depletion on caspase-3 activity was evaluated in BMSCs after treatment with 500 U/ml tumor necrosis factor-alpha (TNFalpha) and 5 microM MG132, an inhibitor of proteasome. Caspase-3 activity increased linearly over a period of 24-hour stimulation (p<.01), but this augmentation was blunted by 50% after DFMO administration (p<.05). The effect of DFMO on TNFalpha/MG132-induced upregulation of caspase-3 activity was reversed by the addition of 100 microM putrescine, confirming that polyamines were really involved in the apoptotic process. Also, the number of apoptotic BMSCs after TNFalpha/MG132 treatment, as determined by terminal transferase-mediated dUTP nick end-labeling (TUNEL) assay, were threefold reduced after polyamine depletion (p<.05). On the contrary, DFMO did not affect the MG132-mediated increase in p53 abundance, nor its translocation to the nucleus. Thus, polyamine depletion can be considered a useful tool for counteracting programmed cell death in BMSCs without involving the p53 proapoptotic protein.
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PMID:Polyamine depletion reduces TNFalpha/MG132-induced apoptosis in bone marrow stromal cells. 1594 55

Thallium acetate is a known neurotoxic agent. In this study, we investigated the mechanisms by which thallium acetate induces cell cycle arrest and cell apoptosis in cultured LC6 glioma cells. Exposure of C6 glioma cells to thallium acetate decreased cell viability as demonstrated by the MTT assay. Incubation of thallium acetate arrested cell cycle progression at the G2/M phase and caused cellular apoptosis at 300 microM as determined by trypan blue exclusion and flow cytometric analysis. The G2/M arrest was associated with a decrease in expression of CDK2 protein and an upregulation of p53 and the CDK inhibitor p21(Cip1), but not p27(Kip1). Thallium acetate did not alter the protein levels of cyclin A and B; cyclin D1, D2, and D3; and CDK4 expression in C6 glioma cells. Incubation of C6 glioma cells with thallium acetate upregulated the expression of proapoptotic proteins Bad and Apaf and downregulated the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. In conclusion, these data suggest that thallium acetate inhibits cell cycle progression at G2/M phase by suppressing CDK activity through the p53-mediated induction of the CDK inhibitor p21(Cip1). Impairment of cell cycle progression may trigger the activation of a mitochondrial pathway and shifts the balance in the Bcl-2 family toward the proapoptotic members, promoting the formation of the apoptosome and, consequently, apoptosis.
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PMID:Thallium acetate induces C6 glioma cell apoptosis. 1596 99

Nitric oxide has been reported to have cytotoxic effects in several tumor cells. The objective of this study was to investigate the effects of exogenous nitric oxide on apopotosis in oral squamous cell carcinoma cells and to reveal its possible mechanism. Tca8113 cells were cultured with various concentrations of nitric oxide that were released from sodium nitroprusside (SNP). Nitrite/nitrate levels in the culture supernatant were determined using a commercial available nitric oxide kit. Cellular proliferation was determined by MTT assay. Apoptosis was detected by flow cytometry. Expression of inducible nitric oxide synthase (iNOS) was determined by immunocytochemistry. p53 expression was assessed by Western blot. SNP can release nitric oxide into the culture medium in a dose-dependent manner. Nitric oxide remarkably inhibits proliferation in a dose and time-dependent manners and lead to apoptosis of the Tca8113 cell. The p53 expression was elevated accompanying by the increased apoptotic cells. No difference of iNOS was found whether or not the cells were treated with SNP. Exogenous nitric oxide had an inhibitory effect on Tca8113 cells proliferation in a dose and time-dependent manners and possibly via p53 dependent apoptosis pathway. Exogenous nitric oxide had no significant effect on cellular iNOS protein.
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PMID:Nitric oxide induces oral squamous cell carcinoma cells apoptosis with p53 accumulation. 1597 83

The nitroimidazole radiosensitizer CI-1010 ((R)-alpha-[[(2-bromoethyl)-amino]methyl]-2-nitro-1H-imidazole-1-ethanol monohydrobromide) causes selective, irreversible, retinal photoreceptor apoptosis in vivo. The mouse 661 W photoreceptor cell line was used as a neuronotypic model of CI-1010-mediated retinal degeneration. Exposure to CI-1010 for 24 h induced apoptosis in 661 W cells, as determined by ultrastructural analysis, agarose electrophoresis and analysis of TUNEL-positive nuclei. CI-1010 caused a loss of viability in 661 W cells, as measured by the reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). A clear link was established between the onset of apoptosis and activity of caspase-3 and caspase-8, prior to poly[ADP-ribose]polymerase (PARP) cleavage. Pretreatment with caspase inhibitors, ZVAD.fmk or DEVD-CHO, prevented morphological changes in most CI-1010-treated cells. Evaluation of mitochondrial inner membrane potential (Deltapsi(m)) in live 661 W cells using the fluorescent dye, tetramethylrhodamine methyl ester revealed retention of (Deltapsi(m)) until after caspase activation. Absence of cytochrome c in the cytoplasm in treated cells further supports the hypothesis of a mitochondrial-independent mechanism of cell death. Significant increase in DNA crosslinks observed in 661 W cells correlates with induction and phosphorylation of p53 at multiple serine sites. Cell cycle analysis of 661 W cells reveals a G(2) arrest in response to CI-1010-induced DNA damage and neuronal cell death. Increased protein expression of Bax, Fas, and FasL, concomitant to the loss of Bcl-xL in treated 661 W cells may be modulated by p53. This study evaluates in vitro mechanisms of CI-1010-induced cell death in photoreceptors and provides evidence in support of a p53-linked activation of caspase-3 in response to DNA damage caused by CI-1010.
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PMID:Photoreceptor cell apoptosis induced by the 2-nitroimidazole radiosensitizer, CI-1010, is mediated by p53-linked activation of caspase-3. 1612 43

The cytotoxic effects of Triphala (TPL), an Indian Ayurvedic formulation with known anti-cancer properties, has been investigated on two human breast cancer cell lines differing in their p53 status. In vitro studies showed that MCF 7 with wild type p53 was more sensitive to TPL than T 47 D, which is p53 negative. TPL induced loss of cell viability was determined by MTT assay. After 72h incubation, the IC 50 values for MCF 7 was found to be approximately 8microg/ml and that for T 47 D was approximately 26microg/ml. Moreover, TPL inhibited the clonogenic growth of MCF 7 cells, which was significantly recovered by pifithrin-alpha, the p53 inhibitor. However, pifithrin-alpha, did not modify TPL induced cytotoxicity in T 47 D cells. Exogenous addition of antioxidants, glutathione (GSH) and N-Acetyl-Cysteine (NAC) inhibited the anti-proliferative ability of TPL in both MCF 7 and T47 D. Annexin-V and propidium iodide double staining of cells treated with TPL for 2h revealed that TPL induced significant apoptosis in both the cell lines in a dose dependant manner but magnitude of apoptosis was significantly higher in MCF 7 than in T 47-D cells. TPL was also found to induce dose and time dependent increase in intracellular reactive oxygen species in both the cell lines. Present results have demonstrated that MCF 7 and T 47 D cells exhibited differential sensitivity to TPL, which seems to be dependant on their p53 status. Inhibition of anti-proliferative ability of TPL by antioxidants suggests a role for TPL induced ROS in the induction of apoptosis. It is concluded that p53 status of cancer cells formed an important factor in predicting the response of cancer cells to prooxidant drugs.
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PMID:Cytotoxic response of breast cancer cell lines, MCF 7 and T 47 D to triphala and its modification by antioxidants. 1613 98

The second open reading frame of avian reovirus S1 gene segment encodes a 17 kDa non-structural protein, named p17. The biological role of p17 is fully unknown so far. Using trypan blue dye exclusion and MTT assay, we demonstrated that the ectopic expression of p17 results in the reduction of viable cell number and cell proliferation rate of Vero, BHK, 293, and HeLa cells. Measurement of LDH activity and DNA fragmentation analysis revealed that p17 expression did not cause cell death or apoptosis. These data indicated that the p17 possessed the growth retardation function. Semi-quantitative RT-PCR and Western blotting revealed that p17-expressing cells induced the expression of CDK inhibitor p21cip1/waf1 in a time- and dose-dependent manner, but the transcripts of CDK inhibitor p15INK4b, p16INK4a, or p27kip were not altered. In the presence of p17, the p53 protein level and p53-driven reporter activity were elevated significantly. Dominant negative p53 alleviated the p21 accumulation, p53 activation, and growth inhibition effect induced by p17. Taken together, these studies revealed a possible intrinsic function of p17 in growth regulation through the activation of p53 and p21cip1/waf1.
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PMID:Retardation of cell growth by avian reovirus p17 through the activation of p53 pathway. 1614 10

Leishmania, an obligate intracellular parasite of host macrophages, infects the macrophage through receptor-mediated phagocytosis that either activates or deactivates macrophages to eliminate the parasite or allow the parasite to grow intracellularly. ICAM-L, an intercellular adhesion molecule from L. amazonensis, results in lower MTT tests and proliferative responses of macrophages when incubated in vitro. The inhibition of cell proliferation, however, results from temporary retardation of the cell cycle progression at the G1 to S phase transition rather than cell death. The retardation is due to the upregulation of two CKI proteins, p21 and p27, in a p53-independent manner which, control the G(1) to S phase transition checkpoint.
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PMID:Retardation of cell cycle progression of macrophages from G1 to S phase by ICAM-L from Leishmania. 1618 62


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