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)

Even though we previously reported that dietary lutein can inhibit mammary tumor growth, the mechanism of this action was unknown. Here, we studied the action of dietary lutein through its possible regulation of apoptosis and angiogenesis. Female BALB/c mice were fed a semi-purified diet containing 0 (control), 0.002 or 0.02% lutein (n = 20/treatment) for 2 weeks prior to inoculation with 100,000 -SA mouse mammary tumor cells into the right mammary fat pad. Tumor volume was measured daily until day 50 postinoculation when all mice were killed. Angiogenesis and apoptosis activities in the tumors were measured by immunohistochemistry. Apoptosis and necrosis of blood lymphocytes were quantitated by flow cytometry using Annexin V-FITC and propidium iodide staining. The expression of the p53, Bax and Bcl-2 mRNA was measured by RT-PCR amplification. Lutein was not detectable in the plasma, liver or tumor of unsupplemented mice, but increased in a dose-dependent manner in lutein-supplemented mice. Mice fed lutein had tumors that were 30 to 40% smaller (p < 0.05) on day 50 post-inoculation compared to unsupplemented mice. Final tumor volume was lowest in mice fed 0.002% lutein. Mice fed lutein had higher apoptotic activity in the tumors but lower apoptotic activity in blood lymphocytes as compared to unsupplemented animals. These observations were supported by the observed increase in the expression of the proapoptotic genes, p53 and Bax, together with a decrease in the expression of the antiapoptotic gene, Bcl-2, and consequently an increase in the Bax:Bcl-2 ratio in tumors from lutein-fed mice. Furthermore, lutein-fed mice also had lower (p < 0.05) angiogenic activity in the tumors as compared to unsupplemented mice. The greatest beneficial effect on apoptosis and angiogenesis was observed with mice fed 0.002% lutein. Therefore, dietary lutein, especially at 0.002%, inhibited tumor growth by selectively modulating apoptosis, and by inhibiting angiogenesis.
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PMID:Dietary lutein inhibits mouse mammary tumor growth by regulating angiogenesis and apoptosis. 1292 72

We demonstrated that enhancement of X-ray-induced apoptosis/rapid cell death by wortmannin accompanied by increased activation of JNK/SAPK in human leukemia MOLT-4 cells. Rapid cell death/apoptosis was determined either by the dye exclusion test or by the appearance of Annexin V-positive cells and cleaved PARP fragments. Enhancement was observed only at higher concentrations of wortmannin, i.e. 1 microM or more. At these high concentrations, both DNA-PK and ATM were inhibited. X-ray-induced phosphorylation of Ser 15 of p53/TP53, accumulation of both p53/TP53 and p21/WAF1/CDKN1A, and phosphorylation of XRCC4 were all suppressed. The enhancement of apoptosis/rapid cell death by wortmannin was prevented by addition of caspase inhibitors, Z-VAD-FMK or Ac-DEVD-CHO, or by transfection and overexpression of mouse Bcl2, which is known as an anti-apoptosis protein. The requirement for a high concentration of wortmannin, i.e. 1 microM or more, indicates that inhibition of both DNA-PK and ATM was necessary for the enhanced apoptosis/rapid cell death. Phosphorylation of AKT/PKB was completely suppressed at a much lower concentration, i.e. 0.1 microM wortmannin, where no enhancement of X-ray-induced apoptosis/rapid cell death was observed. On the other hand, X-ray-induced phosphorylation of JNK and its kinase activity as well as apoptosis/rapid cell death were all significantly enhanced only at high concentrations of wortmannin, i.e. 1 microM or more. Furthermore, the extent of enhancement of both JNK phosphorylation and of apoptosis/rapid cell death by wortmannin was less in Rh1a cells, which are ceramide- and radiation-resistant variant cells compared to the parental MOLT-4 cells. Therefore, activation of the JNK pathway was considered important for the enhancement of X-ray-induced apoptosis/rapid cell death of MOLT-4 cells by wortmannin, because of the requirement for a higher concentration of wortmannin than that required for inhibition of AKT phosphorylation. The suppression of the AKT-dependent pathway by wortmannin may have some underlying role in activating the JNK pathway toward the enhancement of cell death in the current system.
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PMID:Wortmannin-enhanced X-ray-induced apoptosis of human T-cell leukemia MOLT-4 cells possibly through the JNK/SAPK pathway. 1296 28

Amifostine is used as a cytoprotective agent in cancer treatments. Amifostine protects from apoptosis in some models and has been used as hematopoiesis stimulator in myeloid malignancies. As the apoptosis induced by many antitumoral agents is mediated by p53, we studied the effect of amifostine on p53-mediated apoptosis. We used human myeloid leukemia K562 and NB4 cells expressing the temperature-conditional p53-Val(135) mutant. Both cell lines undergo apoptosis at 32 degrees C due to the presence of p53 in wild-type conformation. We found that amifostine dramatically reduced apoptosis by p53 in both cell lines, as assessed by cell morphology, annexin V binding, fraction of sub-G(1) cells, and DNA laddering. To explore the mechanism responsible for this apoptosis protection, we tested the effect of amifostine on p53 transcriptional activity. We found that amifostine reduced p53-mediated transactivation of target promoters in NB4 and K562. Macroarray analysis confirmed that several p53 target genes as p21(Waf1), mdm2, gadd45, pig8, and pig3 were down-regulated at the mRNA level by amifostine in NB4 and K562. Also, c-myc was up-regulated by amifostine in K562 in the presence of p53, consistently with the impairment of p53-mediated apoptosis exerted by c-Myc in these cells. We conclude that amifostine impairs p53-dependent apoptosis of myeloid leukemia cells by reducing the activation of apoptosis-related genes. Our results open the possibility that amifostine could reduce the effectiveness of antitumoral treatments when it is dependent on active p53.
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PMID:Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells. 1455 8

It has been demonstrated recently that rabbit renal proximal tubule cells (RPTC) express a novel Ca(2+)-independent phospholipase A(2) (iPLA(2)) whose activity localizes to the endoplasmic reticulum (ER-iPLA(2)) and is similar to group VIB PLA(2). In this study, the expression of group VIB PLA(2) was examined and the role of ER-iPLA(2) in cisplatin-induced apoptosis was determined. Cisplatin induced both time- and concentration-dependent RPTC apoptosis as determined by p53 nuclear localization, annexin V staining, caspase 3 activity, and chromatin condensation. Inhibition of ER-iPLA(2) with bromoenol lactone (5 microM) reduced cisplatin-induced annexin V binding 40%, chromatin condensation 55%, and caspase 3 activity 42%, but had no effect on p53 nuclear localization. Treatment of RPTC with the protein kinase C stimulator phorbol 12-myristate 13-acetate increased the activity of ER-iPLA(2) 2-fold and increased cisplatin-induced RPTC apoptosis. These studies demonstrate that group VIB PLA(2) is expressed in RPTC and suggest that RPTC ER-iPLA(2) is the rabbit homolog of group VIB PLA(2). These data also demonstrate that ER-iPLA(2) acts downstream of p53 and upstream of caspase 3 to mediate cisplatin-induced RPTC apoptosis. Finally, ER-iPLA(2) seems to be regulated by protein kinase C.
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PMID:Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis. 1463 37

Hydroxyurea (HU) is an inhibitor of nucleotide synthesis extensively used to control the chronic phase of myeloid leukemia. This antimetabolite has been employed in the clinic for several decades but in recent years the leukemogenic potential of HU has been suspected. In the present study, a B-lymphoblastoid cell line transformed by the Epstein-Barr virus was used to investigate the apoptotic effects of HU and delineate some of the molecular pathways implicated in the cytotoxic action. The cell line, characterized by immunophenotyping, cytogenetic and fluorescence in situ hybridization (FISH) studies, showed no chromosomal abnormalities, even after a prolonged exposure to HU. Different flow cytometry assays were used to measure HU-induced impairment of the cell cycle, inhibition of DNA synthesis, and the occurrence of apoptosis. The treatment with HU leads to the appearance of a hypo-diploid DNA content peak (sub-G1) characteristic of the apoptotic cell population. The drug also induces a cell block in S phase as measured by 5-bromo-2'-deoxyuridine (BrdU) incorporation. Inhibition of DNA synthesis precedes induction of apoptosis by HU. A drug-induced loss of plasma membrane asymmetry was characterized by flow cytometry using annexin V-FITC to stain phosphatidylserine residues. The implication of the antiapoptotic protein Bcl-2 and the tumor suppressor p53 in the development of HU-mediated apoptosis was also evidenced. The drug appears to promote cell death by regulating the expression levels of these two proteins. Different criteria define the apoptotic response of the lymphoblastoid cells to the treatment with HU. However, the extent of drug-induced cell death is limited, and no DNA fragmentation and no activation of the caspase cascade was observed in this model. Beyond the specific interest in HU-induced apoptosis, the work reported here illustrates the utility of the EBV immortalization process to investigate the pharmacological activity of specific drugs from clinical samples.
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PMID:Hydroxyurea-induced apoptosis in an EBV-immortalized lymphoblastoid cell line. 1497 55

p53 plays an important role in tumour suppression in cells exposed to some genotoxic stresses. We found that the p53 protein level was increased in a variety of cell lines infected with human herpesvirus 6 (HHV-6). Because the elevation in p53 began very soon after infection (4 h) and did not occur with UV-inactivated virus infection, it appeared to require the expression of one or more viral immediate-early (IE) genes. To elucidate the mechanism of p53 induction, we investigated its regulation at the protein level. Pulse-chase analysis showed that the stability of p53 increased in HHV-6-infected cells. In addition, the ubiquitination of p53 decreased after infection, indicating that the stability of p53 was increased through deubiquitination. We showed by confocal microscopy that the additional p53 mainly localized to the cytoplasm and that p53 was retained in the cytoplasm even after UV irradiation, but that it translocated into the nucleus in mock-infected cells. Furthermore, DNA fragmentation analysis, a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay and annexin V staining showed that infected cells were resistant to UV-induced apoptosis. These results lead us to propose that HHV-6 has a mechanism for retaining p53 within the cytoplasm and protects the infected cells from apoptosis.
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PMID:Productive human herpesvirus 6 infection causes aberrant accumulation of p53 and prevents apoptosis. 1503 30

S100 proteins belong to the EF-hand Ca2+-binding protein family and are involved in the regulation of a variety of cellular processes. Individual S100 proteins are expressed in cell- and tissue-specific manners, and functional deterioration of S100 proteins leads to a number of human diseases, including cancer. We previously demonstrated that S100C/A11 was translocated to nuclei and inhibited DNA synthesis in human keratinocytes when exposed to high Ca2+. In the present study we examined the effects of synthetic partial peptides of S100C/A11 on human carcinoma cell lines. Only an N-terminal peptide with 19 amino acid residues (MAK19) showed cytotoxicity to the cell lines in dose- and time-dependent manners when introduced into cells by flanking the HIV-TAT protein transduction domain (TAT-MAK19). Pulse field electrophoresis revealed that DNA of the treated cells was partially degradated. Annexin V, a marker of cellular apoptosis, was detected in the cells treated with TAT-MAK19 by immunostaining and flow cytometry. The induction of apoptotic cell death was apparently independent of p53, p21WAF1/CIP1, and caspase activity, but treatment with TAT-MAK19 resulted in partial translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. These results indicate that MAK19 induces apoptosis in human cell lines and may therefore lead to the establishment of a new molecular target for the treatment of human cancer.
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PMID:Introduction of an N-terminal peptide of S100C/A11 into human cells induces apoptotic cell death. 1524

Angelica sinensis (Oliv.) Diels, a traditional Chinese medicine, has been widely prescribed in treatment of gynecological diseases. Bio-based assays for extracts of Angelica sinensis showed that the acetone extract (AE-AS) had dose-dependently antiproliferative effect on A549, HT29, DBTRG-05MG and J5 human cancer cells. The IC50 values of AE-AS on mentioned cancer cells ranged from 35 to 50 microg/ml after 24 h of treatment. After 72 h of exposure, AE-AS (40 microg/ml) significantly reduced A549 cell proliferation to 24 +/- 3.2% of control. In A549 cells, the cell cycle analysis showed that AE-AS induced a significant increase in the number of cells in G0/G1, with a concomitant decrease in the number of cells in S phase. AE-AS-induced chromatin changes and apoptosis of A549 cells were confirmed by Hoechst 33342 DNA staining and annexin V staining. A549 cells treated with AE-AS caused activation of caspase-9 and -3, and AE-AS-induced apoptosis could be inhibited by the broad-spectrum caspase inhibitor, z-VAD-fmk. The Western blot indicated the AE-AS-triggered apoptosis is mediated via suppression of Bcl-2 oncoprotein expression rather than p53 or Bax. Besides, AE-AS decreased the levels of cdk4 protein was observed. These results indicate that the AE-AS could induce G1/S arrest and activate the mechanism of apoptosis in human cancer cells. Extracts obtained from different methods of fractionation might possess distinct bioactivity. These results prompted us to further evaluate the in vivo anticancer effects and elucidate the chemical composition profile of AE-AS.
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PMID:Acetone extract of Angelica sinensis inhibits proliferation of human cancer cells via inducing cell cycle arrest and apoptosis. 1526 63

Cisplatin (CDDP) is among the most widely used and most effective chemotherapeutic agent for many types of human cancer. Because killing cancer cells by chemotherapy is principally executed by apoptosis, a defective apoptotic program might acquire drug resistance. Flow cytometric Annexin V assay demonstrated that HEp-2 cells (human laryngeal cancer) were persistently resistant to CDDP as compared to HeLa cells (human uterine cervical cancer), despite the same histological type and wild-type p53 status. CDDP treatment caused steady induction of p53 protein in both cancer cell types, although it was more dramatic in CDDP-resistant HEp-2 cells, which was correlated well with p53 Ser15 phosphorylation, but not with the expression level of HPV type 18 E6 oncoprotein in these cells. Importantly, CDDP differently activated caspase cascades between HEp-2 and HeLa cells. CDDP activated the caspase-8 pathway through TNFR superfamily receptors such as Fas, but not caspase-9 in HeLa cells. On the other hand, the caspase-9 pathway was significantly activated in HEp-2 cells, although the activation of caspase-8 by CDDP was deficient. This different response to CDDP in caspase-8 activation was not related with the expression level of either Fas or FasL in these cells. We concluded from these results that loss of the caspase-8 activation pathway in HEp-2 cells was a possible mechanism for its resistance to CDDP-induced apoptosis. The caspase-8 pathway might play an important role in CDDP-induced apoptosis in HPV-positive human squamous cell carcinomas.
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PMID:Loss of caspase-8 activation pathway is a possible mechanism for CDDP resistance in human laryngeal squamous cell carcinoma, HEp-2 cells. 1528 75

In the present studies, the role of oxidative stress in radiosensitization by a combination of 2-DG and 6-aminonicotinamide (6-AN) was examined in a human glioma cell line (BMG-1: wild type p53). Presence of 2-DG or 6-AN for 4 hr after irradiation (gamma ray 2.5 Gy) significantly enhanced the radiation-induced cell death by 18% and the combination (2-DG + 6-AN) enhanced the cell death by 35%. Neither 2-DG nor 6-AN had any further significant effect on the glutathione levels in irradiated cells. However, the combination (2-DG + 6-AN) caused a significant decrease in GSH content, increase in GSSG levels, and enhanced the superoxide radical generation under these conditions. The enhanced cell death caused by the combination (2-DG + 6-AN) mainly resulted by the process of apoptosis as revealed by annexin V binding and was associated with elevated levels of Cyclin B1. However, no significant change was observed in the levels of Bcl-2. Thus, for the first time, our results have demonstrated that the radiosensitizing effects of these modifiers could also be mediated through alterations in the oxidative stress besides energy limited inhibition of repair and recovery processes.
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PMID:Contribution of oxidative stress to radiosensitization by a combination of 2-DG and 6-AN in human cancer cell line. 1532 Apr 90

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