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)

Increasing evidence provides support for oxidative stress to be closely linked to apoptosis. Reactive oxygen species (ROS) are thought to be involved in many forms of programmed cell death. Though heat shock is a universal phenomenon, BC-8, a macrophage-like cell line failed to mount a typical heat shock response. In the absence of heat shock proteins and functional p53, BC-8 cells undergo apoptosis through CD95 signaling. In the present study, we have investigated the role of ROS in the regulation of apoptosis in these cells. We show that cells transfected with hsp70 and functional p53 are resistant to heat-induced apoptosis through inhibition of CD95 expression and ROS induction. Furthermore, apoptosis in BC-8 cells resulted in two bursts of ROS generation, one correlated with heat stress and intracellular depletion of GSH and the other with Bax overexpression and cytochrome c release. Antioxidants could not protect these cells from heat-induced apoptosis and the death pathway seems to be dependent on initial signaling cascade subsequently altering the intracellular redox. Hence, our data suggest that ROS generation in BC-8 cells upon heat shock is facultative but not obligatory for apoptosis.
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PMID:A cross talk between cellular signalling and cellular redox state during heat-induced apoptosis in a rat histiocytoma. 1182 47

Intrinsic chemoresistance constitutes a major problem in the therapy of malignant gliomas. In vitro experiments with four astrocytoma/glioblastoma (AC/GBM) cell lines revealed that the chemoresistance of two cell lines, A172 and T98G, to cisplatin and etoposide was due to resistance to drug-induced apoptosis. In contrast, all the AC/GBM cell lines tested were sensitive to treatment with the lipophilic ether lipid erucylphosphocholine, ErPC. ErPC-induced apoptosis was independent of wild-type p53-signaling and triggering of the CD95/CD95 ligand (CD95L) system. Inhibition of protein and RNA synthesis by cycloheximide and actinomycin D did not abrogate ErPC-induced apoptosis. However, expression of members of the bcl-2 protein family was modulated during ErPC treatment. Activation of caspase 3 and mitochondrial alterations were central to ErPC-induced apoptosis. We conclude that ErPC-induced activation of the mitochondrial pathway enables cell death in the chemoresistant AC/GBM cells.
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PMID:Erucylphosphocholine-induced apoptosis in chemoresistant glioblastoma cell lines: involvement of caspase activation and mitochondrial alterations. 1184 99

Activation of the p53-stress response pathway has been implicated in excitotoxic neuronal cell death. Recent studies have demonstrated an age-dependent induction of both p53 mRNA and protein in the rat brain following lithium-pilocarpine-mediated status epilepticus (LPSE). We investigated whether other proteins that have been shown to participate in the p53 cascade are induced by LPSE. We used immunohistochemistry to examine the expression of Mdm2, Bax, CD95/Fas/APO-1, ATM, Ref-1 and ubiquitin. A significant increase in nuclear Mdm2 immunoreactivity, which colocalized with p53, was observed in cells within hippocampal pyramidal cell layers, dentate gyrus, piriform cortex, amygdala and thalamus. Dual immunofluorescence microscopy revealed a reduction in free ubiquitin expression in cells with p53 and Mdm2 accumulation. Increased immunoreactivity for CD95/Fas/APO-1 and Bax was also detected in the same p53-positive cells. Moreover, expression of Ref-1 and ATM, which are involved in the response to oxidative stress-induced DNA damage and regulation of p53 function, were increased. Colocalization of Ref-1 and p53 suggests that Ref-1 might activate p53 function in LPSE-induced neurodegeneration. In contrast, ATM immunoreactivity was predominantly cytoplasmic suggesting that ATM may not directly modulate p53 activity in injured neurons. These results extend our previous observations with regard to activation and stabilization of p53 in injured central nervous system neurons. The data indicate that p53 induction following LPSE may activate downstream pro-apoptotic genes leading to neurodegeneration.
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PMID:Immunohistochemical study of p53-associated proteins in rat brain following lithium-pilocarpine status epilepticus. 1185 39

Previously we have reported that deregulated expression of c-myc in normal and leukemic myeloid cells blocked differentiation and, concomitantly, induced p53-independent apoptosis. Here, we show that this morbidity was due to premature recruitment of the Fas/CD95 cell death pathway which normally operates to induce apoptosis at the end of the terminal myeloid differentiation program. Analysis of the regulated components of this pathway revealed that IL6-mediated induction of differentiation resulted in rapid cell surface expression of CD95 receptor. Deregulated c-myc prevented the downregulation of CD95 ligand by maintaining its transcription, but caused premature downregulation of c-FLIP. First, the Type II (mitochondria-dependent, bcl-2-sensitive) and, then, the Type I (mitochondria-independent, bcl-2-insensitive) pathway were activated. Stable exogenous c-FLIP expression completely rescued the apoptotic phenotype. Furthermore, when the deregulated c-myc transgene was stably transduced into bone marrow cells from Fas(lpr/lpr) (CD95 receptor mutant) and FasL(gld/gld) (CD95 ligand mutant) mice, cell death was significantly suppressed relative to c-myc-transduced wild type bone marrow cells upon induction of differentiation. These data indicate that c-myc-mediated apoptosis associated with blocks in myeloid differentiation is dependent on the Fas/CD95 pathway. Our findings offer important new insights into understanding how deregulated c-myc alters normal blood cell homeostasis, and how additional mutations might promote leukemogenesis.
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PMID:Deregulated c-Myc prematurely recruits both Type I and II CD95/Fas apoptotic pathways associated with terminal myeloid differentiation. 1189 89

The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas.
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PMID:Fas/CD95-mediated apoptosis in human glioblastoma cells: a target for sensitisation to topoisomerase I inhibitors. 1191 40

Although ganciclovir (GCV) is most often used in suicide anticancer gene therapy, the mechanism of GCV-induced cell killing and apoptosis is not fully understood. We analysed the mechanism of apoptosis triggered by GCV using a model system of CHO cells stably transfected with HSV-1 thymidine kinase (HSVtk). GCV-induced apoptosis is due to incorporation of the drug into DNA resulting in replication-dependent formation of DNA double-strand breaks and, at later stages, S and G2/M arrest. GCV-provoked DNA instability was likely to be responsible for the observed initial decline in Bcl-2 level and caspase-9/-3 activation. Further decline in the Bcl-2 level was due to cleavage of the protein by caspase-9, as demonstrated by use of caspase inhibitors and transfection with trans-dominant negative caspase expression vectors. Bcl-2 cleavage resulted in the appearance of a pro-apoptotic 23 kDa Bcl-2 fragment and in excessive cytochrome c release, dephosphorylation of BAD, cleavage of PARP and finally DNA degradation. Since Fas/CD95 and caspase-8 were only slightly activated we conclude GCV-induced apoptosis to occur in this cell system mainly by activating the mitochondrial damage pathway. This process is independent of p53 for which the cells are mutated. Caspase-9 mediated cleavage of Bcl-2 accelerates the apoptotic process and may explain the high potential of GCV to induce apoptosis. Data are also discussed as to implications for HSVtk gene therapy utilizing GCV.
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PMID:Ganciclovir-induced apoptosis in HSV-1 thymidine kinase expressing cells: critical role of DNA breaks, Bcl-2 decline and caspase-9 activation. 1194 97

Interferon-gamma (IFN-gamma), as one of interferon family that regulates antiviral, antiproliferative, and immunomodulatory responses, has been implicated for the growth regulation of ovarian cancer cells. However, the molecular mechanisms are not yet fully defined. To analyze detailed mechanisms, the ovarian cancer cell lines (2774, PA-1, OVCAR-3, and SKOV-3) were treated with IFN-gamma. The growth of 2774 was most effectively suppressed than that of other cells in both time-course and dose-dependent experiments. The order of sensitivity in other cells was PA-1 >> OVCAR-3 > SKOV-3 (not responded at all). The DNA fragmentation and DAPI staining assays suggested that the IFN-gamma-mediated cytotoxicity could be triggered by apoptosis. The treatment induced IFN regulatory factor-1 (IRF-1) in two IFN-gamma-sensitive cells (2774, PA-1), whereas IRF-1 was not induced in two IFN-gamma-resistant cells (OVCAR-3, SKOV-3). The levels of p53 and p21WAF1 were not strikingly changed in all four cells. Interestingly, the expression of interleukin-converting enzyme (ICE, or caspase-1) was increased by the treatment in a kinetically consistent manner to the induction of IRF-1. However, CD95 (Fas/APO-1) was not changed. Apoptosis was greatly induced, when IRF-1 was transiently expressed in PA-1 without the treatment of IFN-gamma. However, it was repressed when IRF-1 together with IRF-2, an antagonist of IRF-1, were coexpressed. In addition, the effect of IFN-gamma was reduced in the 2774 and PA-1 cells stably expressing either IRF-1 antisense or IRF-2 sense, as shown by the cytotoxicity and FACS analysis. Furthermore, the IFN-gamma-induced apoptosis was greatly reduced, when inhibitors of ICE were treated into PA-1 cells. Taken together, these results suggest that IRF-1 directly mediates the IFN-gamma-induced apoptosis via the activation of caspase-1 gene expression in IFN-gamma-sensitive ovarian cancer cells.
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PMID:Interferon regulatory factor-1 mediates interferon-gamma-induced apoptosis in ovarian carcinoma cells. 1194 92

Apoptosis induced in male germ cells following ionizing radiation is dependent on functional p53 (Trp53) being present. We sought to determine whether Fas (Tnfrsf6/CD95/APO-1), an apoptotic factor, is involved in this p53-dependent germ cell death. In p53 knock-out mice exposed to 5 Gy of x-radiation, germ cells were protected from cell death, as assessed by counting apoptotic seminiferous tubules 12 h following radiation. Similarly, spermatid head counts in p53 knock-out mice remained near normal 29 days after exposure to 0.5 Gy of radiation, whereas wild-type animals had a more than twofold reduction in spermatid head counts. Fas mRNA expression remained at pretreatment levels in p53 knock-out mice; however, Fas increased in a time-dependent manner in wild-type mice following exposure to 5 Gy of radiation, indicating that radiation-induced Fas expression is p53-dependent. The functional significance of Fas involvement was demonstrated when lpr(cg) mice, having a nonfunctional Fas receptor, were exposed to 5 Gy of radiation; the number of apoptotic seminiferous tubules 12 h following radiation was significantly reduced compared to that of wild-type mice. Additionally, lpr(cg) mice exposed to 0.5 Gy of radiation had increased spermatid head counts 29 days following radiation compared to wild-type mice. Interestingly, gld mice with a non-functional Fas ligand (Tnfsf6/FasL/CD95L) were as sensitive to radiation as wild-type animals, and levels of FasL mRNA were not affected by radiation treatment. These results indicate that apoptosis and up-regulation of Fas following radiation are both p53-dependent events. Although Fas is necessary, in part, for radiation-induced p53-dependent apoptosis, FasL is not.
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PMID:Fas is involved in the p53-dependent apoptotic response to ionizing radiation in mouse testis. 1196 10

Thymidylate synthase (TS) is a critical target for chemotherapeutic agents such as 5-fluorouracil (5-FU) and antifolates such as tomudex (TDX),multitargeted antifolate, and ZD9331. Using the MCF-7 breast cancer line, we have developed p53 wild-type (M7TS90) and null (M7TS90-E6) isogenic lines with inducible TS expression (approximately 6-fold induction compared with control after 48 h). In the M7TS90 line, inducible TS expression resulted in a moderate approximately 3-fold increase in 5-FU IC-50(72 h) dose and a dramatic >20-fold increase in the IC-50(72 h) doses of TDX, multitargeted antifolate, and ZD9331. S-phase cell cycle arrest and apoptosis induced by the antifolates were abrogated by TS induction. In contrast, cell cycle arrest and apoptosis induced by 5-FU was unaffected by TS expression levels. Inactivation of p53 significantly increased resistance to 5-FU and the antifolates with IC-50(72 h) doses for 5-FU and TDX of >100 and >10 microM, respectively, in the M7TS90-E6 cell line. Furthermore, p53 inactivation completely abrogated the cell cycle arrest and apoptosis induced by 5-FU. The antifolates induced S-phase arrest in the p53 null cell line; however, the induction of apoptosis by these agents was significantly reduced compared with p53 wild-type cells. Both inducible TS expression and the addition of exogenous thymidine (10 microM) blocked p53 and p21 induction by the antifolates but not by 5-FU in the M7TS90 cell line. Similarly, inducible TS expression and exogenous thymidine abrogated antifolate but not 5-FU-mediated up-regulation of Fas/CD95 in M7TS90 cells. Our results indicate that in M7TS90 cells, inducible TS expression modulates p53 and p53 target gene expression in response to TS-targeted antifolate therapies but not to 5-FU.
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PMID:The role of thymidylate synthase induction in modulating p53-regulated gene expression in response to 5-fluorouracil and antifolates. 1198 Jun 62

Non-small cell lung cancer (NSCLC) is a malignant tumor with poor prognosis. Although the prognostic variables determining short-term survival have been well described, relatively little attention has been paid to factors associated with long-term survival. In search of these factors we studied the expression of several molecular markers in NSCLC. Only tumor samples of patients with squamous cell carcinomas and stage III tumors with a postoperative survival of at least 5 years and those of patients who died within 2 years after resection were selected for this study. The expression of several parameters including oncogene and suppressor gene products, proliferative, apoptotic, angiogenic and resistance-related factors were investigated and the differences in these two extreme populations were determined by the Wilcoxon rank sum test. Factors involved in proliferation (ras, fos, erbB-1, jun, cyclin A) were downregulated whereas factors involved in apoptosis (p53, bcl-2, CD95) were upregulated in the long survival group. Direct measurement of parameters of proliferation (cell cycle analysis by flow cytometry, PCNA index) revealed a lower proliferative activity in tumors of the long survivors compared to short survivors. In conclusion, tumors of the long survival group are characterized by a downregulation of factors involved in proliferation and an upregulation of factors involved in apoptosis. These tumors may grow more slowly and this may influence long-term survival of patients with NSCLC.
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PMID:Characteristics of long-term survivors of untreated lung cancer. 1200 38


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