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

Signal transduction pathways involving the c-Raf protein kinase are frequently activated in tumor cells. We have addressed the relevance of this activation by a loss-of-function approach. An anti-sense phosphorothioate oligonucleotide (ODN) specifically targeted against c-raf mRNA (Monia et al., 1996a) was used to block c-Raf protein expression in four different cell lines derived from lung, cervical, prostate and colon carcinomas. Concomitant with the abrogation of c-Raf expression we observed the occurrence of classical apoptotic markers, including chromatin condensation, inter-nucleosomal DNA cleavage, annexin V binding and cleavage of PARP, which was followed by cell death, affecting most of the cell population. This induction of apoptosis occurred independent of the p53 status of the cell. These findings demonstrate that c-Raf can protect tumor cells from undergoing programmed cell death, and suggest that the interference with c-Raf expression or function by ODNs or specific drugs could represent a powerful means for improving the efficacy of anti-cancer therapy.
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PMID:Abrogation of c-Raf expression induces apoptosis in tumor cells. 958 88

Mechanism of cell killing by transfer of Herpes simplex virus type-1 thymidine kinase (HSVtk) and subsequent ganciclovir (GCV) treatment was examined in B16F10 murine melanoma model. While parental B16F10 melanoma cells were resistant to GCV at 100 microM or higher, HSVtk-transduced B16F10 melanoma cell clones became susceptible to GCV with IC50 of 0.1 to 0.3 microM. By means of various parameters including characteristic morphological changes, in situ DNA end-labeling, DNA ladder pattern, flow cytometric detection of sub-G1 DNA content, and annexin V binding of inverted cell surface phosphatidylserine, apoptosis was shown to be associated with the cell killing of ganciclovir on HSVtk-transduced melanoma B16F10 cells. Kinetic analysis showed that the signs of apoptosis were observed not until 60 h of continued GCV treatment and preceded first by a rise in p53 protein level in 12 h and then by S-phase/G2-phase cell cycle arrest associated with corresponding increases in the level of cyclin B1 protein but no apparent change in protein level of Bax or Cdc2. These results suggest that apoptosis occurred as a result of ganciclovir-induced cell cycle arrests rather than direct chemical effect on HSVtk-transduced B16F10 melanoma cells.
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PMID:S- and G2-phase cell cycle arrests and apoptosis induced by ganciclovir in murine melanoma cells transduced with herpes simplex virus thymidine kinase. 963 14

Signals from the IL-7R are essential for normal thymocyte development. We isolated thymocytes from early developmental stages and observed that suspensions of pro-T1, -T2, and -T3 cells rapidly died in culture. Addition of IL-7 promoted their survival, but did not induce cell division. Pro-T4 cells did not undergo rapid cell death, and their survival was therefore independent of IL-7. Death in the absence of IL-7 showed the hallmarks of apoptosis, including DNA fragmentation and annexin V binding; however, caspase inhibitors blocked DNA fragmentation, but did not block cell death. The trophic effect of IL-7 was partially inhibited by blocking protein synthesis. The p53 pathway was not involved in this death pathway, since pro-T cells from p53-/- mice also underwent cell death in the absence of IL-7. The Fas/Fas ligand pathway was not involved in cell death, since Fas-deficient pro-T cells died normally in the absence of IL-7, anti-Fas Abs did not protect cells from death in the absence of IL-7, and Fas expression was undetectable on cells at these stages. The IL-7 trophic affect correlated with increased intracellular levels of Bcl-2 and decreased levels of Bax, whereas no Bcl-X(L), Bcl-w, or Bad was detectable. Thus, maintaining a favorable Bcl-2/Bax ratio may account for the trophic action of IL-7.
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PMID:The trophic action of IL-7 on pro-T cells: inhibition of apoptosis of pro-T1, -T2, and -T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways. 963 82

Chromosomal instability and persistent reproductive cell death show a significant correlation after cells are exposed to ionizing radiation. To examine the possible role of apoptosis in persistent reproductive cell death, we analyzed subsets of chromosomally stable and unstable clones for relationships between chromosome stability, reproductive integrity, and apoptosis. All clones were generated from the GM10115 cell line and derived from single progenitor cells surviving 10 Gy of X-rays, and all measurements were made approximately 60-80 generations after irradiation. The incidence of apoptosis, as measured by both annexin V binding of phosphatidylserine residues and terminal deoxynucleotidyl transferase labeling of DNA strand breaks, was significantly higher in chromosomally unstable clones than it was in chromosomally stable clones (P < 0.05; ANOVA and Student's t test). Furthermore, statistical analyses of the biological end points of persistent reproductive cell death and apoptosis were consistent, showing R2 values of 0.78 and 0.76, respectively. These results suggest that persistent reproductive cell death can, in part, be explained by the predisposition of a fraction of the clonal population to undergo apoptosis or necrosis. Immunological blot analyses of protein levels and DNA bandshift assays confirmed the mutant status of p53 in the host cell line, implying an apoptotic pathway that is independent of p53. Induction of apoptosis by agents such as actinomycin D, etoposide, and staurosporine and induction of necrosis by sodium azide were accompanied by an increase in the level of intracellular peroxy radicals and lipid peroxidation products, two independent end points that are typically associated with oxidative stress. Similar findings were observed in several subclones showing persistent apoptosis. These results suggest that the elevated levels of free radical damage that we detected were derived from the fraction of cells dying by apoptotic or necrotic processes. Possible mechanisms whereby oxidative stress may contribute indirectly to the perpetuation of chromosomal instability are discussed.
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PMID:Apoptosis, reproductive failure, and oxidative stress in Chinese hamster ovary cells with compromised genomic integrity. 972 83

C2-ceramide, a cell-permeable analogue of ceramide, induced significant, dose- and time-dependent death in human retinoblastoma Y79 cells. Dying cells strongly displayed the morphology of apoptosis as characterized by microscopic evidence of cell shrinkage, membrane blebbing, nuclear and chromatin condensation and degeneration of the nucleus into membrane-bound apoptotic bodies. Upon induction of apoptosis Y79 cells evidence early phosphatidylserine externalization, as shown by annexin V-FITC. Apoptosis was also assessed by monitoring changes in cell granularity by staining with the combined fluorescent dyes acridine orange and ethidium bromide. C2-ceramide induced these morphological changes without a concomitant production of oligonucleosomal fragments responsible for the DNA ladder and without changes in p53 protein level. Apoptosis was accompanied by accumulation of a modified Bcl-2 protein with a slower-mobility form, and by proteolytic cleavage of PARP. The effect seemed to be specific for C2-ceramide, as C2-dihydroceramide, or other amphiphilic lipid analogues, or products of ceramide hydrolysis were ineffective. The effect also depended on mRNA and protein synthesis as it was markedly inhibited by actinomycin D and cycloheximide. Sphingomyelinase and interleukin-1beta, which are known to activate the sphingomyelin turnover leading to ceramide generation, also induced apoptosis mimicking the effects of ceramide. These findings propose ceramide as an activator of the suicidal program in Y79 cells.
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PMID:Induction of programmed cell death in human retinoblastoma Y79 cells by C2-ceramide. 974 6

Apoptosis is considered to be a protective mechanism that limits lung injury. However, apoptosis might contribute to the inflammatory burden present in the injured lung. The exposure of mice to bleomycin (BLM) is a well-established model for the study of lung injury. BLM exposure induces DNA damage and enhances tumor necrosis factor (TNF)-alpha expression in the lung. To evaluate the importance of alveolar macrophage (AM) apoptosis in the pathogenesis of lung injury, we exposed BLM-sensitive (C57BL/6) and BLM-resistant (BALB/c) mice to BLM (120 mg/kg) and studied the induction of apoptosis [by light-microscopy changes (2, 8, 12, 24, 48, and 72 h) and annexin V uptake by flow cytometry (24 h)], the secretion of TNF-alpha (measured by ELISA), and the expression of p53 (by immunoblotting) in AM retrieved from these mice. BLM, but not vehicle, induced apoptosis in AM from both murine strains. The numbers of apoptotic AM were significantly greater (P < 0.001) in C57BL/6 mice (52.9%) compared with BALB/c mice (40.8%) as demonstrated by annexin V uptake. BLM induction of apoptosis in AM was preceded by an increased secretion of TNF-alpha in C57BL/6 but not in BALB/c mice. Furthermore, double TNF-alpha receptor-deficient mice, developed on a C57BL/6 background, demonstrated significantly (P < 0.001) lower numbers of apoptotic AM compared with C57BL/6 and BALB/c mice. BLM also enhanced p53 expression in AM from both murine strains. However, p53-deficient mice developed BLM-induced lung injury, exhibited similar lung cell proliferation (measured as proliferating cell nuclear antigen immunostaining), and accumulated similar amounts of lung hydroxyproline (65 +/- 6.9 microgram/lung) as did C57BL/6 (62 +/- 6.5 microgram/lung) mice. Therefore, AM apoptosis is occurring during BLM-induced lung injury in a manner that correlates with murine strain sensitivity to BLM. Furthermore, TNF-alpha secretion rather than p53 expression contributes to the difference in murine strain response to BLM.tumor necrosis factor; strain susceptibility
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PMID:Alveolar macrophage apoptosis and TNF-alpha, but not p53, expression correlate with murine response to bleomycin. 984 59

Spontaneous germ cell death is a common cellular process in the mammalian testis, although the function of this process during spermatogenesis is unclear. An investigation was undertaken to determine whether p53 serves as a mechanism in germ cell quality control by causing spontaneous germ cell death. Using an annexin V assay, lower levels of spontaneous apoptosis were found in the testes of p53-/- mice compared to p53+/+ mice. Propidium iodine staining revealed that the greatest reduction in apoptosis and the largest increase in cell numbers occurred in the tetraploid germ cell population of p53-/- mice. Microscopic examination of sperm morphology showed an increased percentage of abnormal forms in p53-/- mice. Furthermore, p53-/- mice sired fewer offspring than p53+/+ mice did when both groups were mated with p53+/+ females. These results suggest that p53 mediates spontaneous testicular germ cell apoptosis and failure to remove defective germ cells by this mechanism results in increased percentages of abnormal sperm and reduced fertility. p53-mediated apoptosis may be an effector of cellular proofreading that acts to maintain the cellular integrity of germ cells during spermatogenesis.
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PMID:p53-mediated germ cell quality control in spermatogenesis. 985 50

To determine the role of cholesterol deprivation in cell proliferation and, eventually, in apoptosis, HL-60 promyelocytic cells were incubated in a cholesterol-depleted medium in the presence of SKF 104976, a specific inhibitor of lanosterol 14-alpha demethylase. As expected, SKF 104976 efficiently blocked the [14C]-acetate incorporation into cholesterol, whereas it induced the accumulation of both lanosterol and, especially, dihydrolanosterol. As a consequence, cell proliferation was greatly depressed at 24 h of treatment with the drug, and clear signs of apoptosis--annexin V binding, condensed and fragmented nuclei and DNA ladder--were observed thereafter. Provided that the HL-60 cell line does not express p53, it may be concluded that apoptosis induced by cholesterol deprivation is not dependent on this tumor suppressor protein. Supplementing the incubation medium with LDL-cholesterol or pure free cholesterol, fully prevented cell growth inhibition and apoptosis induction, whereas mevalonate was ineffective. These results indicate that cholesterol plays a specific role in cell proliferation, a function that is not shared by its precursors lanosterol and dihydrolanosterol.
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PMID:Induction of apoptosis in p53-null HL-60 cells by inhibition of lanosterol 14-alpha demethylase. 989 47

Recently, a C to T transition mutation in exon 8 of the p53 gene has been identified in a subculture of the genetically engineered human lymphoblastoid cell line AHH-1 and this mutation was proposed to cause a loss of function of the p53 suppressor protein and may limit the use of this cell culture in genotoxicology test assays. This led us to investigate early passage cultures of AHH-1 and its derivative MCL-5 to determine the distribution of the mutation. In order to characterise the presence of mutations at the p53 locus, exon 8 was analysed using restriction enzyme analysis and automated sequencing to locate possible changes of sequence. Mutations were identified at codon 282, and treatment with the Msp1 restriction enzyme led to incomplete digestion suggesting the presence of heterozygosity at the site which was confirmed by sequencing. Our results indicate that the p53 gene is heterozygous at the interface between the codons 281 and 282 in both AHH-1 and MCL-5. An Annexin V labeling study was carried out and both AHH-1 and MCL-5 cell lines were shown to undergo DNA damage induced cell death after a 1-h exposure to MNNG.
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PMID:P53 integrity in the genetically engineered mammalian cell lines AHH-1 and MCL-5. 1002 73

Caspases play a pivotal role in neuronal cell death during development and after trophic factor withdrawal. However, the mechanisms regulating caspase activity and the role played by caspase activation in response to neuronal injury is poorly understood. The tumor suppressor gene p53 has been implicated in the loss of neuronal viability caused by excitotoxic and DNA damaging agents. In the present study we determined if p53-mediated neuronal cell death required caspase activation. DNA damage increased caspase activity in both cultured embryonic telencephalic and postnatal cortical neurons in a p53-dependent manner. Caspase inhibitors protected embryonic telencephalic neurons, but not postnatal cortical neurons, from DNA damage-induced cell death as measured by direct cell counting and annexin V staining. In marked contrast to the caspase inhibitors, an inhibitor of the DNA repair enzyme, poly(ADP-ribose) polymerase, conferred significant protection from genotoxic and excitotoxic cell death on postnatal cortical neurons but had no effect on embryonic neurons. Glutamate-mediated excitotoxicity in postnatal neurons was not associated with measurable changes in caspase activity, consistent with the failure of caspase inhibitors to prevent cell death under these conditions. Moreover, adenovirus-mediated overexpression of p53 killed embryonic and postnatal neurons without activating caspases. Thus, p53-mediated neuronal cell death may occur via both caspase-dependent and caspase-independent pathways. These results demonstrate that p53 is required for caspase activation in response to some forms of neuronal injury. However, the relative importance of caspase activation in neurons depends on the developmental status of the cell and the specific nature of the death stimulus.
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PMID:Contribution of p53-dependent caspase activation to neuronal cell death declines with neuronal maturation. 1019 17


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