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)

Cellular senescence and apoptosis are two metabolically related and seemingly synergistic processes that are involved in tissue maintenance and homeostasis, anti-tumor protection, and age-related diseases. Despite this apparent co-operativity, senescence can inhibit apoptosis in certain conditions. Here, we describe senescence-apoptosis relationships in human epidermal cells by comparing apoptosis-related effector concentrations in keratinocyte cultures and epidermal skin cells at various stages of ageing. Using western blots, flow cytometry, enzyme-linked immuno-sorbent assay (ELISA) and immunofluorescence, we determined the amounts of apoptotic effectors in aged cells compared to young ones, in parallel with beta-galactosidase activity at neutral pH (senescence-associated beta-galactosidase, SA beta-gal), found to be a good indicator of cellular ageing. We observed increased levels of several Fas-mediated apoptosis effectors (Fas, Fas ligand, FADD, FLICE), both in cell cultures at advanced passages and in skin cells of aged donors (above 45 years). Furthermore, we found that while the pro-apoptotic p53 increased, the anti-apoptotic Bcl-2 declined. In spite of this, the extent of spontaneous apoptosis did not change in senescent keratinocyte cultures. The cells, however, became notably more susceptible to apoptosis when kept in exhausted growth medium, or upon Fas receptor activation by anti-Fas antibody binding. Our results are consistent with recent findings in senescent fibroblasts, showing that the death-signaling pathway is enhanced at senescence.
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PMID:Enhancement of Fas-mediated apoptosis in ageing human keratinocytes. 1501 68

Herpes simplex virus (HSV) can perturb the function of dendritic cells (DC). The underlying mechanisms are not defined. In the present study we demonstrate that HSV induces a substantial number of immature DC to undergo apoptosis by a mechanism involving caspase-8. We found strongly enhanced expression of TNF-alpha and TRAIL but not CD95 ligand after HSV infection. Blocking experiments suggested that these classical death ligands contribute to HSV-induced cell death of immature DC. Because uninfected DC are resistant to the apoptosis-inducing effect of death ligands we searched for a viral "competence-to-die" signal. Further analysis revealed that HSV-infected immature DC down-regulate long cellular FLICE-inhibitory protein (c-FLIP(L)) and up-regulate p53 whereas other apoptosis-regulating proteins (e.g. Bcl-2, RIP, FADD) were not affected. Down-regulation of c-FLIP(L) was not due to diminished gene transcription or reduced mRNA stability because the level of c-FLIP(L) mRNA was rather increased. Moreover, down-regulation of c-FLIP(L) could not be blocked by the anti-herpetic drug acyclovir. Finally, the underlying mechanism was also operative in human umbilical vein endothelial cells, which show a similar susceptibility to HSV infection and strength of c-FLIP(L) expression. These results suggest that HSV targets c-FLIP(L) protein in immature DC and other infectable cells to disrupt their function.
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PMID:Frontline: Induction of apoptosis and modulation of c-FLIPL and p53 in immature dendritic cells infected with herpes simplex virus. 1504 4

Activation of the so-called death receptors, e.g., CD95/Fas/Apo-1, is a potent stimulus to trigger apoptosis. Overexpression of the C-terminal FADD deletion mutant FADD-DN blocks death receptor-induced apoptosis, but despite this antiapoptotic activity, lck FADD-DN transgenic mice do not develop lymphomas. To analyze whether functional inactivation of FADD cooperates with Myc overexpression in tumorigenesis, lck FADD-DN transgenic mice were crossed with Emicro L-myc transoncogenic animals. While no tumors were detected in single transgenic FADD-DN or L-myc mice within 15 months, 5 of 17 (29%) FADD-DN/L-myc double transgenic animals developed lymphomas with an average latency period of 47 weeks. Protein analysis of FADD-DN/L-myc tumors showed, however, undetectable levels of FADD-DN protein. FADD-DN protein expression was again lost in 16 of 17 FADD-DN/p53 k.o. T-cell lymphomas, though no significant acceleration of tumorigenesis in P53-deficient lck FADD-DN mice compared to p53 k.o. animals was observed. These data suggest a strong counterselection against the FADD-DN protein during tumor progression, which could be explained by the cell cycle inhibitory activity of FADD-DN. Such counterselection would have to be compensated for by other antiapoptotic mutations, and indeed, strong upregulation of the antiapoptotic Bcl-2 family member Bcl-xL was found in one of the tumors. This in vivo mouse model demonstrates that an antiapoptotic protein involved in the onset of tumorigenesis is selected against and consequently lost during tumor progression because of its additional antiproliferative activity.
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PMID:Transgenic overexpression of a dominant negative mutant of FADD that, although counterselected during tumor progression, cooperates in L-myc-induced tumorigenesis. 1538 83

A p53 C-terminal peptide (aa 361-382, p53p), fused at its C-terminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The mechanism of cell death by p53p-Ant was through the FADD/caspase-8-dependent pathway without the involvement of the TRAIL pathway, Bcl-2 family and cell cycle changes. Blocking Fas with antibody did not alter the peptide's effect, suggesting that Fas itself did not interact with the peptide. Transfection with a dominant-negative FADD with a deleted N-terminus inhibited p53p-Ant-induced apoptosis. Its mechanism of action is related to the FADD-induced pathway without restoration of other p53 functions. p53p-Ant is a novel anticancer agent with unique selectivity for human cancer cells and could be useful as a prototype for the development of new anti-cancer agents.
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PMID:Selective induction of apoptosis through the FADD/caspase-8 pathway by a p53 c-terminal peptide in human pre-malignant and malignant cells. 1564 52

The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.
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PMID:Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. 1613 47

Mouse embryonic fibroblasts (MEFs) deficient for the transcription factor p53 are hypersensitive to UV-C light. They also show a reduced recovery from UV-C induced replication blockage and are unable to repair UV-C photoproducts. In this study, we utilized wild-type (wt), Apaf-1 deficient (apaf-1(-/-)) and p53 deficient (p53(-/-)) MEFs in order to elucidate the role of non-repaired UV-C lesions in apoptotic signalling. Corresponding with the cellular sensitivity determined by the WST assay, p53(-/-) cells displayed the highest level of apoptosis, whereas wt cells showed moderate apoptosis after UV-C irradiation. Apaf1(-/-) cells were most resistant. In wt cells apoptosis was executed both via the mitochondrial and the receptor-mediated pathway, as shown by Bcl-2 decline, induction of fasR and activation of caspases-3,8,9. In apaf-1(-/-) (p53(+/+)) cells, the mitochondrial pathway was blocked downstream of Bcl-2, indicating that in this case apoptosis was mediated via the induction of fasR and caspase-3,8 activation. In p53 deficient cells, non-repaired UV-C induced DNA lesions triggered sustained up-regulation of fas ligand (fasL) mRNA, which was not seen in wt and apaf-1(-/-) cells. Therefore, in p53(-/-) MEFs, the receptor/ligand triggered pathway appeared to be dominant. This was confirmed by significant reduction of apoptosis after DN-FADD transfection. As opposed to wt and apaf-1(-/-) cells, p53 deficient MEFs showed no induction of Fas receptor and no Bcl-2 decline. Nevertheless, the resulting caspase-8 and -3 activation was stronger compared to wt and apaf-1(-/-) cells. The data indicate that UV-C light activates in MEFs both the Fas (CD95, Apo-1) receptor and the mitochondrial damage pathways. In p53(-/-) cells, however, the high level of non-repaired DNA damage forces signalling by fasL upregulation, leading to enhanced UV-C-induced apoptosis.
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PMID:Apoptosis in UV-C light irradiated p53 wild-type, apaf-1 and p53 knockout mouse embryonic fibroblasts: interplay of receptor and mitochondrial pathway. 1621 90

Despite dramatic advances in adjuvant therapies, patients with malignant glioma face a bleak prognosis. Because many adjuvant therapies seek to induce glioma apoptosis, strategies that lower thresholds for the induction of apoptosis may improve patient outcomes. Therefore, elucidation of the biological mechanisms that underlie resistance to current therapies is needed to develop new therapeutic strategies. Here we proposed a novel mechanism of proapoptotic effect induced by a pharmacological peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, troglitazone, that facilitates caspase signaling in human glioma cells. Troglitazone activates protein-tyrosine phosphatase (PTP)-1B, which subsequently reduces phosphotyrosine 705 STAT3 (pY705-STAT3) via a PPARgamma-independent pathway. Reduction of pY705-STAT3 in glioma cells caused down-regulation of FLIP (FADD-like IL-1beta-converting enzyme-inhibitory protein) and Bcl-2. Furthermore, troglitazone induced Ser-392 phosphorylation of p53 via a PPARgamma-dependent pathway and up-regulation of Bax in a p53 wild-type glioma. When given with tumor necrosis factor-related apoptosis-inducing ligand or caspase-dependent chemotherapeutic agents, such as etoposide and paclitaxel, troglitazone exhibited a synergistic effect by facilitating caspase-8/9 activities. A PPARgamma antagonist, GW9662, did not block this effect, although a PTP inhibitor abrogated it. Knockdown of STAT3 by STAT3-small interfering RNA negated the inhibitory effect of PTP inhibitor on troglitazone, indicating that troglitazone uses a STAT3 inactivation mechanism that makes caspase-8/9 activities susceptible to cytotoxic agents in glioma cells and that PTP1B plays a critical role in the down-regulation of activated STAT3, as well as FLIP and Bcl-2. When taken with caspase-dependent anti-neoplastic agents, troglitazone may be a promising drug for use against malignant gliomas because it facilitates the caspase cascade, thereby lowering thresholds for the apoptosis induction of glioma cells.
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PMID:A peroxisome proliferator-activated receptor-gamma agonist, troglitazone, facilitates caspase-8 and -9 activities by increasing the enzymatic activity of protein-tyrosine phosphatase-1B on human glioma cells. 1631 70

In this report, we demonstrate that a 50% ethanol extract of the plant-derived product, Chios mastic gum (CMG), contains compounds which inhibit proliferation and induce death of HCT116 human colon cancer cells in vitro. CMG-treatment induces cell arrest at G(1), detachment of the cells from the substrate, activation of pro-caspases-8, -9 and -3, and causes several morphological changes typical of apoptosis in cell organelles. These events, furthermore, are time- and dose-dependent, but p53- and p21-independent. Apoptosis induction by CMG is not inhibited in HCT116 cell clones expressing high levels of the anti-apoptotic protein, Bcl-2, or dominant-negative FADD, thereby indicating that CMG induces cell death via a yet-to-be identified pathway, unrelated to the death receptor- and mitochondrion-dependent pathways. The findings presented here suggest that CMG (a) induces an anoikis form of cell death in HCT116 colon cancer cells that includes events associated with caspase-dependent pathways; and (b) might be developed into a chemotherapeutic agent for the treatment of human colon and other cancers.
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PMID:Antiproliferative activity and induction of apoptosis in human colon cancer cells treated in vitro with constituents of a product derived from Pistacia lentiscus L. var. chia. 1671 22

Glutamine and glucose are often controlled at low levels in fed-batch strategies to limit ammonia and lactate accumulation and improve productivity of mammalian cell cultures. However, this risks triggering apoptosis if cells are depleted of glutamine or glucose. To examine the apoptosis cascade during glutamine or glucose limitation, the transcriptional profile of FAS, FASL, FADD, FLIP, BAX, p53 and PEG3 in CRL 1606 hybridoma culture was investigated using quantitative real-time PCR. Activities of caspases 2, 3, 8 and 9 were also analyzed. Increase in the activities of the caspases was observed with up-regulation in the expression of FAS (6-8-fold) and PEG3 (2.5-fold), suggesting that the cells experienced apoptotic cell death via both the death receptor and mitochondrial pathways.
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PMID:Glutamine or glucose starvation in hybridoma cultures induces death receptor and mitochondrial apoptotic pathways. 1685 9

Somatostatin analogs currently used in the treatment of acromegaly and other neuroendocrine tumors inhibit hormone secretion and cell proliferation by binding to somatostatin receptor type (SST) 2 and 5. The antiproliferative pathways coupled to these receptors have been only partially characterized. The aim of this study was to evaluate the effect of octreotide and super selective SST2 (BIM23120) and SST5 (BIM23206) analogs on apoptotic activity and apoptotic gene expression in human somatotroph tumor cells. Eight somatotroph tumors expressing similar levels of SST2 and SST5 evaluated by real-time PCR and western blot analyses were included in the study. In cultured cells obtained from these tumors, octreotide induced a dose-dependent increase of caspase-3 activity (160+/-20% vs basal at 10 nM) and cleaved cytokeratin 18 levels (172+/-25% vs basal) at concentrations higher than 0.1 nM. This effect was due to SST2 activation since BIM23120 elicited comparable responses, while BIM23206 was ineffective. BIM23120-stimulated apoptosis was dependent on phosphatases, since it was abrogated by the inhibitor orthovanadate, and independent from the induction of apoptosis-related genes, such as p53, p63, p73, Bcl-2, Bax, BID, BIK, TNFSF8, and FADD. In somatotroph tumors, both BIM23120 and BIM2306 caused growth arrest as indicated by the increase in p27 and decrease in cyclin D1 expression. In conclusion, the present study showed that octreotide-induced apoptosis in human somatotroph tumor cells by activating SST2. This effect, together with the cytostatic action exerted by both SST2 and SST5 analogs, might account for the tumor shrinkage observed in acromegalic patients treated with long-acting somatostatin analogs.
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PMID:Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. 1695 43


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