Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer's- (AD), Parkinson- (PD), or Huntington's disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g. , Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-beta (TGF-beta ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.
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PMID:Apoptosis modulators in the therapy of neurodegenerative diseases. 1106 Jul 7

Breast tumor cells are relatively refractory to apoptosis in response to modalities which induce DNA damage such as ionizing radiation and the topoisomerase II inhibitor, adriamycin. Various factors which may modulate the apoptotic response to DNA damage include the p53 status of the cell, levels and activity of the Bax and Bcl-2 families of proteins, activation of NF-kappa B, relative levels of insulin like growth factor and insulin-like growth factor binding proteins, activation of MAP kinases and PI3/Akt kinases, (the absence of) ceramide generation and the CD95 (APO1/Fas) signaling pathway. Prolonged growth arrest associated with replicative senescence may represent an alternative and reciprocal response to DNA-damage induced apoptosis that is p53 and/or p21waf1/cip1 dependent while delayed apoptosis may occur in p53 mutant breast tumor cells which fail to maintain the growth-arrested state. Clearly, the absence of an immediate apoptotic response to DNA damage does not eliminate other avenues leading to cell death and loss of self-renewal capacity in the breast tumor cell. Nevertheless, prolonged growth arrest (even if ultimately succeeded by apoptotic or necrotic cell death) could provide an opportunity for subpopulations of breast tumor cells to recover proliferative capacity and to develop resistance to subsequent clinical intervention.
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PMID:Growth arrest and cell death in the breast tumor cell in response to ionizing radiation and chemotherapeutic agents which induce DNA damage. 1107 87

The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces apoptosis in a variety of cancer cells. Recently, we demonstrated that CD437 induces apoptosis in human non-small cell lung cancer (NSCLC) cells expressing wild-type p53 by increasing the level of the death domain-containing cell surface receptor Killer/DR5. In the present study, we investigated whether CD437 induced the expression of Fas (CD95/APO-1), a cell surface protein belonging to the tumor necrosis factor receptor superfamily, which induces apoptosis upon interaction with Fas ligand (FasL) or agonistic antibodies. We found that CD437 increased the level of Fas mRNA in a time- and concentration-dependent manner in NSCLC H460 cells. The increased Fas expression was also identified at the protein level. CD437 induced Fas expression in three NSCLC cell lines with wild-type p53 but not in six NSCLC cell lines containing mutant p53. Moreover, enhanced degradation of wild-type p53 protein in NSCLC cells expressing human papillomavirus-16 E6 oncoprotein blocked CD437-induced Fas expression. These results implicate the involvement of wild-type p53 in CD437-induced Fas expression in human NSCLC cells. CD437 did not change Fas mRNA stability, and actinomycin D abolished CD437-induced expression of Fas mRNA, suggesting that CD437 induces Fas expression at the transcriptional level. The combination of CD437 and FasL or CD437 and agonistic anti-Fas antibody caused synergistic induction of apoptosis. Furthermore, CD437 augmented Fas/ FasL-induced apoptosis in cell lines with wild-type p53 but not in cell lines having mutant p53, indicating that a p53-dependent mechanism is also involved in this effect. Taken together, these results demonstrate that increased Fas expression may play an important role in CD437-induced, p53-dependent apoptosis in human NSCLC cells.
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PMID:Induction of Fas expression and augmentation of Fas/Fas ligand-mediated apoptosis by the synthetic retinoid CD437 in human lung cancer cells. 1110 25

Kaposi's sarcoma (KS) is a multifocal lesion that occurs predominantly in the skin, most frequently in people infected with HIV-1, and that evolves through early stages (patch and plaque) to a tumor-like late stage (nodular). Both, endemic African (EKS) and AIDS-associated (AKS) KS expressed human herpesvirus 8 (HHV-8) as shown by PCR. By immunohistochemistry the expression of cellular Bcl-2 and c-myc was confined in early stages of both EKS and AKS to relatively few endothelial cells (EC) whereas in nodular KS most of spindle cells (SC) strongly expressed both genes. CD40 was usually strongly expressed in SC at all KS stages as well as in EC of non-involved tissue whereas CD40L (CD154) was not demonstrable. Fas (CD95) was moderately to weakly expressed by SC whereas p53 and Waf-1 were found in less than 5% of the SC. In both AKS and EKS at nodular stage almost no apoptotic SC were detected. In most AKS and EKS low levels of cell proliferation were seen but AKS showed consistently higher values compared to EKS. All clinical types and stages of KS showed a diploid cellular DNA content by flow cytometric analysis of microselected lesions. Thus, we conclude that KS during evolution represents diploid, probably reactive, cell proliferation, which progressively increases the expression of strong cellular and also viral (HHV-8) antiapoptotic factors.
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PMID:Proliferation and apoptosis in the evolution of endemic and acquired immunodeficiency syndrome-related Kaposi's sarcoma. 1111 13

Treatment of haematopoietic BA/F3 cells with the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FUdR) activated apoptosis through a mechanism that required continuous protein synthesis and was inhibited by Bcl-2 over-expression. Analysis of p53 levels in cells treated with FUdR indicated a marked accumulation of this protein. Accumulation of p53 was also observed in cells over-expressing Bcl-2. In BA/F3 cells transfected with a cDNA coding for the human papilloma virus protein E6, p53 accumulation after FUdR treatment was inhibited markedly. However, apoptosis was induced in both control and E6 cells to a similar extent. The role of the CD95/CD95 ligand (CD95L) system in FUdR-induced apoptosis was also assessed. As determined by reverse transcriptase PCR, BA/F3 expressed a low constitutive level of CD95L mRNA, which decreased following FUdR treatment. Moreover, blocking CD95-CD95L interactions with antagonistic CD95 monoclonal antibody did not prevent drug-induced apoptosis. Furthermore, analysis of caspase involvement showed important differences in apoptosis induced by CD95-triggering or FUdR treatment. In summary, these results suggest that apoptosis induced by thymineless stress in haematopoietic BA/F3 cells occurs by a mechanism that does not require accumulation of p53 and which is independent of CD95-CD95L interactions.
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PMID:Apoptosis of haematopoietic cells upon thymidylate synthase inhibition is independent of p53 accumulation and CD95-CD95 ligand interaction. 1111 3

Ultraviolet radiation can induce the injury of epidermal keratinocytes, resulting in sunburn cell (apoptotic cell) formation. It has been demonstrated that the protease caspase-3, a downstream molecule of the CD95 pathway, is activated in UV-exposed HaCaT cells, and that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is cleaved by interleukin-1beta converting enzyme (ICE)-like protease during apoptosis induced by X-rays, staurosporine and etoposide. Then, we studied whether the DNA-PKcs is cleaved during UV-induced apoptosis in keratinocytes. We used the well-characterized cloned human keratinocyte cell line HaCaT, which carries p53 mutations. UVB-induced apoptotic cells were observed by TdT-mediated deoxyuridine 5'-triphosphate nick end labeling (TUNEL) assay and agarose gel electrophoresis. Western blot analysis was performed using the antibody against DNA-PKcs. The cleavage occurred during UVB-induced apoptosis in HaCaT cells. It suggests that the cleavage is associated with loss of DNA-PK activity. Thus, a functional relevance of cleavage of DNA-PKcs may be to prevent rejoining fragmented DNA during apoptosis, thereby promoting apoptotic processes. Although apoptosis was not completely blocked by the caspase-3 inhibitor, the cleavage of the DNA-PKcs was blocked. These results indicate that DNA-PKcs is cleaved by the caspase-3 for UVB-induced apoptosis in HaCaT cells.
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PMID:DNA-dependent protein kinase catalytic subunit is cleaved during UV-induced apoptosis. 1115 67

High-dose intravenous immunoglobulin (IVIg) is used as therapy in an increasing number of immune mediated disorders including infections and autoimmune conditions. IVIg exerts profound effects both in vivo as well as in vitro on humoral and cell-mediated immunity. In this study we investigated whether IVIg could alter the pattern of apoptosis and apoptosis related proteins including Bcl-2, Bax, p53, CD95, and p21/WAF-1, a protein well known to arrest cells in G1 phase of the cell cycle and finally proliferation marker Ki-67 on peripheral blood mononuclear cells (PBMC). The cells were cultured either unstimulated or with mitogen in the presence or absence of different IVIg preparations. A dual effect by IVIg was found. The incidence of apoptosis was elevated in activated Ki-67 and CD95 positive PBMC, whereas it was lower in small, nonactivated cells. The cells that survived were associated with a striking increase in the expression of p21/WAF-1 suggesting G1 arrest. A concomitant upregulation of Bcl-2 was also obtained by IVIg exposition resulting in long-term survival. We suggest that these abilities of IVIg to alter cell cycle progression and apoptosis could explain some of the beneficial effects obtained in vivo with IVIg therapy.
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PMID:Human polyspecific immunoglobulin for therapeutic use induces p21/WAF-1 and Bcl-2, which may be responsible for G1 arrest and long-term survival. 1125 39

In Alzheimer Disease (AD), dementia is due to cell loss and impaired synaptic function. The cell loss is mediated by increased apoptosis, predisposition to apoptosis, and impaired mitochondrial function. Previous studies demonstrated that the AD7c-NTP neuronal thread protein gene is over-expressed in AD beginning early in the course of disease, and that in AD, AD7c-NTP protein accumulation in neurons co-localizes with phospho-tau-immunoreactivity. To determine the potential contribution of AD7c-NTP over-expression to cell loss in AD, we utilized an inducible mammalian expression system to regulate AD7c-NTP gene expression in human CNS-derived neuronal cells by stimulation with isopropyl-1-beta-D-thiogalactopyranoside (IPTG). IPTG induction of AD7c-NTP gene expression resulted in increased cell death mediated by apoptosis, impaired mitochondrial function, and increased cellular levels of the p53 and CD95 pro-apoptosis gene products as occur in AD. In addition, over-expression of AD7c-NTP was associated with increased levels of phospho-tau, but not amyloid-beta immunoreactivity. These results suggest that AD7c-NTP over-expression may have a direct role in mediating some of the important cell death cascades associated with AD neurodegeneration, and further establish a link between AD7c-NTP overexpression and the accumulation of phospho-tau in preapoptotic CNS neuronal cells.
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PMID:Alzheimer-associated neuronal thread protein-induced apoptosis and impaired mitochondrial function in human central nervous system-derived neuronal cells. 1127 7

Suicide gene therapy using viral transfer of herpes simplex virus type I (HSV-1) thymidine kinase (TK) and subsequent ganciclovir (GCV) chemotherapy was the first approach used in clinical trials of somatic gene therapy for glioblastoma. The molecular pathways mediating TK/GCV-induced cell death remain to be elucidated. Here, we report that adenoviral (Ad)-TK/GCV-induced death is p53-independent and does not involve altered CD95 or CD95L expression. Ectopic expression of the preferential caspase 8 inhibitor, crm-A, inhibits Ad-CD95L-induced cell death but has no effect on TK/GCV cytotoxicity. LN-18 glioma cells selected for resistance to death receptor-mediated cell death do not acquire cross-resistance to TK/GCV. TK/GCV triggers mitochondrial cytochrome c release and activation of caspases 3, 7, 8 and 9 in a death receptor-independent manner. These events are associated with the loss of BCL-X(L). Forced expression of a BCL-X(L) transgene, or co-exposure to a pseudosubstrate caspase inhibitor, zVAD-fmk, inhibit TK/GCV cytotoxicity. Double-transfected cell lines expressing crm-A and enhanced green fluorescent protein (eGFP) show that the bystander effect in vitro is also death receptor- and caspase 8-independent. TK/GCV therapy does not kill glioma cells in synergy with cancer chemotherapy drugs, including lomustine, temozolomide and topotecan. In contrast, there is strong synergy of TK/GCV and CD95L. Thus, TK/GCV-induced cell death involves a mitochondria-dependent loop of caspase acvtivation that can be synergistically enhanced by death receptor agonists such as CD95L. TK/GCV-mediated sensitization of glioma cells to CD95L expressed on immune effector cells or parenchymal brain cells might account for the immune system's and bystander effects of TK/GCV therapy observed in rodent glioma models in vivo.
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PMID:Death receptor-independent cytochrome c release and caspase activation mediate thymidine kinase plus ganciclovir-mediated cytotoxicity in LN-18 and LN-229 human malignant glioma cells. 1131 26

The CD95 (FAS, Apo-1) system is a major death pathway in normal and tumor cells. Recent evidence indicates that pancreatic cancer cells express CD95R and CD95L but are insensitive to CD95-mediated apoptosis. Here we show that treatment of human pancreatic cancer cells with RNA synthesis inhibitor actinomycin D (ActD) converted the phenotype of cancer cells from CD95 resistant to CD95 sensitive. Flow cytometric analysis demonstrated that all pancreatic cancer cell lines studied responded with cell surface CD95R and CD95L upregulation to bleomycin treatment, and PANC1 (mt p53) cells demonstrated a dose-dependent response to interferon gamma and bleomycin treatment with CD95R and CD95L up-regulation. However, only bleomycin sensitized PANC1 cells to CD95-mediated apoptosis. Taxol sensitized PANC1 and HPAC cells to CD95-mediated apoptosis without surface up-regulation of CD95R. These data suggest that pancreatic cancer cells possess a p53-independent mechanism of CD95R and CD95L surface upregulation and that surface expression of CD95R is not predictive of apoptotic function. Protein extracts of HPAC and PANC1 cells treated for 24 hours with a combination of ActD/agonist anti-CD95 antibodies demonstrated significantly higher Acetyl-Asp-Glu-Val-Asp-ase (DEVDase) cleavage activity (caspase 3-like activity) than extracts from cells treated with ActD only. In the present study, we also investigated the time kinetics of DEVDase (caspase 3-like) activation in PANC1 (mt p53) and HPAC (wt p53) pancreatic cancer cell lines. We found that DEVDase activity in PANC1 cells responds to ActD and ActD/anti-CD95 antibodies earlier than in HPAC cells; however, at 24 hours HPAC cells demonstrated much stronger activation. Cytosolic protein extracts from untreated cells did not influence caspase 3-like activity when added to extracts from the ActD/anti-CD95 antibody-treated cells. Collectively, these data suggest that pancreatic cancer cells have functional CD95-related apoptotic machinery with preserved apoptotic signal transduction, CD95R upregulation. and caspase activation. However, this system is blocked by some unknown protein(s) that is either located in the organelle fraction of the cell and/or requires an intact cell for manifestation of its activity.
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PMID:CD95-related apoptotic machinery is functional in pancreatic cancer cells. 1134 35


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