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)

Several molecular elements of programmed cell death and apoptosis have recently been revealed. The function of gene products which deliver the lethal 'hit' is still not known. Well-characterized and newly discovered cell surface structures (e.g. antigen receptors, FAS/APO-1), as well as transcriptional factors (steroid receptor, c-myc, P53, retinoblastoma protein and others), have been implicated in the initiation of the death pathway. Negative regulators of the process (ced-9 gene product in programmed death of cells in Caenorhabditis elegans and bcl-2 protein in apoptosis) have been described. Biochemical mechanisms responsible for the silent nature of natural deaths of cells include their rapid engulfment (mainly through integrin receptors), transglutaminase-catalyzed cross-linking of cellular proteins, and fragmentation of DNA. Several lines of evidence suggest that distinct molecular mechanisms may operate in various forms of natural cell death.
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PMID:Biochemical events in naturally occurring forms of cell death. 834 12

In HBV related hepatitis it is generally accepted that the liver injury is mediated by an immune response to the virus, since HBV is not directly cytopathic. The first step in cytotoxic T lymphocyte mediated immune reaction in HBV infected mice is the induction of apoptosis. The role of BCL-2, p53 and PCNA (as the main regulators of cell cycle homeostasis) in this process has not been studied. The aim of this pilot study is to estimate immunohistochemically the expression of the BCL-2, p53 and PCNA in a group of HBV infected patients at various stages of the disease. Formalin fixed, paraffin embedded liver biopsies from 5 patients with HBsAG positivity in their serum were used for immunohistochemical study of the expression of BCL-2, PCNA (PC10) and P53 (DO1clone). As the chromogen we used both the DAB and AEC. The results were co-related with the 3 liver biopsies as controls. In the hepatocytes of the all cases (including controls) we did not found any positivity of BCL-2, p53 and PCNA. However the majority of the lymphocytes present in the liver of some cases of HBV infected patients were strongly BCL-2 positive. This preliminary results of very small group of patients could indicate that hepatocytes in the HBV infection are in the quiescent stage as in the controls and that the cell cycle regulation during infection could be controlled by other genes such as bax, bcl-Xs, FAS etc., but further studies are required.
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PMID:Immunohistochemical study of the expression of BCL-2, PCNA and P53 proteins in the patients with hepatitis B. The pilot study. 943

Overexpression of wild-type p53 in M1 myeloid leukemia cells induces apoptotic cell death that was suppressed by the calcium ionophore A23187 and the calcium ATPase inhibitor thapsigargin (TG). This suppression of apoptosis by A23187 or TG was associated with suppression of caspase activation but not with suppression of wild-type-p53-induced expression of WAF-1, mdm-2, or FAS. In contrast to suppression of apoptosis by the cytokines interleukin 6 (IL-6) and interferon gamma, a protease inhibitor, or an antioxidant, suppression of apoptosis by A23187 or TG required extracellular Ca2+ and was specifically abolished by the calcineurin inhibitor cyclosporin A. IL-6 induced immediate early activation of junB and zif/268 (Egr-1) but A23187 and TG did not. A23187 and TG also suppressed induction of apoptosis by doxorubicin or vincristine in M1 cells that did not express p53 by a cyclosporin A-sensitive mechanism. Suppression of apoptosis by A23187 or TG was not associated with autocrine production of IL-6. Apoptosis induced in IL-6-primed M1 cells after IL-6 withdrawal was not suppressed by A23187 or TG but was suppressed by the cytokines IL-6, IL-3, or interferon gamma. The results indicate that these Ca2+-mobilizing compounds can suppress some pathways of apoptosis suppressed by cytokines but do so by a different mechanism.
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PMID:Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds. 953 84

Surgical resection followed by radiation therapy is the mainstay of treatment for glioblastoma multiforme (GBM), the most aggressive of the malignant gliomas. The poor clinical response of GBM and the intrinsic radiation resistance of this tumor type have prompted clinical investigations seeking to define the role of chemotherapy in the treatment of GBM. In this study, we examined the cytotoxic response of GBM-derived cell lines to treatment with both radiation and chemotherapy. We observed that the sensitivity of glioma cells to cisplatin- and FAS-induced apoptosis was diminished by prior treatment with ionizing radiation. Radiation conferred resistance to cisplatin and FAS cytotoxicity in a dose- and time-dependent manner. Radiation diminished the cisplatin-induced cytotoxicity of malignant glioma cells but failed to alter the cisplatin susceptibility of normal primary human astrocytes. Given the role of p53 in the response of cells to irradiation, we evaluated whether p53 function affects the observed radiation-induced resistance to cisplatin. By examining isogenic cell lines differing only in p53 function, we demonstrated that radiation conferred resistance to cisplatin independently of p53. Current clinical strategies in the treatment of astrocytic tumors, which include combined modality therapy, have been empirically derived from limited clinical experience. Further understanding of the molecular determinants of apoptosis associated with combined modality therapy may guide the design of more efficacious multimodality protocols.
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PMID:Ionizing radiation inhibits chemotherapy-induced apoptosis in cultured glioma cells: implications for combined modality therapy. 973 90

Polycystic ovary syndrome (PCOS) is the most prevalent female endocrinopathy and the largest single cause of anovulatory infertility. The PCOS is characterized by multiple small antral follicles arrested in their development but nonatretic and viable. The hyperexpression of some growth factors (e.g. EGF/TGF alpha) in PCOS, considered to be survival or antiapoptotic factors, led to the hypothesis of their involvement in the blocking of apoptosis and atresia leading to an accumulation of multiple small antral follicles. Diminished FSH stimulation and accumulation of androgens could explain the arrest of progress to the preovulatory stage. Further investigation of the pathogenesis of PCOS is needed on the modulation of tumour suppressor and apoptosis genes such as p53, BAX or the APO/FAS system and the over expression of survival genes such as BCL2.
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PMID:Polysystic ovary syndrome--loss of the apoptotic mechanism in the ovarian follicles? 985 9

p53 is a tumor suppressor protein that induces apoptosis at least in part through its ability to act as a sequence-specific transactivator. This work reports that intron 1 of the mouse Fas death receptor gene contains a p53-responsive element (p53RE) that matches the p53 consensus sequence and that is located between nucleotides +1704 and +1723 from the transcription initiation site. This element is specifically bound by p53 and functions as a p53-dependent enhancer in mammalian or in yeast reporter gene assays. Contrary to bax, another known pro-apoptotic p53-target gene, both mouse and human FAS p53REs are still activated by the discriminatory p53 mutants Pro-175 and Ala-143, a class of mutants unable to induce apoptosis. We propose that p53-dependent up-regulation of Fas does not induce apoptosis per se but sensitizes the cell to other pro-apoptotic signal(s). The functional conservation of p53-dependent Fas up-regulation argues strongly in favor of its biological importance and suggests that murine models may be used to study further the in vivo role of Fas in the p53 response.
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PMID:Human and mouse Fas (APO-1/CD95) death receptor genes each contain a p53-responsive element that is activated by p53 mutants unable to induce apoptosis. 1066 May 38

Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML, TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role.
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PMID:Cells of the marginal zone--origins, function and neoplasia. 1116 33

A variety of studies have stressed the importance of the control of inflammatory cell longevity and the balance of pro-survival and pro-apoptotic signalling. Recently, asthma was found to be associated with reduced apoptosis of inflammatory cells in lung tissue. The aim of the study was to investigate the systemic activation of apoptosis pathways using cDNA array technology in atopy and asthma. Eighteen atopic asthmatics (AA), eight atopic non-asthmatic (AN) and 14 healthy control subjects (C) were included in the study. Peripheral blood mononuclear cells were separated with gradient centrifugation, mRNA purified and the reverse-transcribed probes hybridized to cDNA arrays. The signals were compared by standardizing to the 100 most expressed genes and group differences assessed with the Mann-Whitney U-test. We found a concerted up-regulation of several pro-survival cytokines and growth factors in AN and AA. FAS and FASL were not differentially expressed, but FAST kinase was over-expressed in AN and AA. The tumour necrosis factor pathway was activated in AN and AA with increased cytokine and receptor levels and increased TRAF2, an intracellular signalling product. There were indications of a down-regulated p53 system. In contrast, the Bcl-2 family of genes showed a net pro-apoptotic profile in AN and AA. The group of caspases showed a constant gene expression pattern in all groups. In conclusion, significant differences in the expression of apoptosis-related genes were found in peripheral blood of atopic individuals with and without asthma. cDNA array technology proved to be useful and may be complementary to DNA-based studies in order to analyse interactive and multidimensional pathways as shown here for apoptosis.
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PMID:Apoptosis signals in atopy and asthma measured with cDNA arrays. 1120 46

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

The p53 tumor suppressor plays a key role in the cell's response to genotoxic stress and loss of this 'guardian of the genome' is an important step in carcinogenesis. The ability of p53 to induce apoptosis through transactivation of its target genes is critical for its function as tumor suppressor. We have found that overexpression of p53 in human cancer cell lines resulted in apoptosis as measured by PARP cleavage. Furthermore we observed cleavage of both caspase 9 and caspase 8 after overexpression of p53 and found that p53-dependent apoptosis was inhibited by either cellular (c-Flip-s, Bcl-X(L)) or pharmacological inhibitors of caspase 8 or caspase 9 respectively. These results indicate that p53 is mediating apoptosis through both the mitochondrial and death receptor pathways. To elucidate the relevant p53 target genes and examine the caspase pathways utilized in vivo, we treated p53+/+ and age matched p53-/- mice with 5 Gy ionizing radiation or 0.5 mg/animal dexamethasone and harvested tissues at 0, 6 and 24 h. We examined the mRNA expression of p21, bax, KILLER/DR5, FAS/APO1 and EI24/PIG8 using TaqMan real time quantitative RT-PCR in the spleen, thymus and small intestine. Although the basal mRNA levels of these genes did not depend on the presence of p53, we observed a p53-dependent induction of all these targets in response to gamma-irradiation and a p53-independent regulation for p21 and KILLER/DR5 in response to dexamethasone. Furthermore, we have demonstrated that the relative induction of these p53 target genes is tissue specific. Despite observing otherwise similar levels of death in these tissues, our findings suggest that in some cases apoptosis mediated through p53 occurs by redundant pathways or by a 'group effect' while in other tissues one or few targets may play a key role in p53-dependent apoptosis. Surprisingly, KILLER/DR5 is the dominantly induced transcript in both the spleen and small intestine suggesting a potentially important role for this p53 target gene in vivo.
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PMID:Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo. 1149 83


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