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)

Cells expressing the envelope glycoprotein complex (Env) encoded by the human immunodeficiency virus can fuse with cells expressing Env receptors (CD4 and CXCR4). The resulting syncytia undergo apoptosis. We developed a cytofluorometric assay for the quantitation of syncytium formation and syncytial apoptosis. Using this methodology, we show that caspase activation in syncytia is inhibited by pharmacological or genetic intervention on cyclin-dependent kinase-1, p53, and mitochondrial membrane permeabilization (MMP). Thus, transfection of fusing cells with the viral mitochondrial inhibitor of apoptosis encoded by cytomegalovirus, a specific inhibitor of MMP, prevented the mitochondrial cytochrome c release and abolished simultaneously the activation of caspase-3. Conversely, inhibition of caspases did not prevent MMP. These results indicate that Env-elicited syncytial apoptosis involves the intrinsic (mitochondrial) pathway.
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PMID:Mitochondrion-dependent caspase activation by the HIV-1 envelope. 1455 4

CD24, also referred to as the heat-stable Ag, is a T cell differentiation Ag that is highly expressed on both CD4-CD8- double negative and CD4+CD8+ double positive thymocytes. Here, we report that CD24 ligation by a new anti-CD24 Ab, mT-20, induced the apoptosis of both double negative and double positive thymocytes, as well as the Scid.adh thymic lymphoma cell line, in the absence of TCR/CD3 engagement. CD24-mediated apoptosis of mouse thymocytes and its signaling pathway appeared not to be associated with p53, CD95, TNFR, or caspases. Furthermore, we found that cell death was blocked by the addition of scavengers of reactive oxygen species or by Bcl-2 overexpression, implying the role of CD24 signaling in the mitochondrial regulation. In this study, we suggest that CD24 ligation induced the apoptosis of immature thymocytes independently of both caspase and TCR.
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PMID:TCR-independent and caspase-independent apoptosis of murine thymocytes by CD24 cross-linking. 1470 49

Because survivin-null embryos die at an early embryonic stage, the role of survivin in thymocyte development is unknown. We have investigated the role by deleting the survivin gene only in the T lineage and show here that loss of survivin blocks the transition from CD4- CD8- double negative (DN) thymocytes to CD4+ CD8+ double positive cells. Although the pre-T cell receptor signaling pathway is intact in survivin-deficient thymocytes, the cells cannot respond to its signals. In response to proliferative stimuli, cycling survivin-deficient DN cells exhibit cell cycle arrest, a spindle formation defect, and increased cell death. Strikingly, loss of survivin activates the tumor suppressor p53. However, the developmental defects caused by survivin deficiency cannot be rescued by p53 inactivation or introduction of Bcl-2. These lines of evidence indicate that developing thymocytes depend on the cytoprotective function of survivin and that this function is tightly coupled to cell proliferation but independent of p53 and Bcl-2. Thus, survivin plays a critical role in early thymocyte development.
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PMID:Survivin loss in thymocytes triggers p53-mediated growth arrest and p53-independent cell death. 1475 45

Notch is crucial for multiple stages of T cell development, including the CD4+CD8+ double positive (DP)/CD8+ single positive (SP) transition, but regulation of Notchactivation is not well understood. p53 regulates Presenilin1 (PS1) expression, and PS1 cleaves Notch, releasing its intracellular domain (NIC), leading to the expression of downstream targets, e.g. the HES1 gene. We hypothesize that p53 regulates Notch activity during T cell development. We found that Notch1 expression and activation were negatively regulated by p53in several thymoma lines. Additionally, NIC was elevated in Trp53(-/-) thymocytes as compared to Trp53(+/+) thymocytes. To determine if elevated Notch1 activation in Trp53(-/-) thymocytes had an effect on T cell development, CD4 and CD8 expression were analyzed. The CD4+ SP/CD8+ SP T cell ratio was decreased in Trp53(-/-) splenocytes and thymocytes. This alteration in T cell development correlated with the increased Notch1 activation observed in the absence of p53. These data indicate that p53 negatively regulates Notch1 activation during T cell development. Skewing of T cell development toward CD8+SP T cells in Trp53(-/-) mice is reminiscent of the phenotype of NIC-overexpressing mice. Thus, we suggest that p53 plays a role in T cell development, in part by regulating Notch1 activation.
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PMID:p53 regulates thymic Notch1 activation. 1499 2

The coculture of cells expressing the HIV-1 envelope glycoprotein complex (Env) with cells expressing CD4 results into cell fusion, deregulated mitosis, and subsequent cell death. Here, we show that NF-kappaB, p53, and AP1 are activated in Env-elicited apoptosis. The nuclear factor kappaB (NF-kappaB) super repressor had an antimitotic and antiapoptotic effect and prevented the Env-elicited phosphorylation of p53 on serine 15 and 46, as well as the activation of AP1. Transfection with dominant-negative p53 abolished apoptosis and AP1 activation. Signs of NF-kappaB and p53 activation were also detected in lymph node biopsies from HIV-1-infected individuals. Microarrays revealed that most (85%) of the transcriptional effects of HIV-1 Env were blocked by the p53 inhibitor pifithrin-alpha. Macroarrays led to the identification of several Env-elicited, p53-dependent proapoptotic transcripts, in particular Puma, a proapoptotic "BH3-only" protein from the Bcl-2 family known to activate Bax/Bak. Down modulation of Puma by antisense oligonucleotides, as well as RNA interference of Bax and Bak, prevented Env-induced apoptosis. HIV-1-infected primary lymphoblasts up-regulated Puma in vitro. Moreover, circulating CD4+ lymphocytes from untreated, HIV-1-infected donors contained enhanced amounts of Puma protein, and these elevated Puma levels dropped upon antiretroviral therapy. Altogether, these data indicate that NF-kappaB and p53 cooperate as the dominant proapoptotic transcription factors participating in HIV-1 infection.
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PMID:NF-kappaB and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope. 1499 50

The envelope glycoprotein complex (Env), encoded by the human immunodeficiency virus (HIV-1), kills uninfected cells expressing CD4 and/or the chemokine receptor CXCR4 or CCR5, via at least three independent mechanisms. First, the soluble Env product gp120 can induce the apoptotic cell death of lymphocytes, neurons, and myocardiocytes, via interaction with surface receptors. Second, Env present on the surface of HIV-1 infected cells can transiently interact with cells expressing CD4 and CXCR4/CCR5, thereby provoking a hemifusion event that results in the death of the uninfected cell. Third, the interaction between Env on infected cells and its receptors on uninfected cells can result in syncytium formation. Such syncytia undergo apoptosis after a phase of latency. In several models of Env-induced apoptosis, early signs of mitochondrial membrane permeabilization (MMP) become manifest. Such signs include a loss of the mitochondrial transmembrane potential and the release of cytochrome c and AIF. The mechanisms of Env-triggered apoptotic MMP may involve an elevation of cytosolic Ca(2+), reactive oxygen species and/or the transcriptional activation of p53, with the consequent expression of pro-apoptotic proteins such as Bax, which permeabilizes mitochondrial membranes. The implications of these findings for the pathophysiology of HIV-1 infection is discussed.
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PMID:Mitochondrial apoptosis induced by the HIV-1 envelope. 1503 90

Repair of mismatches in mammalian cell DNA is mediated by a complex of proteins that constitute the so-called mismatch repair system (MMR), the main post-replicative pathway for the correction of replication errors. Loss of MMR (as exemplified by germline mutations in some MMR genes, leading to hereditary non-polyposis colorectal cancer) results in increased mutation rates at both coding sequences and in non-coding regions such as microsatellites. In order to evaluate possible functional alterations of this repair system during ageing that could affect immune system efficiency, we studied microsatellite instability at five different loci interspersed in the genome (CD4, VWA31, Tpox, Fes/FPS and p53) in total DNA from T lymphocyte clones derived from hematopoietic stem cells, or peripheral T cells of young or elderly subjects. In addition, these clones had been maintained for different periods in vitro to represent a culture model of ageing. We observed increasing instability accumulating with increasing passages in culture, particularly in CD34+cell-derived clones, but no clear donor age relationship.
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PMID:Microsatellite instability in in vitro ageing of T lymphocyte clones. 1505 Feb 83

We studied the clinicopathologic features of 42 cases of nasal-type extranodal natural killer (NK)/T-cell lymphoma in Singapore and compared our findings with other series reported in the Asian and Western populations. A panel of immunohistochemical stains, which included CD2, CD3, CD4, CD8, CD56, T-cell intracellular Antigen-1 and granzyme B, and in situ hybridization for Epstein-Barr virus encoded RNA (EBER) were performed. Polymerase chain reaction for T-cell receptor-gamma gene rearrangement using both gel and capillary electrophoresis were evaluated to determine the proportion of tumors which are of true T-cell lineage. We also studied the functional status of the overexpressed p53 protein in these lymphomas by correlating p53 expression with its downstream target protein, p21. In all, 31 out of 42 cases presented in the upper aerodigestive tract. The other sites of involvement included gastrointestinal tract, skin, soft tissue, testis, liver, spleen, bone marrow and brain. The tumors displayed characteristic morphologic features. In situ hybridization for EBER was detected in 41 out of 42 cases (97.6%). The only significant adverse prognostic factor identified was an International Prognostic Index of two or more. A significantly higher proportion of the tumors (27%), compared to previous studies, demonstrated monoclonal T-cell receptor-gamma gene rearrangement. There was, however, no difference in survival or clinicopathologic features between the true NK-cell tumors and their T-cell counterparts. Overexpression of p53 was present in 40% of the cases, but no significant difference in survival rate was detected in patients with p53 overexpression and there was no association between p53 overexpression with large cell morphology, and advanced stage of disease. These findings suggest that molecular aberrations other than those of the p53 pathway may be operative in the pathogenesis of this malignancy.
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PMID:Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and genotypic study of 42 cases in Singapore. 1519 7

Local radiation is an established therapy for human tumors. Radiation also has been shown to alter the phenotype of target tissue, including gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. We demonstrate a biological synergy between local radiation of tumor and active vaccine therapy. The model used consisted of mice transgenic for human carcinoembryonic antigen (CEA) and a murine carcinoma cell line transfected with CEA. The vaccine regimen consisted of a prime and boost strategy using vaccinia and avipox recombinants expressing CEA and three T-cell costimulatory molecules. One dose of 8-Gy radiation to tumor induced up-regulation of the death receptor Fas in situ for up to 11 days. However, neither radiation at this dose nor vaccine therapy was capable of inhibiting growth of 8-day established tumor. When vaccine therapy and local radiation of tumor were used in combination, dramatic and significant cures were achieved. This was mediated by the engagement of the Fas/Fas ligand pathway because Ag-bearing tumor cells expressing dominant-negative Fas were not susceptible to this combination therapy. Following the combination of vaccine and local radiation, tumors demonstrated a massive infiltration of T cells not seen with either modality alone. Mice cured of tumors demonstrated CD4(+) and CD8(+) T-cell responses specific for CEA but also revealed the induction of high levels of T-cell responses to two other antigens (gp70 and p53) overexpressed in tumor, indicating the presence of a consequential antigen cascade. Thus, these studies demonstrate a new paradigm for the use of local tumor irradiation in combination with active specific vaccine therapy to elicit durable antitumor responses of established tumors.
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PMID:External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. 1520 48

The p53 gene product is overexpressed by almost 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated rejection of established p53-overexpressing tumors without stimulating autoimmunity by immunization with modified vaccinia Ankara-expressing murine p53 (MVAp53). Tumor rejection was enhanced through antibody-mediated CTL-associated antigen 4 (CTLA-4) blockade. We examined the role of synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanine (CpG) motifs (CpG ODN) in enhancing MVAp53-mediated tumor rejection. CpG ODN with MVAp53 resulted in tumor rejection in BALB/c mice bearing poorly immunogenic 11A-1 murine mammary carcinomas or Meth A sarcomas and C57Bl/6 mice bearing MC-38 colon carcinomas. The effect was similar to that seen in tumor-bearing mice treated with MVAp53 along with CTLA-4 blockade. Monoclonal antibody depletion experiments demonstrated that the adjuvant effects of CpG ODN and CTLA-4 blockades were CD8 dependent. CpG ODN were partially natural killer cell dependent and ineffective in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice, whereas CTLA-4 blockade was partially CD4 dependent and functional in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice. In addition, when administered with MVAp53, both adjuvants enhanced p53-specific cytotoxicity and demonstrated an additive effect when combined. The combination of CpG ODN and CTLA-4 blockade worked synergistically to reject palpable 11A-1 and MC-38 tumors. These experiments demonstrate the potential for augmenting MVAp53-mediated antitumor immunity using CpG ODN and CTLA-4 blockade. This cell-free immunotherapy approach is a candidate for evaluation in cancer patients.
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PMID:Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. 1528 49


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