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)

Survivin is a good candidate for cancer immunotherapy since it is overexpressed in most common human cancers, poorly expressed in most normal adult tissues and is essential for cancer cell survival. Previously, we and others have demonstrated that survivin-specific immune responses can be generated in mice and cancer patients. These responses resulted in a substantial antitumor effect. However, the fact that survivin is expressed in normal hematopoietic progenitor cells and endothelial cells may potentially limit the use of vaccination against survivin in the clinic due to possible toxicity. In this study, we have evaluated this risk by using dendritic cells (DC) transduced with an adenovirus encoding mutant human survivin (Ad-surv DCs). Immunization of mice with Ad-surv DCs resulted in generation of CD8 T cells recognizing multiple epitopes from mouse survivin. These responses provided significant antitumor effect against 3 different tumors EL-4 lymphoma, MC-38 carcinoma, and MethA sarcoma. Survivin-specific T-cells did not affect bone marrow hematopoietic progenitor cells and no autoimmune abnormalities were observed. However, as was the case with other tumor vaccines it provided only partial antitumor effect against established tumors. The existing paradigm suggests that generation of immune response against multiple tumor-associated antigens may provide a better antitumor effect. Here, we directly tested this hypothesis by combining vaccines targeting different tumor-associated proteins: survivin and p53. Despite the fact that combination of 2 vaccines generated potent antigen specific T-cell responses against both molecules they did not result in the improvement of antitumor effect in any of the tested experimental tumor models.
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PMID:Dendritic cell-based full-length survivin vaccine in treatment of experimental tumors. 1747 Nov 64

Systemic IL-2 is currently employed in the therapy of several tumor types, but at the price of often severe toxicities. Local vector mediated delivery of IL-2 at the tumor site may enhance local effector cell activity while reducing toxicity. To examine this, a model using CEA-transgenic mice bearing established CEA expressing tumors was employed. The vaccine regimen was a s.c. prime vaccination with recombinant vaccinia (rV) expressing transgenes for CEA and a triad of costimulatory molecules (TRICOM) followed by i.t. boosting with rF-CEA/TRICOM. The addition of intratumoral (i.t.) delivery of IL-2 via a recombinant fowlpox (rF) IL-2 vector greatly enhanced anti-tumor activity of a recombinant vaccine, resulting in complete tumor regression in 70-80% of mice. The anti-tumor activity was shown to be dependent on CD8(+) cells and NK1.1(+). Cellular immune assays revealed that the addition of rF-IL-2 to the vaccination therapy enhanced CEA-specific tetramer(+) cell numbers, cytokine release and CTL lysis of CEA(+) targets. Moreover, tumor-bearing mice vaccinated with the CEA/TRICOM displayed an antigen cascade, i.e., CD8(+) T cell responses to two other antigens expressed on the tumor and not the vaccine: wild-type p53 and endogenous retroviral antigen gp70. Mice receiving rF-IL-2 during vaccination demonstrated higher avidity CEA-specific, as well as higher avidity gp70-specific, CD8(+) T cells when compared with mice vaccinated without rF-IL-2. These studies demonstrate for the first time that the level and avidity of antigen specific CTL, as well as the therapeutic outcome can be improved with the use of i.t. rF-IL-2 with vaccine regimens.
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PMID:Intratumoral delivery of vector mediated IL-2 in combination with vaccine results in enhanced T cell avidity and anti-tumor activity. 1750 41

The protein p53 has been shown to be an efficient tumour antigen in both murine and human cancer vaccine studies and cancer vaccines targeting p53 based on major histocompatibility complex (MHC) class I binding p53-derived peptides that induce cytotoxic T lymphocytes (CTLs) without p53-specific CD4(+) T-cell help have been tested by several research groups including ours. To obtain such CD4(+) T-cell help and cover a broader repertoire of MHC haplotypes we have previously attempted to produce recombinant human p53 for vaccination purposes. However, attempts to refold a hexahis-tagged p53 protein in our laboratory were unsuccessful. Here, we show that fusion of an 11-amino-acid region of the human immunodeficiency virus TAT protein transduction domain (PTD) to human p53 increases the solubility of the otherwise insoluble p53 protein and this rTAT-p53 protein can be transduced into human monocyte-derived dendritic cells (DCs). The induction of a p53-specific HLA-A*0201 immune response was tested in HLA-A*0201/K(b) transgenic mice after immunization with rTAT-p53-transduced bone-marrow-derived DCs. In these mice, p53-specific CD4(+) and CD8(+) T-cell proliferation was observed and immunization resulted in the induction of HLA-A*0201-restricted CTLs specific for two human p53-derived HLA-A*0201-binding peptides, p53(65-73) and p53(149-157). Addition of GrpE to generate rTAT-GrpE-p53 led to a further increase in protein solubility and to a small increase in DC maturation but did not increase the observed p53-specific T-cell responses. The use of rTAT-p53 in ongoing clinical protocols should be applicable and offers advantages to current strategies omitting the use of HLA-typed patients.
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PMID:Addition of TAT protein transduction domain and GrpE to human p53 provides soluble fusion proteins that can be transduced into dendritic cells and elicit p53-specific T-cell responses in HLA-A*0201 transgenic mice. 1761 May 3

p63, a homologue of the tumor suppressor p53, is pivotal for epithelial development, because its loss causes severe epithelial dysgenesis, although no information is so far available on the role of p63 in the thymus. We identified the expression of all p63 isoforms in the developing thymus. The p63(-/-) thymi show severe abnormalities in size and cellularity, even though the organ expresses normal levels of keratins 5 and 8, indicating a p63-independent differentiation of thymic epithelial cells (TEC). TEC were sufficiently developed to allow a significant degree of education to produce CD4/CD8 single- and double-positive T cells. To study the selective contribution of transactivation-active p63 (TAp63) and amino-deleted p63 (DeltaNp63) isoforms to the function of the TEC, we genetically complemented p63(-/-) mice by crossing p63(+/-) mice with transgenic mice expressing either TAp63alpha or DeltaNp63alpha under the control of the keratin 5 promoter. Thymic morphology and cellularity were partially restored by complementation with DeltaNp63, but not TAp63, one downstream effector being fibroblast growth factor receptor 2-IIIb (FgfR2-IIIb). Indeed, FgfR2-IIIb is regulated directly by p63, via its interaction with apobec-1-binding protein-1, and its knockout shows thymic defects similar to those observed in p63(-/-) thymi. In addition, expression of Jag2, a component of the Notch signaling pathway known to be required for thymic development, was enhanced by p63 in vivo genetic complementation. Like Jag2(-/-) thymi, p63(-/-) thymi also show reduced gammadelta cell formation. Therefore, p63, and particularly the DeltaNp63 isoform, is essential for thymic development via enhanced expression of FgfR2 and Jag2. The action of DeltaNp63 is not due to a direct regulation of TEC differentiation, but it is compatible with maintenance of their "stemness," the thymic abnormalities resulting from epithelial failure due to loss of stem cells.
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PMID:DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. 1762 81

Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines. Six HLA-A2 or HLA-A24-restricted wt p53 peptides were evaluated for their ex vivo immunogenicity and their potential for use in cancer vaccines. Peripheral blood mononuclear cells (PBMC) obtained from HLA-A*0201(+) and/or HLA-A*2402(+) normal donors and subjects with squamous cell carcinoma of the head and neck (SCCHN) were analyzed for p53 peptide-specific reactivity in ELISPOT IFN-gamma assays. CD8(+) T cells in 7/10 normal donors (HD) and 11/23 subjects with SCCHN responded to at least one of the wt p53 peptides. CD8(+) T cell precursors responsive to wt p53 epitopes were detected in the circulation of most subjects with early disease, and an elevated blood Tc(1)/Tc(2) ratio distinguished wt p53 peptide responders from non-responders. The identification of multiple wt p53 peptides able to induce cytolytic T lymphocytes in most subjects with cancer promotes the development of multi-epitope p53 vaccines.
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PMID:Toward the development of multi-epitope p53 cancer vaccines: an in vitro assessment of CD8(+) T cell responses to HLA class I-restricted wild-type sequence p53 peptides. 1763 Oct 51

Cell proliferation is strictly controlled during differentiation. In T cell development, the cell cycle is normally arrested at the CD4(+)CD8(+) stage, but the mechanism underlying such differentiation-specific exit from the cell cycle has been unclear. Fbxw7 (also known as Fbw7, Sel-10, hCdc4, or hAgo), an F-box protein subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle, such as c-Myc, c-Jun, cyclin E, and Notch. FBXW7 is often mutated in a subset of human cancers. We have now achieved conditional inactivation of Fbxw7 in the T cell lineage of mice and found that the cell cycle is not arrested at the CD4(+)CD8(+) stage in the homozygous mutant animals. The mutant mice manifested thymic hyperplasia as a result of c-Myc accumulation and eventually developed thymic lymphoma. In contrast, mature T cells of the mutant mice failed to proliferate in response to mitogenic stimulation and underwent apoptosis in association with accumulation of c-Myc and p53. These latter abnormalities were corrected by deletion of p53. Our results suggest that Fbxw7 regulates the cell cycle in a differentiation-dependent manner, with its loss resulting in c-Myc accumulation that leads to hyperproliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells.
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PMID:Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. 1798 2

The expression of beta-catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising that the transgenic expression of oncogenic beta-catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report, we demonstrate that this is because the expression of oncogenic beta-catenin induces DNA damage, growth arrest, oncogene-induced senescence (OIS), and apoptosis of immature thymocytes. In p53-deficient mice, the expression of oncogenic beta-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. beta-Catenin-induced thymic lymphomas are distinct from lymphomas that arise in p53(-/-) mice. They are CD4(-) CD8(-), while p53-dependent lymphomas are largely CD4(+) CD8(+), and they develop at an earlier age and in the absence of c-Myc expression or Notch1 signaling. Thus, we report that oncogenic beta-catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic beta-catenin.
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PMID:Beta-catenin expression results in p53-independent DNA damage and oncogene-induced senescence in prelymphomagenic thymocytes in vivo. 1816 Jul 17

CD8+ T cells play a pivotal role in protection against Mycobacterium tuberculosis infection. We identified a novel HLA-A*0201-restricted CD8+ T-cell epitope on a dominant secreted antigen of M. tuberculosis, MPT51, in HLA-A*0201 transgenic HHD mice. HHD mice were immunized with plasmid DNA encoding MPT51 with gene gun bombardment, and gamma interferon (IFN-gamma) production by the immune splenocytes was analyzed. In response to overlapping synthetic peptides covering the mature MPT51 sequence, the splenocytes were stimulated to produce IFN-gamma by only one peptide, p51-70. Three-color flow cytometric analysis of intracellular IFN-gamma and cell surface CD4 and CD8 staining revealed that the MPT51 p51-70 peptide contains an immunodominant CD8+ T-cell epitope. Further analysis using computer algorithms permitted identification of a bona fide T-cell epitope, p53-62. A major histocompatibility complex class I stabilization assay using T2 cells confirmed that this epitope binds to HLA-A*0201. The T cells were capable of lysing MPT51 p53-62 peptide-pulsed T2 cells. In addition, MPT51 p53-62-specific memory CD8+ T cells were found in tuberculin skin test-positive HLA-A*0201+ healthy individuals. Use of this HLA-A*0201-restricted CD8+ T-cell epitope for analysis of the role of MPT51-specific T cells in M. tuberculosis infection and for design of vaccines against tuberculosis is feasible.
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PMID:Identification of an HLA-A*0201-restricted T-cell epitope on the MPT51 protein, a major secreted protein derived from Mycobacterium tuberculosis, by MPT51 overlapping peptide screening. 1821 86

Senescent and suppressor T cells are reported to be increased in select patients with cancer and are poor prognostic indicators. Based on the association of these T cells and poor outcomes, we hypothesized that tumors induce senescence in T cells, which negatively effects antitumor immunity. In this report, we show that human T cells from healthy donors incubated with tumor for only 6 h at a low tumor to T-cell ratio undergo a senescence-like phenotype, characterized by the loss of CD27 and CD28 expression and telomere shortening. Tumor-induced senescence of T cells is induced by soluble factors and triggers increases in expression of senescence-associated molecules such as p53, p21, and p16. Importantly, these T cells are not only phenotypically altered, but also functionally altered as they can suppress the proliferation of responder T cells. This suppression requires cell-to-cell contact and is mediated by senescent CD4(+) and CD8(+) subpopulations, which are distinct from classically described natural T regulatory cells. Our observations support the novel concept that tumor can induce senescent T cells with suppressor function and may effect both the diagnosis and treatment of cancer.
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PMID:Tumor-induced senescent T cells with suppressor function: a potential form of tumor immune evasion. 1824 89

Radiolabeled monoclonal antibodies (mAb) have demonstrated measurable antitumor effects in hematologic malignancies. This outcome has been more difficult to achieve for solid tumors due, for the most part, to difficulties in delivering sufficient quantities of mAb to the tumor mass. Previous studies have shown that nonlytic levels of external beam radiation can render tumor cells more susceptible to T cell-mediated killing. The goal of these studies was to determine if the selective delivery of a radiolabeled mAb to tumors would modulate tumor cell phenotype so as to enhance vaccine-mediated T-cell killing. Here, mice transgenic for human carcinoembryonic antigen (CEA) were transplanted with a CEA expressing murine carcinoma cell line. Radioimmunotherapy consisted of yttrium-90 (Y-90)-labeled anti-CEA mAb, used either alone or in combination with vaccine therapy. A single dose of Y-90-labeled anti-CEA mAb, in combination with vaccine therapy, resulted in a statistically significant increase in survival in tumor-bearing mice over vaccine or mAb alone; this was shown to be mediated by engagement of the Fas/Fas ligand pathway. Mice receiving the combination therapy also showed a significant increase in the percentage of viable tumor-infiltrating CEA-specific CD8(+) T cells compared to vaccine alone. Mice cured of tumors demonstrated an antigen cascade resulting in CD4(+) and CD8(+) T-cell responses not only for CEA, but for p53 and gp70. These results show that systemic radiotherapy in the form of radiolabeled mAb, in combination with vaccine, promotes effective antitumor response, which may have implications in the design of future clinical trials.
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PMID:Use of radiolabeled monoclonal antibody to enhance vaccine-mediated antitumor effects. 1825 32


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