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)

Cell lineage-specific cellular proteins, oncogenes from viral or cellular origin and tumor suppressor genes encode tumor-specific/associated antigens. Such antigens can elicit an major compatibility complex (MHC) class I-restricted cytotoxic T lymphocyte (CTL) response, either naturally in cancer patients or following appropriate immunostimulation (in vitro or in vivo). The reported immune responses in humans to the melanoma-associated MAGE gene products, GP100 and tyrosinase, all self-proteins, support the idea to use wild-type p53 products as targets for T cells. An important step towards this goal is identification of potential p53 CTL epitopes. We identified the wild-type p53 peptides with the highest affinity to the HLA-A*0201 molecule using two assays: the previously described MHC peptide-binding assay and the peptide competition assay. We obtained CTL against four p53 peptides with a high affinity for the HLA-A*0201 molecule. These findings are discussed next to a short review concerning the p53 literature.
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PMID:p53, a potential target for tumor-directed T cells. 808 74

The treatment of cancer with tumor vaccines has been a goal of physicians and scientists ever since effective immunization against infectious disease with vaccines was developed. In the past, major tumor antigens had not been molecularly characterized. Recent advances are, however, beginning to define potential molecular targets and strategies and this had evolved with the principle that T-cell mediated responses are a key target for approaches to cancer immunization. In addition, these antigens are not truly foreign and tumour antigens fit more with a self/altered self paradigm, compared to a non-self paradigm for antigens recognized in infectious diseases. Potential antigens include the glycolipids and glycoproteins (e.g. gangliosides), the developmental antigens (e.g. MAGE, tyrosinase, melan-A and gp75) and mutant oncogene products (e.g. p53, ras, and HER-2/neu). Innovations for construction of cancer vaccines are emerging from these advances in molecular immunology and cancer biology. While vaccines against infectious agents are models for vaccine development, there are clearly distinct considerations and problems associated with cancer vaccines. One of the focal issues in designing active cancer immunotherapy is that cancer cells are derived from normal host cells. Thus, the antigenic profile of cancer cells closely mimics that of normal cells. How the immune system identifies and destroys cancer cells is therefore crucial. Clearly, the ultimate goal of tumor vaccine design is the generation of antigen-specific vaccines. The recent success identifying molecularly defined tumor antigens opens up potentially novel strategies for this approach. Vaccine possibilities include purified proteins and glycolipids, peptides, cDNA expressed in various vectors, and a range of immune adjuvants. The molecular and structural definition of tumor antigens provides an opportunity for cautious optimism that we are entering an era when we will soon begin to recapitulate the success of immunization against infectious disease.
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PMID:Definition of tumor antigens suitable for vaccine construction. 893 70

Given the plethora of well-documented breast carcinoma-associated antigens in humans including MAGE-1, -2 and -3, mutated p53, p21ras, HER-2/neu and DF3/MUC-1, coupled with evidence that humoral and cytotoxic T-cell responses against these antigens exist, the central dilemma facing tumor immunologists is why the host immune response is so inefficient. One possibility is that tumor cells themselves are either inefficient or ineffective antigen-presenting cells (APCs). The failure of tumor cells to function as APCs may be due to their inability to process and present the antigen, the absence or insufficient numbers of adhesion and costimulatory molecules or, potentially, the secretion of inhibitory cytokines. Therefore, we sought to determine whether human breast cancer cell lines could function as APCs and, if not, to identify mechanism(s) responsible for this defect. Here, we show that human breast cancer cell lines fail to present alloantigen. This defect does not reside in their inherent capacity to present antigen but rather is due to apoptosis of activated T cells induced by exposure to the breast carcinoma-associated mucin antigen, DF3/MUC1. These results support the hypothesis that DF3/MUC1 may contribute to the paucity of clinically significant anticarcinoma-specific immune responses.
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PMID:Breast cancer-associated antigen, DF3/MUC1, induces apoptosis of activated human T cells. 894 37

For the presentation of peptide antigens to cytotoxic CD8+ T lymphocytes of the immune system, the expression of human leukocyte antigen (HLA) class I molecules on the cell surface is necessary. There is increasing evidence that surface HLA class I antigen expression is altered in a variety of human tumours by either loss or down-regulation of these molecules, which may be a strategy for evasion of immunosurveillance by malignant cells. This study has examined the expression of HLA class I molecules in head and neck squamous cell carcinoma (HNSCC) specimens by immunohistochemistry, using a wide panel of antibodies directed against allele-specific as well as monomorphic determinants of these molecules. The expression of TAP proteins, HLA-DR and the co-stimulatory molecule ICAM-1 were also studied. In addition, the expression of the tumour-associated antigens (TAA) p53 and MAGE genes was determined. Aberrant allelic expression of HLA class I antigens was detected in 17 out of 34 (50%) of the specimens stained, whereas HLA class I expression determined by W6/32 staining was found to be heterogeneous in only 2 out of 34 (6%) cases. Decreased expression of ICAM-1 was observed in 12 out of 34 (35%) tumour specimens and de novo expression of HLA-DR (HLA class II) by carcinoma cells in 13 out of 34 (38%) cases. Aberrant expression of HLA class I antigens was frequently observed in cases in which MAGE genes and p53 overexpression were detected. The altered expression of these immunomodulatory molecules in HNSCC may affect prognosis and has important implications for peptide-based immunotherapy strategies for these patients.
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PMID:An immunohistochemical study of altered immunomodulatory molecule expression in head and neck squamous cell carcinoma. 932 40

Adenocarcinomas of the breast behave clinically and epidemiologically in ways that show host resistance factors are important for outcome in addition to grade and stage of malignancy. Immune reactivity to autologous tumors is indicated by the general presence of lymphoid infiltration (LI) and regional lymph node changes; however, these changes predict favorable outcome only in non-metastatic disease. LI is characterized by CD4+ and CD8+ tumor infiltrating lymphocytes reflecting latent cell-mediated immunity (CMI). CMI and humoral immune reactivity have been demonstrated to autologous tumor and a variety of tumor-associated antigens (TAA) have been implicated including CEA, HER-2/neu, MAGE-1, p53, T/Tn and MUC-1. Immune incompetence involving CMI is progressive with the stage of breast cancer and is prognostically significant. Immunotherapy of several types has been designed to address this immunodeficiency and the TAAs involved. Animal models have employed drug therapy, cytokine transfection, vaccines with autologous tumor, cytokines like interferon alpha (IFN-alpha) and interleukin-2 (IL-2), TAA tumor vaccines, and immunotoxins with evidence of tumor regression by immunologic means. Immunotherapy of human breast cancer is a rapidly growing experimental area. Positive results have been obtained with natural IFN and interleukins, particularly in combination strategies (but not with high dose recombinant IFN or IL-2), with autologous tumor vaccine (but not yet with transfected autologous tumor); with a mucin carbohydrate vaccine (Theratope) in a combination strategy (but not with mucin core antigen) and with several immunotoxins. Combination strategies involving immunorestoration, contrasuppression, adjuvant, and immunotoxins are suggested for the future.
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PMID:The immunology and immunotherapy of breast cancer: an update. 1023 Aug 72

Tumor-associated antigens that can be recognized by the immune system include the MAGE-family, p53, MUC-1, HER2/neu and p21ras. Despite their expression of these distinct antigens, tumor elimination by the immune system is often inefficient. Postulated mechanisms include insufficient expression of co-stimulatory or adhesion molecules by tumor cells, or defective processing and presentation of antigens on their cell surfaces. Tumor cells may also evade immune attack by expressing CD95 (APO-1/Fas) ligand or other molecules that induce apoptosis in activated T cells. Here we describe RCAS1 (receptor-binding cancer antigen expressed on SiSo cells), a membrane molecule expressed on human cancer cells. RCAS1 acts as a ligand for a putative receptor present on various human cell lines and normal peripheral lymphocytes such as T, B and NK cells. The receptor expression was enhanced by activation of the lymphocytes. RCAS1 inhibited the in vitro growth of receptor-expressing cells and induced apoptotic cell death. Given these results, tumor cells may evade immune surveillance by expression of RCAS1, which would suppress clonal expansion and induce apoptosis in RCAS1 receptor-positive immune cells.
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PMID:Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated antigen RCAS1. 1042 6

We report the immunological characterization of three colon carcinoma cell lines, COLO 205, SW620 and SW403, which we selected to combine with cytokine-secreting fibroblasts for the development of an allogeneic tumour cell vaccine. The cell lines expressed HLA-A2 as well as shared tumour-associated antigens (TAAs) representative of colon carcinomas: CEA, Ep-CAM, MUC1, HER2/neu and MAGE antigens. They did not secrete high levels of the immunosuppressive factors TGF-beta, IL-10 or prostaglandins. The lines presented TAAs in a manner recognized by immune effector cells, which was demonstrated by the lysis of SW620 by HLA-A2-restricted anti-p53 cytotoxic T lymphocytes (CTL). COLO 205 and SW620 were genetically modified to express the co-stimulatory molecule CD80 (B7.1), which increased the ability of the cells to stimulate CTL in vitro. CTL clones derived from HLA-A2+ peripheral blood mononuclear cells stimulated with the CD80-expressing lines lysed the stimulator cell and an HLA-A2+ colon cancer cell line, but did not lyse an isogeneic fibroblast line or an HLA-A2- colon cancer cell line. CTL clones derived from colon carcinoma patients immunized with an allogeneic vaccine containing these lines demonstrated killing of autologous tumour cells, the vaccine cell lines and other HLA-A2+ colon cancer cell lines, but not fibroblasts isogeneic to certain of the target cell lines. Our studies demonstrate that these colon carcinoma cell lines express shared TAAs that can induce CTLs which recognize and lyse other colon carcinoma cells, and support the continued clinical evaluation of the CD80 gene modified allogeneic colon cell/cytokine-secreting fibroblast carcinoma vaccine.
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PMID:Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine. 1210 28

The ability of the immune system to recognize structurally altered, amplified or aberrantly expressed proteins can be used to identify molecules of etiologic relevance to cancer and to define targets for cancer immunotherapy. In the current study, ninety-four distinct antigens reactive with serum IgG from breast cancer patients were identified by immunoscreening breast cancer-derived cDNA expression libraries (SEREX). A serological profile was generated for each antigen on the basis of reactivity with allogeneic sera from normal individuals and cancer patients, and mRNA expression profiles for coding sequences were assembled based upon the tissue distribution of expressed sequence tags, Northern blots and real-time RT-PCR. Forty antigens reacted exclusively with sera from cancer patients. These included well-characterized tumor antigens, e.g. MAGE-3, MAGE-6, NY-ESO-1, Her2neu and p53, as well as newly-defined breast cancer antigens, e.g. kinesin 2, TATA element modulatory factor 1, tumor protein D52 and MAGE D, and novel gene products, e.g. NY-BR-62, NY-BR-75, NY-BR-85, and NY-BR-96. With regard to expression profiles, two of the novel gene products, NY-BR-62 and NY-BR-85, were characterized by a high level of testicular mRNA expression, and were overexpressed in 60% and 90% of breast cancers, respectively. In addition, mRNA encoding tumor protein D52 was overexpressed in 60% of breast cancer specimens, while transcripts encoding SNT-1 signal adaptor protein were downregulated in 70% of these cases. This study adds to the growing list of breast cancer antigens defined by SEREX and to the ultimate objective of identifying the complete repertoire of immunogenic gene products in human cancer (the cancer immunome).
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PMID:Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression. 1274 65

Gankyrin, a recently discovered oncoprotein, is a promising target for drug therapy because it is overexpressed in most hepatocellular carcinomas. Since gankyrin interacts with MAGE-A4, we made several MAGE-A4 mutants and assessed their effects on cell growth. We found that the C-terminal 107 amino acids of MAGE-A4 (MAGE-A4DeltaN1) induced p53-dependent and p53-independent apoptosis. MAGE-A4DeltaN1 increased the p53 protein level, but decreased the p21(Cip1) transcript and protein levels. During apoptosis Bcl-xL was down-regulated and mitochondrial integrity was disrupted. A yeast two-hybrid screen identified Miz-1 as a MAGE-A4DeltaN1-binding protein. MAGE-A4DeltaN1 was recruited through association with Miz-1 to the p21(Cip1) promoter and down-regulated transcription of p21(Cip1). In 293T cells and U-2 OS cells, full-length MAGE-A4 was processed to generate a C-terminal fragment of 104 amino acids with activities similar to MAGE-A4DeltaN1. Processing was inhibited with a broad range caspase inhibitor Z-VAD-FMK, but not by site-directed mutagenesis of aspartic acids in MAGE-A4, suggesting an indirect involvement of caspase(s) in the processing. The amount of the processed form was increased by exposure of cells to adriamycin. Transduction with a HIV Tat-MAGE-A4DeltaN1 fusion protein suppressed anchorage-independent growth of gankyrin-overexpressing cells in vitro and in vivo. These results demonstrate that the C-terminal fragment of MAGE-A4 induces apoptosis at least partly by binding to Miz-1, and that the fragment may be exploited as an anticancer agent. Furthermore, the finding that a C-terminal fragment with pro-apoptotic activity is generated from full-length MAGE-A4 after genotoxic stress in human cells suggests a novel function for MAGE-A4.
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PMID:A cleaved form of MAGE-A4 binds to Miz-1 and induces apoptosis in human cells. 1473 98

hNRAGE, a neurotrophin receptor p75 interacting MAGE homologue, is cloned from a human placenta cDNA library. hNRAGE can inhibit the colony formation of and arrest cell proliferation at the G1/S and G2/M stages in hNRAGE overexpressing cells. Interestingly, hNRAGE also increases the p53 protein level as well as its phosphorylation (Ser392). Further studies demonstrated that hNRAGE does not affect the proliferation of mouse p53-/- embryonic fibroblasts, suggesting that p53 function is required for hNRAGE induced cell cycle arrest. Moreover, the cell cycle inhibiting protein p21(WAF) is induced by hNRAGE in a p53 dependent manner. The data provide original evidence that hNRAGE arrests cell growth through a p53 dependent pathway.
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PMID:hNRAGE, a human neurotrophin receptor interacting MAGE homologue, regulates p53 transcriptional activity and inhibits cell proliferation. 1509 62


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