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)

The anti-HIV agent MAP30 (Momordica anti-HIV protein, 30 kDa) inhibits the proliferation of BC-2, an AIDS-related primary effusion lymphoma (PEL) cell line derived from an AIDS patient. BC-2 cells are latently infected with Kaposi's sarcoma-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV8). We examined the effect of MAP30 on the expression of viral and cellular genes in BC-2 during latent and lytic states of the viral life cycle. By Northern analysis and RT-PCR, we found that MAP30 downregulates the expression of viral cyclin D (vCD), viral interleukin-6 (vIL-6), and viral FLIP (vFLIP), genes involved in cell cycle regulation, viral pathogenesis, and apoptosis. By pathway-specific cDNA microarray analysis, we found that BC-2 cells express high levels of egr-1, ATF-2, hsp27, hsp90, IkappaB, mdm2, skp1, and IL-2, cellular genes involved in mitogenesis, tumorigenesis, and inhibition of apoptosis in NFkappaB and p53 signaling pathways. These results define for the first time the specific cellular pathways involved in AIDS-related tumorigenesis and suggest specific novel targets for the treatment. Furthermore, we found that MAP30 downregulates the expression of egr-1, ATF-2, hsp27, hsp90, IkappaB, mdm2, and Skp1, while it upregulates the pro-apoptotic-related genes Bax, CRADD, and caspase-3. Thus, MAP30 modulates the expression of both viral and cellular genes involved in KS pathogenesis. These results provide valuable insight into the molecular mechanisms of MAP30 anti-KS action and suggest its utility as a therapeutic agent against AIDS-related tumors.
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PMID:Anti-HIV agent MAP30 modulates the expression profile of viral and cellular genes for proliferation and apoptosis in AIDS-related lymphoma cells infected with Kaposi's sarcoma-associated virus. 1157 62

In 44 patients with advanced ovarian carcinoma (OC) a fraction of CD45RO(+) lymphocytes in the blood and peritoneal carcinomatous fluid (PCF) was investigated. Thirty-one patients received cisplatinum with cyclophosphamide +/- doxorubicin. This group was followed from 2.2 to 9 years (mean: 45 months). In 23 out of 31 patients, the percentage of CD45RO(+) lymphocytes was higher in the PCF than in the blood samples. Patients with these higher lymphocyte levels experienced longer survival than those who did not show any excess of CD45RO(+) lymphocytes in PCF ( P=0.02). This was further verified by the use multivariate Cox analysis which included an assessment of the percentage of CD45RO(+) lymphocytes in PCF, age, FIGO status, histology, treatment (CAP or CP) and residual disease (RD) post-surgery. This analysis revealed that two factors had an independent power of prediction: RD ( P=0.02) and the percentage of CD45RO(+) cells in PCF ( P=0.04). Therefore, CD45RO(+) lymphocytes were studied in further detail in a group of 20 patients. This study revealed that PCF CD45RO(+) lymphocytes were characterized by: (1) a higher proportion of cells co-expressing activation markers (HLA-DR, CD28) and higher levels of mRNA for CXC chemokines (IP-10, IL-8) and for IL-10, but with lower levels for IL-2; (2) higher levels of Ki67, bcl-2 and p53 mRNA as compared to those in blood. In conclusion, in the present study it was found that an accumulation of activated CD45RO(+) cells in PCF had a beneficial effect on the survival of patients receiving platinum-based chemotherapy.
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PMID:Accumulation of CD45RO(+) cells in peritoneal carcinomatous fluid favours survival of ovarian carcinoma patients. 1235 23

In this study, we demonstrate that p53 directly inhibits expression of the T cell growth factor (IL-2) in activated T cells. This repression is independent of the intrinsic transcriptional activity of p53 and is mediated by the Tax-responsive CD28RE-3'-12-O-tetradecanoylphorbol-13-acetate response element (AP1) element of the IL-2 promoter. Coexpression of the Tax oncogene causes full reversal of this repression through coordinate targeting of p300, CREB, and the NF-kappaB pathways. Paradoxically, IL-2 repression by p53 is not reversed by mdm2. Instead, mdm2 represses the IL-2 promoter by a mechanism that is synergistic with p53 and resistant to Tax reversal. The p300 structure-function studies show that these effects are linked to competitive associations among p53, Tax, and mdm2 with multiple domains of p300. The functional outcome of these antagonistic associations is revealed further by the observation that Tax and p53 induce apoptosis in activated T cells through separate and mutually exclusive pathways. Interestingly, both pathways are abrogated by mdm2. These results provide evidence that a dynamic interplay, between Tax and specific elements of the p53 network, mediates growth factor expression and programmed cell death in activated T cells.
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PMID:Cross-regulation of T cell growth factor expression by p53 and the Tax oncogene. 1247 Nov 8

Antibody-based targeted immunotherapy has shown promise as an approach to treat cancer. However, many known tumor-associated antigens are not expressed as integral membrane proteins and cannot be utilized as targets for antibody-based therapeutics. In order to expand the limited target range of antibodies, we have constructed a soluble single-chain T-cell receptor (TCR) fusion protein designated 264scTCR/IL-2. This fusion protein is comprised of a three-domain HLA-A2-restricted TCR specific for a peptide epitope of the human p53 tumor suppressor protein, which is overexpressed in a broad range of human malignancies. The 264scTCR/IL-2 fusion protein has been expressed at high levels in mammalian cells, and milligram quantities have been purified. MHC-restricted antigen-specific binding properties are maintained in the single-chain, three-domain TCR portion of the fusion protein, and the IL-2 portion retains bioactivity similar to that of free recombinant IL-2. Moreover, this fusion protein is capable of conjugating target and effector cells, remains intact in the blood and substantially increases the half life of the IL-2 portion of the molecule. Finally, the 264scTCR/IL-2 fusion protein can be used to stain tumor cells and is capable of reducing lung metastases in an experimental model of metastasis. Thus, TCR-based fusion proteins may provide a novel class of targeted immunotherapeutics for cancer.
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PMID:A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity. 1461 Jun 21

IL-7 induction of protein tyrosine phosphorylation was examined in an IL-7-dependent thymocyte cell line, D1, which was generated from a p53-/- mouse. Anti-phosphotyrosine antibody was used both to immunoprecipitate and Western blot, and showed that IL-7 induced tyrosine phosphorylation of a protein with a molecular weight of approximately 200 kDa. The P200 band was purified by reversed-phase high-performance liquid chromatography. Amino acid sequencing by mass spectrometry revealed three peptides identical to rat clathrin heavy chain (CHC) 1 (192 kDa), and this was confirmed by blotting with an anti-clathrin antibody. Stimulation of normal pro-T cells by IL-7 showed an increased tyrosine phosphorylation of clathrin heavy chain. Tyrosine phosphorylation of clathrin heavy chain was strongly induced by IL-7 and to a lesser extent by IL-4, while no effect could be observed with the cytokines IL-2, IL-9 and IL-15, whose receptors share the gammac chain. Phosphorylation of clathrin heavy chain was found to be sensitive to Jak3 inhibitors but not to Src inhibitors. Clathrin is involved in internalization of many receptors, and its phosphorylation by IL-7 stimulation may affect the internalization of the IL-7 receptor.
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PMID:IL-7 induces tyrosine phosphorylation of clathrin heavy chain. 1463 98

Peptides derived from over-expressed p53 protein are presented by class I MHC molecules and may act as tumour-associated epitopes. Due to the diversity of p53 mutations, immunogenic peptides representing wild-type sequences are preferable as a basis for a broad-spectrum p53-targeting cancer vaccine. Our preclinical studies have shown that wild-type p53-derived HLA-A2-binding peptides are able to activate human T cells and that the generated effector T cells are cytotoxic to human HLA-A2+, p53+ tumour cells. In this phase I pilot study, the toxicity and efficacy of autologous dendritic cells (DCs) loaded with a cocktail of three wild-type and three modified p53 peptides are being analysed in six HLA-A2+ patients with progressive advanced breast cancer. Vaccinations were well tolerated and no toxicity was observed. Disease stabilisation was seen in two of six patients, one patient had a transient regression of a single lymph node and one had a mixed response. ELISpot analyses showed that the p53-peptide-loaded DCs were able to induce specific T-cell responses against modified and unmodified p53 peptides in three patients, including two of the patients with a possible clinical benefit from the treatment. In conclusion, the strategy for p53-DC vaccination seems safe and without toxicity. Furthermore, indications of both immunologic and clinical effect were found in heavily pretreated patients with advanced breast cancer. An independent clinical effect of repeated administration of DCs and IL-2 can not of course be excluded; further studies are necessary to answer these questions.
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PMID:Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. 1498 57

The gene expressions for macrophage chemoattractant protein-1 (MCP-1), interleukin (IL)-1 beta, IL-2 and p53 were examined by semi-quantitative RT-PCR in corpora lutea (CL) of rabbits during spontaneous luteolysis at days 13, 15, 18 and 22 of pseudopregnancy. In the same luteal tissue, total activity of nitric oxide (NO) synthase (NOS) and genes for both endothelial (eNOS) and inducible (iNOS) isoforms were also analysed. From day 13 to 15, MCP-1 and IL-1 beta mRNA levels rose (P < or = 0.01) almost 2-fold, and the transcript for p53 almost 8-fold, but then all dropped (P < or = 0.05) from day 18 onward. IL-2 mRNA abundance was higher (P < or = 0.01) on day 13 and then gradually declined. During luteolysis, eNOS mRNA decreased 40% (P < or = 0.05) by day 15, but thereafter remained unchanged, while iNOS mRNA was barely detectable and did not show any clear age-related pattern throughout the late luteal stages. Total NOS activity progressively increased (P < or = 0.01) from day 13 to 18 of pseudopregnancy and then dropped to the lowest (P < or = 0.01) levels on day 22. Luteal progesterone content also declined during CL regression from 411 to 17 pg/mg found on days 13 and 22 respectively, in parallel with the decrease in blood progesterone concentrations. These data further support a physiological role of NO as modulator of luteal demise in rabbits. Locally, luteal cytokines may be involved in the up-regulation of NOS activity, while downstream NO may inhibit steroroidogenesis and induce expression of p53 gene after removal of the protective action of progesterone.
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PMID:Expression patterns of cytokines, p53 and nitric oxide synthase isoenzymes in corpora lutea of pseudopregnant rabbits during spontaneous luteolysis. 1505 89

Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease, usually associated with cigarette smoking. Stimulated peripheral blood T cells from patients with COPD have an increased propensity to undergo apoptosis. The mitochondrial apoptotic pathway is regulated by pro-apoptotic proteins (including p53 and Bax) as well as anti-apoptotic proteins (e.g. Bcl-2) and cytokines (IL-2, IL-4 and IL-7). We hypothesized that alterations in expression of these apoptosis-related proteins, cytokines and cytokine receptors may be important in determining the susceptibility of T cells to undergoing apoptosis in COPD. We further hypothesized that inhaled corticosteroids (GCS) contribute to the increased rates of T-cell apoptosis observed in COPD. The process of apoptosis (assessed by Annexin V and ssDNA staining), as well as Bcl-2, Bax, p53, IL-2, IL-4 and receptors IL-7R, IL-4R and IL-2Rgamma were investigated in PHA-stimulated peripheral blood-derived T cells, using flow cytometry. Fifteen patients with COPD receiving inhaled GCS (four of who received additional prednisolone), eight patients with COPD receiving symptom control medication, and 16 control subjects were studied. T cells (CD4(+) and CD8(+)) from GCS-treated COPD patients showed an increased propensity to undergo apoptosis, associated with significantly decreased Bcl-2 and IL-7 receptor expression. No significant differences were observed for the COPD patients who were receiving symptom control medication. These findings may suggest a negative peripheral effect of inhaled GCS on the immune system in COPD, although the clinical significance of these effects remains uncertain.
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PMID:Increased peripheral blood T-cell apoptosis and decreased Bcl-2 in chronic obstructive pulmonary disease. 1574 12

Cancer is a big problem in the developed world as well as in developing countries. Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. RCC is more common in men than in women (2:1), and it most often occurs in patients between the ages of 50-70 years. In all cancers the cancerous cells release particular kind of proteins (called tumour markers) and blood tests are used to detect the presence of these markers. These tumour markers nowadays are an area of interest for oncologists who search for a possible solution in the detection and treatment of RCC. Different kinds of biochemical and molecular markers such as ferritin, MN/CA9, apoptotic index, p53, IL-2, gamma-enolase, CD44, CD95, chromosome instability and loss of heterozygosity have been tested in RCC, but so far no marker fulfils one or the other criteria to be considered as an ideal marker for RCC. This review gives basic and updated information about the different kinds of biomarkers studied in RCC and about the role implementation of genomics and proteomics in RCC.
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PMID:Biochemical and molecular markers in renal cell carcinoma: an update and future prospects. 1619 85

Mesothelioma may be particularly well suited for gene therapy treatment owing to its accessibility, allowing both intrapleural and intratumoral gene delivery. At least four gene therapy trials have been carried out in mesothelioma patients, using different vector systems (adenovirus, vaccinia virus, irradiated tumor cells), and different transgenes (herpes simplex virus thymidine kinase (HSVtk) combined with ganciclovir, IL-2, IFN-beta). Although small in scale, these trials have given an inkling of hope for therapeutic efficacy. However, it is clear that gene therapy protocols need to be optimized further. This paper will review progress made in (i) vector development, (ii) defining optimal transgenes, and (iii) gene delivery. Adenoviruses are the most commonly used vectors for gene therapy, and are continuously being improved. With respect to the nature of the transgenes, five categories can be distinguished: (i) 'suicide' or sensitivity genes (e.g., HSVtk), (ii) cytokines and other immune modulators, (iii) replacements for mutant tumor suppressor genes (e.g., p53), (iv) antiangiogenic proteins and (v) tumor antigens. It seems clear that expression of a single transgene is unlikely to be sufficient to eradicate a tumor, such as mesothelioma, that is diagnosed late in disease progression. Hence, multimodality therapy, including conventional therapy (chemo- and radiotherapy, surgery) with one or more transgenes has a higher chance of success.
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PMID:Gene therapy for malignant mesothelioma: beyond the infant years. 1643 92


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