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)

Retrovirally expressed interleukin-2 gene, granulocyte macrophage-colony stimulating factor gene, herpes simplex virus-thymidine kinase gene and p53 gene in human esophageal cancer cells showed antitumor effects in a nude mice xenotransplant model. We established a clinical protocol of gene therapy for advanced esophageal cancer using the wild type p53 gene with an adenovirus vector. In December of 2000, we began the first tumor suppressor gene therapy trial. Now, this trial, which has 9 patients. There have been no serious adverse event excluding fever and local pain. The feasibility of this treatment appears fairly good in these 9 cases. Furthermore, we developed a new method for transducing genes without a virus vector since a virus vector has several potentially unwanted properties. In vivo electroporation is a useful strategy for cancer gene therapy. Moreover, electric pulse to established solid tumors increases intracellular concentrations of chemotherapeutic agents. Transduction of the wild-type p53 gene by electroporation decreased the amount of nedaplatin required for tumor suppression. Electrochemo-gene therapy is a relatively simple method and can produce a better therapeutic effect.
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PMID:[Progress of gene therapy for esophageal cancer in Japan]. 1289 8

Exposure of murine bone marrow (BM) cells to ionizing radiation (IR; 4 Gy) resulted in >95% inhibition of the frequency of various day types of cobblestone area-forming cells in association with the induction of apoptosis in hematopoietic stem cell alike cells (Lin(-) ScaI(+) c-kit(+) cells; IR: 64.8 +/- 0.4% versus control: 20.4 +/- 0.5%; P < 0.001) and progenitors (Lin(-) ScaI(-) c-kit(+) cells; IR: 46.2 +/- 1.4% versus control: 7.8 +/- 0.5%; P < 0.001). Incubation of murine BM cells with busulfan (BU; 30 micro M) for 6 h also inhibited the cobblestone area-forming cell frequency but failed to cause a significant increase in apoptosis in these two types of hematopoietic cells. After 5 weeks of long-term BM cell culture, 33% and 72% of hematopoietic cells survived IR- and BU-induced damage, respectively, as compared with control cells, but they could not form colony forming units-granulocyte macrophages. Moreover, these surviving cells expressed an increased level of senescence-associated beta-galactosidase, p16(Ink4a), and p19(Arf). These findings suggest that IR inhibits the function of hematopoietic stem cell alike cells and progenitors primarily by inducing apoptosis, whereas BU does so mainly by inducing premature senescence. In addition, induction of premature senescence in BM hematopoietic cells also contributes to IR-induced inhibition of their hematopoietic function. Interestingly, the induction of hematopoietic cell senescence by IR, but not by BU, was associated with an elevation in p53 and p21(Cip1/Waf1) expression. This suggests that IR induces hematopoietic cell senescence in a p53-p21(Cip1/Waf1)-dependent manner, whereas the induction of senescence by BU bypasses the p53-p21(Cip1/Waf1) pathway.
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PMID:Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. 1450 Mar 76

Tumors of endothelial origin develop rarely. Until now, only two angiosarcoma (AS)-derived endothelial cell lines have been be isolated, ISO-HAS and AS-M. Both AS-derived endothelial cell lines presented the typical endothelial characteristics, such as the expression of CD31 and von Willebrand factor, but differed from normal endothelial cells in a nuclear expression of p53, in a delayed angiogenic reaction, and a reduced expression of caveolin. In addition, differences in the expression of cytokines and cell adhesion molecules responsive to proinflammatory stimuli were observed. While AS-M showed an expression pattern similar to that of human umbilical vein endothelial cells (HUVEC), ISO-HAS clearly differed from primary endothelial cells by a constitutive expression of E-selection, granulocyte macrophage colony-stimulating factor, and vascular endothelial cell adhesion molecule-1. Even though the telomeres of both AS-derived established cell lines were longer than telomeres of freshly isolated HUVEC, neither transcripts encoding telomerase nor telomerase activity were detected, suggesting that the tumor cells of endothelial origin may use a telomerase-independent mechanism for maintaining the telomere length. This observation has implications for development of therapeutic approaches for angiosarcoma.
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PMID:Tumorigenic conversion of endothelial cells. 1451 78

We investigated whether detection of cytokeratin-positive (CK+) cells in the peripheral blood (PB) of breast cancer patients before chemotherapy could be a prognostic factor. Blood from a total of 92 breast cancer patients was evaluated for the presence of CK+ cells. Blood samples were collected before chemotherapy. Patients entered in the study included: neoadjuvant (n = 25), adjuvant (n = 42) and metastatic (n = 25). Blood samples (10 ml) were centrifuged using a double density-gradient to recovering the mononuclear cell (MNC) and granulocyte cell (GC) fractions. Subsequently, positive immunomagnetic cell separation was carried out to isolating CK+ cells. The enriched cell fraction was cytocentrifuged and then immunocytochemically labeled using an anti-cytokeratin antibody. Our results indicated that breast tumor cells sediment with both MNC and GC fractions. We therefore recommend examination of both fractions in all enrichment protocols. CK+ cells in PB were identified in 57 of 92 (62%) patients when MNC and GC fractions were assessed (range = 1-61 cells, median = 8). No CK+ cells were detected in blood samples of 16 healthy donors. There were significant differences in the presence of CK+ cells according to estrogen receptor expression (p = 0.049), and lymph node status (p = 0.033), but not to the age, menopausal status, type of patient (neoadjuvant, adjuvant or metastatic), TNM stage, histological type, progesterone receptor expression, c-erbB2 expression, p53 expression or Ki67 expression. Regarding the relationship between tumor size (T) and the presence of CK+ cells, a borderline significant trend was observed (p = 0.07). The median follow-up of the patients was 21 months and statistical analysis (Kaplan-Meier analysis) showed that using the method we present, the detection of CK+ cells in PB before starting the chemotherapy in breast cancer patients was significantly correlated with both progression-free survival (p = 0.058) and overall survival (p = 0.003). In conclusion, the present study suggests that detection of CK+ cells in PB before chemotherapy might identify breast cancer patients with poor prognosis.
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PMID:Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. 1460 Oct 59

In this study, we investigated the localization and functional significance of p53 tumor suppressor-like molecules, p63 and p73, in human thymic epithelial cells (TECs). Immunohistochemical studies showed particular distribution profiles of p63 and p73 in thymic epithelium, in which cortical TECs preferentially expressed p63 in their nuclei whereas subcapsular and medullary TECs expressed both p63 and p73 in their nuclei. The wide distribution of p63 in TECs was further suggested by studies using TECs of primary culture. In vitro studies using two human TEC lines demonstrated that p63 was capable of up-regulating intercellular adhesion molecule-1 (ICAM-1) and enhancing the production of IL-6 and IL-8. Moreover, in vitro studies also indicated that p73, but not p63, had the capacity to induce granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) in the TEC lines. These findings suggest that p63 would regulate the cell adhesive property through ICAM-1/LFA-1 interaction and the production of IL-6 and IL-8, probably in all TEC subtypes. p73 in subcapslar and medullary TECs was suggested to play a role in the regulation of the production of GM-CSF and G-CSF, which might stimulate other stromal cells such as dendritic cells, macrophages and endothelial cells around these regions.
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PMID:Expression profiles and functional implications of p53-like transcription factors in thymic epithelial cell subtypes. 1512 18

A C6 beta-chemokine, CKbeta8-1, suppressed the colony formation of CD34+ cells of human cord blood (CB). Molecular mechanisms involved in CKbeta8-1-medicated suppression of colony formation of CD34+ cells are not known. To address this issue, the level of various G1/S cell cycle regulating proteins in CKbeta8-1-treated CD34+ cells were compared with those in untreated CD34+ cells. CKbeta8-1 did not significantly alter the expression of the G1/S cycle regulation proteins (cyclin D1, D3, and E), CDK inhibitor (p27and Rb), and other cell proliferation regulation protein (p53) in CB CD34+ cells. Here we describe an in vitro system in which CB CD34+ cells were committed to a multipotent progenitor lineage of colony forming units-granulocyte/macrophage (CFU-GM) by a simple combination of recombinant human (rh) GM-CSF and rhIL-3. In this culture system, we found that cyclin E protein appeared later and disappeared faster in the CKbeta8-1-treated cells than in the control cells during CFU-GM lineage development. These findings suggested that cyclin E may play a role in suppressing the colony formation of CFU-GM by CKbeta8-1.
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PMID:CKbeta8-1 alters expression of cyclin E in colony forming units-granulocyte macrophage (CFU-GM) lineage from human cord blood CD34+ cells. 1639 23

Benzene is a recognized hematotoxicant and carcinogen that produces genotoxic damage. DNA double-strand breaks (DSB) are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites. DSB may lead to chromosome aberrations, apoptosis and hematopoietic progenitor cell suppression. We hypothesized that genetic polymorphisms in genes involved in DNA DSB repair may modify benzene-induced hematotoxicity. We analyzed one or more single nucleotide polymorphisms (SNPs) in each of seven candidate genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4) in a study of 250 workers exposed to benzene and 140 controls in China. Four SNPs in WRN (Ex4 -16 G > A, Ex6 +9 C > T, Ex20 -88 G > T and Ex26 -12 T > G), one SNP in TP53 (Ex4 +119 C > G) and one SNP in BRCA2 (Ex11 +1487 A > G) were associated with a statistically significant decrease in total white blood cell (WBC) counts among exposed workers. The SNPs in WRN and TP53 remained significant after accounting for multiple comparisons. One or more SNPs in WRN had broad effects on WBC subtypes, with significantly decreased granulocyte, total lymphocyte, CD4(+)-T cell, CD8(+)-T cell and monocyte counts. Haplotypes of WRN were associated with decreased WBC counts among benzene-exposed subjects. Likewise, subjects with TP53 Ex4 +119 C > G variant had reduced granulocyte, CD4(+)-T cell and B cell counts. The effect of BRCA2 Ex11 +1487 A > G polymorphism was limited to granulocytes. These results suggest that genetic polymorphisms in WRN, TP53 and BRCA2 that maintain genomic stability impact benzene-induced hematotoxicity.
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PMID:Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity. 1672 35

A close association between inflammatory bowel disease (IBD) and increased risk of developing adenocarcinoma exists. Moreover, chronic induction of high levels of nitric oxide (NO) produced from inducible nitric oxide synthase (iNOS) is a consistent observation in IBD. In this study we made interleukin-10/inducible nitric oxide synthase double-deficient (IL-10(-/-)/iNOS(-/-)) mice and studied the development of adenocarcinoma. Mice >6 months of age were compared with healthy wild-type (WT) controls. Inflammation was assessed using macroscopic/histological scores and myeloperoxidase activity as an indication of granulocyte infiltration. Mucosal polyps were scored macroscopically and hyperproliferation was quantified by 5-bromo-2-deoxyuridine immunohistochemistry. Dysplastic changes were assessed histologically based on cytologic and architectured atypia as well as the presence of submucosal invasion. The p53 and beta-catenin messenger RNA mRNA and protein expression were assessed using real-time polymerase chain reaction and immunohistochemistry, respectively. Inflammatory indices were significantly elevated in interleukin-10-deficient (IL-10(-/-)) over WT and not significantly different from IL-10(-/-)/iNOS(-/-) mice. The incidence of mucosal polyps was similar between IL-10(-/-) (79%) and IL-10(-/-)/iNOS(-/-) (83%) mice; however, significantly higher numbers of polyps were observed in the absence of iNOS (P < 0.05). Hyperproliferation was noted in both groups. Signs of dysplasia and submucosal invasion were significantly higher in IL-10(-/-)/iNOS(-/-) compared with IL-10(-/-) mice (P < 0.05). No significant increase in p53 and beta-catenin mRNA levels was observed in IL-10(-/-) over WT mice; however, a 2-fold (P = 0.06) and 3-fold (P < 0.05) increase, respectively, was noted in IL-10(-/-)/iNOS(-/-) mice. Our data suggest exposure to chronic NO limits abnormal p53 and beta-catenin expression and reduces incidence of adenocarcinoma in IL-10(-/-) mice.
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PMID:Induction of inducible nitric oxide synthase: a protective mechanism in colitis-induced adenocarcinoma. 1711 28

Little information is available regarding the existence of gender dimorphism of tumor growth for most types of tumors. In a previous report we have demonstrated the existence of gender dimorphism in the growth of a murine T cell lymphoma, designated as Dalton's lymphoma (DL); moreover, tumor-associated macrophages (TAM) were found to play a central role in the manifestation of gender dimorphism observed in the growth of this T cell lymphoma. In view of these observations, the present investigation was undertaken to study if gender dimorphism in the growth of a T cell tumor also could be associated with a gender-dependent differential myelopoiesis of bone marrow cells. We have demonstrated the existence of a gender dimorphism in the proliferation, apoptosis and myeloid differentiation of bone marrow cells obtained from male and female tumor-bearing hosts. Androgen and estrogen were found to alter directly the growth properties of bone marrow cells, as also determined by the use of receptor antagonists of these hormones, flutamide and tamoxifen. Bone marrow cells of male and female tumor-bearing hosts also showed a differential expression of the cell cycle and apoptosis regulatory protein p53 and macrophage-colony stimulating factor (M-CSF) genes. Bone marrow cells of male tumor-bearing hosts showed a predominant differentiation in the macrophage lineage whereas those of female tumor-bearing mice were in the granulocyte lineage. Bone marrow-derived macrophages (BMDM) from male and female tumor-bearing mice also showed the existence of gender dimorphism with respect to their differentiation and activation. These observations are of clinical significance with respect to understanding of the host-tumor relationship at the level of gender dimorphism of myelopoiesis.
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PMID:Gender dimorphism in the myeloid differentiation of bone marrow precursor cells in a murine host bearing a T cell lymphoma. 1727 17

DeltaNp73alpha, the N-terminal truncated form of p73alpha is a candidate tumor antigen because of its selective expression in many human cancers and lack of expression in normal tissues. Therefore, we investigated the effects of dendritic cells infected with adenoviral DeltaNp73alpha (DNp73alpha) on breaking immune tolerance and induction of immunity against DNp73alpha-expressing (A549 lung cancer, K-562 leukemia) and non-expressing (MCF-7 breast cancer) cell lines. Immature dendritic cells generated in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor from a human umbilical cord blood were transduced with a recombinant adenoviral (Ad) vector encoding full-length human DNp73alpha cDNA (Ad-DNp73alpha) or a control vector Ad-EGFP, using the centrifugal force method. Induction of DNp73alpha-specific CTL response was evaluated by a cytotoxic assay against the three human tumor cell lines with different DNp73alpha expression levels. The viability and activation status of transduced dendritic cells were assessed by flow cytometry. The dendrocyte/Ad-DNp73alpha-activated cytotoxic T lymphocytes showed significantly higher cytotoxicity against the cell lines A549/DNp73alpha, K-562 that expressed DNp73alpha than the DNp73alpha-null MCF-7 cells. The DCs/Ad-DNp73alpha showed higher survival rates than the DCs/Ad-EGFP or untransduced DCs, presumably due to the inhibition of cell death. These findings, with potential applications for immunotherapy, demonstrate that dendrocytes transduced with Ad-DNp73alpha can induce specific and sustained T cell responses against tumors expressing this variant p53-related gene.
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PMID:In vitro antitumor cytotoxic T lymphocyte response induced by dendritic cells transduced with DeltaNp73alpha recombinant adenovirus. 1791 57


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