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)

It was previously demonstrated that p53 status in human multiple myeloma (MM) cells regulates distinct cell cycle responses to CD40 activation. In this study, the production of vascular endothelial growth factor (VEGF) and migration in MM cells triggered by CD40 activation was examined, and the influence of p53 status in regulating this process was determined. Two human MM cell lines that express wild-type p53 at permissive (28 degrees C) and mutant p53 at restrictive (37 degrees C) temperatures were used as a model system. CD40 activation induces a 4-fold (RPMI 8226) and a 6-fold (SV) increase in VEGF transcripts, respectively, under restrictive, but not permissive, temperatures. VEGF expression is significantly induced after CD40 activation in patient MM cells expressing mutant p53. Increased VEGF transcripts result in increased protein and secretion levels, as evidenced by immunoblotting and enzyme-linked immunosorbent assay. In a double-chamber transmigration assay, CD40 activation of MM cells induced a 3-fold (RPMI 8226) and a 5-fold (SV) increase in migration under restrictive, but not permissive, conditions. A 2- to 8-fold induction in migration of patient MM cells expressing mutant p53 was similarly observed. Transduction of MM cells with a luciferase reporter under the control of a human VEGF promoter further indicated that CD40-induced VEGF expression was mediated through a transcriptional control mechanism. Finally, adenovirus-mediated wild-type p53 overexpression down-regulated CD40-induced VEGF expression and transmigration in MM cells expressing mutant p53. These studies demonstrate that CD40 induces VEGF secretion and MM cell migration, suggesting a role for CD40 in regulating MM homing and angiogenesis.
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PMID:CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells. 1183 Apr 95

To evaluate the predictive role of the oncogene p53, the proliferating marker Ki-67, angiogenic factors platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/dThdPase) and vascular endothelial growth factor (VEGF) in primary hypopharyngeal carcinoma, we immunohistochemically studied a series of 84 primary hypopharyngeal carcinoma patients who were treated at the Department of Otolaryngology of Kurume University Hospital between 1990 and 1997. The correlation of each score according to the intensity and percentage of the labeled cells with the TNM stage, histological grade, metastasis and survival status was analyzed. The positive rate of p53 was 52.4%. The percentages of Ki-67 labeled cells in patients with or without metastasis showed a significant difference (p = 0.011). VEGF also showed a significant difference between the live and death groups (p < 0.05) and also among the differentiation group (p < 0.05). A statistically significant correlation was also seen between the score of Ki-67 and VEGF (r = 0.438, p < 0.001) or the score of Ki-67 and PD-ECGF (r = 0.259, p < 0.001), respectively. In conclusion, the present study suggests that a correlation exists between proliferating and angiogenesis, and VEGF and Ki-67 are thus considered to be possible prognostic discriminators in hypopharyngeal carcinoma.
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PMID:The predictive value of p53, Ki-67 and angiogenetic factors in primary hypopharyngeal carcinoma. 1183 Sep 25

The degree of DNA instability as determined by immunohistochemical staining with anti-single-stranded DNA antibody after acid hydrolysis (the DNA instability test) was used as a marker of malignancy. The test was applied to tissues of oral leukoplakia assessed histopathologically as hyperplasia (38 cases), mild (12 cases), moderate (11 cases) and severe (8 cases) dysplasia, and invasive squamous cell carcinoma (SCC, 20 cases). Tissues were subjected to immunohistochemical staining for proliferating cell nuclear antigen (PCNA), p53, DNA-fragmentation factor 45 (DFF45), analysis of various AgNORs parameters, and triple immunostaining for vascular endothelial growth factor (VEGF), CD34, and PCNA. The DNA instability test was positive in 20 (100%) SCC cases, 8 (100%) severe dysplasia cases, 8 (72.7%) moderate dysplasia cases, 6 (50.0%) mild dysplasia cases, and 9 (23.7%) hyperplasia cases, indicating malignancy. The proportion of lesions positive for PCNA, p53, DFF45, and values of AgNORs parameters steadily increased from hyperplasia to mild, moderate and severe dysplasia, and SCC, especially in those showing positive DNA instability test, indicative of malignancy. Based on these results, 44.9% of leukoplakia were malignant tissues, namely carcinoma in situ. The proportion of PCNA-positive vascular endothelial cells in the vicinity of VEGF-positive epithelial lesion was significantly higher than that of negative DNA instability lesions, as revealed by immunohistochemical triple staining for VEGF, CD34, and PCNA. Our results suggest that increased DNA instability, enhanced proliferative activity, p53 mutation, and induction of DFF45 and VEGF may allow cancer cell proliferation, enhance their survival by escaping apoptosis, and provide abundant nutrients during early-stage carcinogenesis of oral leukoplakia.
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PMID:Immunohistochemical detection of early-stage carcinogenesis of oral leukoplakia by increased DNA-instability and various malignancy markers. 1184 1

The brain-specific angiogenesis inhibitor 1 gene has been isolated in an attempt to find fragments with p53 "functional" binding sites. As reported herein and by others, brain-specific angiogenesis inhibitor 1 expression is present in some normal tissues, but is reduced or lost in tumour tissues. Such data and its particular structure prompted the hypothesis that brain-specific angiogenesis inhibitor 1 may act as a mediator in the local angiogenesis balance. We herein demonstrate that brain-specific angiogenesis inhibitor 1 over-expression suppresses tumour angiogenesis, delaying significantly the human tumour growth in immunodeficient mice. The inhibitory effect of brain-specific angiogenesis inhibitor 1 was documented using our intravital microscopy system, strongly implicating brain-specific angiogenesis inhibitor 1 as a mediator in the control of tumour angiogenesis. In contrast, in vitro tumour cell proliferation was not inhibited by brain-specific angiogenesis inhibitor 1 transfection, whereas some level of cytotoxicity was assessed for endothelial cells. Immunohistochemical analysis of tumour samples confirmed a reduction in the microvessel density index in brain-specific angiogenesis inhibitor 1-overexpressing tumours. At messenger level, moderate changes could be detected, involving the down-regulation of vascular endothelial growth factor and collagenase-1 expression. Furthermore, brain-specific angiogenesis inhibitor 1 expression that was lost in a selection of human cancer cell lines could be restored by wild-type p53 adenoviral transfection. Brain-specific angiogenesis inhibitor 1 should be considered for gene therapy and development of efficient drugs based on endogenous antiangiogenic molecules.
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PMID:Overexpression of the p53-inducible brain-specific angiogenesis inhibitor 1 suppresses efficiently tumour angiogenesis. 1187 20

Tumours of patients with node-positive rectal cancer were studied by immunohistochemistry for p53, BAX and vascular endothelial growth factor expressions. Results were correlated to the relapse rate, the pattern of relapse and the event-free survival after radical surgery and adjuvant chemoradiation. After a median follow-up of 60 months, 39 patients remained disease-free and 40 patients relapsed (18 local relapses and 22 distant metastases). The majority of disease-free patients showed p53 negative and vascular endothelial growth factor negative tumours. Local relapses occurred more frequently in patients with p53 overexpressing tumours (P<0.01), while distant metastases were in patients with vascular endothelial growth factor positive tumours (P<0.003). Patients with p53 negative or vascular endothelial growth factor negative tumours showed better event-free survival than patients with p53 positive or vascular endothelial growth factor positive tumours. BAX analysis did not show any association with patients' outcome and it was unrelated to the p53 status. Adjuvant treatment strategies for node-positive rectal cancer may be improved by identifying categories of high-risk patients. In this study, vascular endothelial growth factor and p53 expressions correlated with recurrent disease, pattern of relapse and poor event-free survival.
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PMID:An analysis of p53, BAX and vascular endothelial growth factor expression in node-positive rectal cancer. Relationships with tumour recurrence and event-free survival of patients treated with adjuvant chemoradiation. 1187 37

Peroxisome proliferator-activated receptor gamma (PPAR gamma) immunohistochemical expression was analyzed in 75 human bladder tumor specimens, where the expression of some angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PDECGF), and tumor progression markers, such as epidermal growth factor receptor (EGFr), p16, mutated p53, and normal pRB, were also analyzed. The results were then compared to the clinical and pathological characteristics of the disease. PPAR gamma was expressed more significantly in papillary tumors than in solid cancers, and its presence was associated with statistical significance to low incidence of tumor recurrence or progression. This significant association was observed also when PPAR gamma was expressed in the presence of PDECGF, which resulted, when considered alone, to an angiogenic factor typical of solid cancers and appeared related to poor prognosis. In the presence of bFGF, on the contrary, PPAR gamma expression no longer resulted to a significant association with low incidence of tumor recurrence or progression, suggesting a possible worsening role of this angiogenic factor, typical of papillary cancers, in its interaction with PPAR gamma.
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PMID:The role of peroxisome proliferator-activated receptor gamma in bladder cancer in relation to angiogenesis and progression. 1188 83

Advanced glycation end products (AGE) have been implicated in the pathogenesis of glomerulosclerosis in diabetes. However, their involvement in the development of the early phase of diabetic nephropathy has not been fully elucidated. We investigated the effects of AGE on growth and on vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) expression in human cultured mesangial cells. We prepared three immunochemically distinct AGE by incubating bovine serum albumin (BSA) with glucose, glyceraldehyde, or glycolaldehyde. When human mesangial cells were cultured with various types of AGE-BSA, viable cell numbers as well as DNA syntheses were significantly decreased. All of the AGE-BSA were found to significantly increase p53 and Bax protein accumulations and subsequently induce apoptotic cell death in mesangial cells. An antioxidant, N-acetylcysteine, significantly prevented the AGE-induced apoptotic cell death in mesangial cells. Human mesangial cells stimulated prostacyclin production by co-cultured glomerular endothelial cells. Furthermore, various types of AGE-BSA were found to up-regulate the levels of mRNAs for VEGF and stimulate the secretion of VEGF and MCP-1 proteins in mesangial cells. The results suggest that AGE disturbed glomerular homeostasis by inducing apoptotic cell death in mesangial cells and elicited hyperfiltration and microalbuminuria by stimulating the secretion of VEGF and MCP-1 proteins, thereby being involved in the pathogenesis of the early phase of diabetic nephropathy.
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PMID:Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. 1191 19

In order to develop a new therapeutic intervention for pancreatic cancer, we have examined the effect of gene therapy for pancreatic disease. The transfection of the gene for UPRT, a 5-FU-converting enzyme, resulted in a significant change in the sensitivity of pancreatic cancer cells against 5-FU, resulting in the decrease of the tumor volume disseminated in the abdominal cavity of mice. Although the production levels of vascular endothelial growth factor (VEGF) in pancreatic cancer cell lines are different, anti-angiogenesis gene therapy using a soluble form of VEGF receptor (flt-1) has been demonstrated to be a promising strategy for pancreatic cancer. The transfection efficacy is the crucial point for the success of gene therapy; therefore, it is necessary to develop a vector system for solid tumors. It has been revealed that replication-competent adenoviruses are not only a strong weapon themselves, but are also useful carriers of genes possessing anti-tumor activities as virus vectors specific to tumors without normal p53 function or intact Rb pathway. Determining whether these experimental results are universally true will require clinical trials in the future.
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PMID:[Gene therapy for pancreatic cancer]. 1191 29

Inhibition of pulmonary metastases poses a difficult clinical challenge for current therapeutic regimens. We have developed an aerosol system utilizing a cationic polymer, polyethyleneimine (PEI), for topical gene delivery to the lungs as a novel approach for treatment of lung cancer. Using a B16-F10 murine melanoma model in C57BL/6 mice, we previously demonstrated that aerosol delivery of PEI-p53 DNA resulted in highly significant reductions in the tumor burden (P < .001) in treated animals, and also lead to about 50% increase in the mean length of survival of the mice-bearing B16-F10 lung tumors. The mechanisms of this antitumor effect of p53 are investigated in this report. Here, we demonstrate that the p53 transfection leads to an up-regulation of the antiangiogenic factor thrombospondin-1 (TSP-1) in the lung tissue and the serum of the mice. Furthermore, there is a down-regulation of vascular endothelial growth factor (VEGF) in the lung tissue and serum of the B16-F10 tumor-bearing mice treated with PEI-p53 DNA complexes, compared with untreated tumor-bearing animals. In addition, staining for von Willebrand factor (vWF), a marker for the angiogenic blood vessels, revealed that p53 treatment leads to a decrease in the angiogenic phenotype of the B16-F10 tumors. Immunohistochemistry for transgene expression reveals that the PEI-p53 aerosol complexes transfect mainly the epithelial cells lining the airways, with diffuse transfection in the alveolar lining cells, as well as, the tumor foci in the lung tissue. There was also some evidence of apoptosis in the lung tumor foci of animals treated with p53. The data suggest that aerosol delivery of PEI-p53 complexes leads to inhibition of B16-F10 lung metastases, in part by suppression of angiogenesis.
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PMID:Aerosol delivery of PEI-p53 complexes inhibits B16-F10 lung metastases through regulation of angiogenesis. 1191 42

The active involvement of physical exercise in the evolution of a variety of cancers is well documented. However, its role in solid leukemia tumor development is essentially unknown. Solid leukemia tumor cells were transplanted into 21 hybrid BDF1 control mice, exercise-trained mice that did not exercise during leukemia and exercise-trained mice that exercised during leukemia. The tumor size of the continuously exercising group was ~50% of that of control and exercise-terminated animals 18 days after the transplantation. The activity of antioxidant enzymes and the levels of lipid peroxidation and 8-hydroxy-2'-deoxyguanosine were not different in the tumors of the three groups. The level of carbonylated proteins was smaller in tumors of continuously exercising animals. The mutant form of cell regulatory protein p53 and vascular endothelial growth factor were present in similar amounts in the tumor cells of each group. On the other hand, the protooncogene Ras and I-kappaB proteins were present in higher concentrations in tumors of continuously exercising rats. The present data suggest that exercise during leukemia attenuates the development of tumors in mice. The selective alteration of regulatory proteins might play a role in the beneficial effects of exercise during leukemia.
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PMID:Attenuation of the development of murine solid leukemia tumor by physical exercise. 1197 Aug 55


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