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)

We have previously suggested that tumor angiogenesis in human gliomas is regulated by a paracrine mechanism involving vascular endothelial growth factor (VEGF) and flt-1 (VEGF-receptor 1). VEGF, an endothelial-cell-specific mitogen, is abundantly expressed in glioma cells which reside along necrotic areas, whereas flt-1, a tyrosine-kinase receptor for VEGF, is expressed in tumor endothelial cells, but not in endothelial cells in normal adult brain. Recently, a second tyrosine-kinase receptor which binds VEGF with high affinity, designated KDR or flk-1, has been described. We performed in situ hybridization for VEGF mRNA, flt-1 mRNA and KDR mRNA on serial sections of normal brain, low-grade and high-grade glioma specimens. We show that KDR mRNA is co-expressed with flt-1 in vascular cells in glioblastoma but not in low-grade glioma. Since flt-1 and KDR are not expressed in endothelial cells in the normal adult brain, the coordinate up-regulation of 2 receptors for VEGF appears to be a critical event which controls tumor angiogenesis. Immunocytochemistry with a monoclonal anti-VEGF antibody revealed significant amounts of VEGF protein in the same glioma cells that expressed VEGF mRNA. The largest amount of VEGF immunoreactivity, however, was detected on the vasculature of glioblastomas, the site where VEGF exerts its biological functions. These findings suggest that VEGF is produced and secreted by glioma cells and acts on tumor endothelial cells which express VEGF receptors. To further characterize VEGF-producer cells in vivo, we investigated cellular proliferation, immunoreactivity to the p53 tumor-suppressor gene product and epidermal-growth-factor-receptor (EGFR) expression on serial sections by immunocytochemistry. VEGF-producer cells did not show increased cellular proliferation, p53 immunoreactivity or EGFR immunoreactivity as compared with glioma cells which did not express VEGF. Our studies therefore do not demonstrate evidence for a growth advantage of VEGF-producer cells in vivo or VEGF induction by p53 mutation or EGFR over-expression.
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PMID:Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. 752 92

PDGF-B released from colon tumor cells regulated tumor growth in athymic mice in a paracrine manner by inducing blood vessel formation. A positive correlation was found between expression of PDGF B-chain in cells grown in vitro and the number of factor VIII-positive blood vessels in tumors induced by three classes of colon carcinoma cell lines. Elevated expression of PDGF-B was also correlated with tumor size. Each cell line had the same mutations in the colon cancer genes APC, DCC, and p53 and had wild type c-K-ras genes (Huang et al. [1994] Oncogene, 9:3701-3706.) eliminating the possibility that any differences in tumor blood vessel formation were due to mutations and/or deletions in these genes. Colon carcinoma cells released biologically active PDGF capable of stimulating the growth of NIH3T3 cells, which was inhibited by neutralizing antisera to PDGF-AB chains. An inverse correlation was found between induction of factor VIII-positive blood vessels and expression of vascular endothelial growth factor (VEGF), while no correlation was seen with expression of either TGF alpha or k-FGF. Basic fibroblast growth factor (FGF) expression was not detected in these tumor cells. TGF beta 1 was capable of inducing PDGF-B expression in the undifferentiated U9 colon carcinoma cell line, but this sensitivity was not seen in differentiated cells. In contrast, TGF beta 1 inhibited VEGF expression in both undifferentiated cells and differentiated colon cancer cells. Thus, TGF beta 1 has two roles in the growth of undifferentiated U9 colon carcinoma cells in vivo: direct stimulation of cell proliferation as we have showed in earlier studies, and an increase in angiogenesis by inducing PDGF-B.
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PMID:Platelet-derived growth factor-B increases colon cancer cell growth in vivo by a paracrine effect. 759 1

Results from our studies on the clinical applicability of proliferation markers and growth factors in the histopathological assessment of malignancy and prognosis of ovarian neoplasms are presented. Bromodeoxyuridine incorporation, Ki 67 antigen visualization and proliferation cell nuclear antigen expression indicated location and extent of cell proliferation, though not uniformly as compared to flow cytometry and mitotic counting. Clinicopathological correlations of the occurrence of programmed cell death, apoptosis, as indicated by morphology gave inconclusive results, as did analysis of Bcl-2 expression. Increased visualization of p53 protein was associated with increased degree of malignancy but was inconsistent in individual specimens. Growth factor expression, in particular transforming growth factor beta staining intensity, gave additional information on cell behaviour as did vascular endothelial growth factor distribution on vascularization and vessel neoformation when compared to platelet derived growth factor expression, useful in isolated specimens, and to basic fibroblast growth factor expression. The markers presented are indispensible in certain tumour types and give additional information improving our understanding of ovarian neoplasms and tumour classification in general but are mostly not yet reliable enough for clinically applicable conclusions of individual patients.
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PMID:Cell proliferation markers and growth factors in ovarian cancer. 774 6

We previously immortalized normal human oral keratinocytes by transfection with recombinant HPV-16 DNA and subsequently exposed the cells to benzo(a)pyrene for 7 days. The exposure to benzo(a)pyrene modified the immortalized cells: the modified cells (HOK-16B-BaP) proliferated in an ordinary culture medium containing physiological calcium level (1.5 mM), but demonstrated only enhanced proliferation capacity without tumor formation in nude mice and failed to show in vitro anchorage-independency. In this study, we further modified the HOK-16B-BaP cells by subculturing the cells in a medium containing benzo(a)pyrene for 6 months. The cells were further modified with a chronic benzo(a)pyrene exposure and were termed HOK-16B-BaP-T cells (1) demonstrated a malignant phenotype in organotypic 'raft' culture, (2) showed in vitro anchorage-independency, (3) developed tumors in nude mice when injected subcutaneously, (4) contained a significantly higher copy number of intact and integrated HPV-16 DNA; (5) contained higher level of HPV-16 E6/E7 messages and E7 protein, (6) were more resistant to transforming growth factor-beta 1 and (7) secreted higher level of vascular endothelial growth factor with molecular weight of 56 kd than parental HOK-16B-BaP cells. However, the levels of p53 and ras proteins and the levels of p53, c-myc and c-fos transcripts in the HOK-16B-BaP-T cells were not different from those in the HOK-16B-BaP cells. The highly conserved coding regions of the p53, c-Ha-ras1, and c-Ki-ras2 genes of the tumor cells were not mutated. These data indicate that the HPV-immortalized human oral keratinocytes can convert to tumorigenic cells by chronic exposure to benzo(a)pyrene. The tumorigenic conversion seems to be associated with (1) the overexpression of viral oncogenes such as E6 and E7 genes, (2) the higher resistance of cells to transforming growth factor-beta 1 and (3) the high secretion of 56 kd vascular endothelial growth factor from the cells.
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PMID:Combined oral carcinogenicity of HPV-16 and benzo(a)pyrene: an in vitro multistep carcinogenesis model. 778 58

The mechanism(s) involved in immortalization that constitute the first step during malignant transformation has been the subject of our interest. By the use of spontaneously immortalized mouse embryonic fibroblasts we have earlier identified two stages of immortalization which are characterized by growth characteristics of the cells, their conditioned medium and the protein markers such as p53, p81 and mortalin (Kaul et al. (1994) Biochim. Biophys. Acta, in press). The present study was planned to purify the mitogenic factors from the conditioned medium of stage II cells. Sequential purification by chromatography followed by peptide sequencing has characterized one of these as vascular endothelial growth factor (VEGF). Further analysis by RT-PCR suggests that the spontaneously immortalized stage II fibroblasts have enhanced synthesis and secretion of VEGF as compared to their mortal parent cells. Expression of a novel 304 bp long form of VEGF is identified in immortal fibroblasts in addition to the three known alternatively spliced forms. The study points to the involvement of VEGF function during spontaneous immortalization of mouse embryonic fibroblasts.
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PMID:Enhanced expression of multiple forms of VEGF is associated with spontaneous immortalization of murine fibroblasts. 780 91

Many tumor cells produce vascular endothelial growth factor (VEGF), which is thought to be a pivotal mediator of tumor neoangiogenesis. Expression of the VEGF gene can be induced by tumor promoting phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), which activate protein kinase C (PKC). Here we show that in transient transfection assays a mutated form of the murine p53 tumor suppressor gene (ala135-->val) induces expression of VEGF mRNA and potentiates TPA stimulated VEGF mRNA expression. In NIH 3T3 cells which stably overexpress the temperature sensitive p53 (ala135-->val), displaying mutant phenotype at 37 degrees C and wildtype phenotype at 32.5 degrees C, induction of VEGF mRNA and protein by activated PKC is strongly synergistic with mutant, but not wildtype p53. Mutant p53 specifically increases TPA induction of VEGF without affecting the expression of other TPA inducible genes. TPA dependent VEGF expression is also enhanced by human p53 mutated at amino acid 175. Thus, our data link PKC and p53, the gene most frequently altered in human tumors, with the regulation of tumor angiogenesis.
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PMID:Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. 810 42

Angiogenesis, the development of new capillaries, is tightly controlled by the balance of positive and negative regulatory pathways. A newly described angiogenic factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), binds exclusively to endothelial cells and promotes their proliferation. Here we have studied the role of p53, a tumor suppressor, and v-Src, an oncogene on VEGF regulation. Wild-type p53 down-regulated endogenous VEGF mRNA level, as well as VEGF promoter activity, in a dose-dependent manner, whereas mutant forms of p53 had no effect. Overexpression of v-Src, known to up-regulate VEGF expression, activated a VEGF promoter-luciferase construct in a dose-dependent manner. Moreover, v-Src, in the presence of wt-p53, was unable to activate transcription of the VEGF promoter. Collectively, these data suggest that wild-type p53 may play a role in suppressing angiogenesis.
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PMID:Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. 852 8

Biopsies from 25 juvenile nasopharyngeal angiofibromas (JNAs) and respective normal inferior turbinates were examined and compared. The expression patterns of the messenger RNAs (mRNAs) for various growth factors possibly involved in the growth of mesenchymal cells, as well as angiogenesis and fibrosis, were also compared. These growth factors included insulin-like growth factor II (IGF-II), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming growth factors-beta1 (TGF-beta1) and platelet-derived growth factors (PDGF-A and PDGF-B). Quantification of mRNA coding for proto-oncogenes and suppressor genes related to proliferation (i.e., c-myc, c-fos, p53) was also undertaken. Tumor and turbinates expressed similar levels of bFGF, VEGF, TGF-beta1, c-myc, c-fos, and PDGF-A mRNAs. The presence of TGF-beta1 protein was confirmed by immunohistochemistry in several structures that characterize the lesions of JNA, which suggests that TGF-beta1 may play a role in the development of the fibrous component of this tumor. PDGF-B and p53 were overexpressed (i.e., twice the mean level found in turbinates) in 50% and 32% of JNAs, respectively but there was no statistical significance when compared with controls. Statistically significant increased expression of IGF-II mRNA was observed in JNA (P = .04). IGF-II mRNA levels were correlated to p53 (P = .05) and PDGF-B (P = .034), indicating a possible synergistic action of such factors in JNA. The results of this study suggest that IGF-II might be a potential growth regulator of nasopharyngeal angiofibromas.
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PMID:Expression of growth factors, proto-oncogenes, and p53 in nasopharyngeal angiofibromas. 858 52

One event that accompanies glioma progression is the upregulation of angiogenesis. Low-grade gliomas are moderately vascularized tumors whereas high-grade gliomas show prominent microvascular proliferations and areas of high vascular density. To analyze the molecular mechanisms underlying glioma angiogenesis, we studied the expression of vascular endothelial growth factor (VEGF) and its tyrosine kinase receptors VEGFR-1 and VEGFR-2 during normal brain development and glioma-induced angiogenesis. Our results suggest a paracrine control of angiogenesis and endothelial cell proliferation that is tightly regulated and transient in the embryonic brain, switched off in the normal adult brain, and turned on in tumor cells (VEGF) and the host vasculature (VEGFR-1 and -2) during tumor progression. It is unknown how VEGF and VEGF receptors are upregulated during glioma angiogenesis, but there is recent evidence that VEGF as well as endogenous inhibitors of angiogenesis could be under control of the tumor suppressor genes p53 and VHL.
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PMID:Angiogenesis in malignant gliomas. 858 68

Recently, the importance of tumor angiogenesis in the process of tumor growth, progression and metastasis in solid tumors has been widely accepted. The prognostic value of angiogenesis has been demonstrated in a variety of solid tumors including breast cancer. In this report, we reviewed recent studies investigating on the value of intratumoral microvessel density (MVD), assessed by a sermiquantitative immunohistochemical assay with using factor-VIII related antibody or anti CD-31 antibody, as a prognostic indicator in primary breast cancer patients. Studies using factor-VIII related antibody showed that the average MVD ranged from 67.3 to 84.0 counts per mm2 area. When used by anti CD-31 monoclonal antibody, the average MVD were 120.3 approximately 135 counts per mm2 area in the range. More than 8 clinical investigations have showed that MVD was a potent prognostic indicator for relapse free survival and/or overall survival in both node-negative and -positive patients. Two reports concluded no prognostic value of MVD, however the average MVD of these two studies significantly differed from other reports. Thus, at present, angiogenesis grade seems to provide an independent prognostic value when the MVD was properly assessed. With respect to the relationship with conventional prognostic indicators, several reports showed the tendency that increased MVD was correlated with younger age and increase of tumor size below 3 cm diameter, however, some reports failed to demonstrate the tendency, suggesting that these correlations are still in controversial. Biological markers including ER, p53 and c-erB2 showed no correlation with the MVD in many studies including our investigation. Only a significant correlation we found was that MVD was increased in tumors with the expression of vascular endothelial growth factor and platelet-derived endothelial cell growth factor, which are noted to be potent endothelial growth factor. Since the evaluation of tumor angiogenesis as a prognostic indicator is now widely investigated in a prospective study, MVD might be introduced to the category of the criteria for determining the schedule of postoperative adjuvant therapy of breast cancer.
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PMID:[The importance of tumor angiogenesis as a prognostic indicator in primary breast cancer]. 870 39


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