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)

As normal cells progress toward malignancy, they must switch to an angiogenic phenotype to attract the nourishing vasculature that they depend on for their growth. In cultured fibroblasts from Li-Fraumeni patients, this switch was found to coincide with loss of the wild-type allele of the p53 tumor suppressor gene and to be the result of reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis. Transfection assays revealed that p53 can stimulate the endogenous TSP-1 gene and positively regulate TSP-1 promoter sequences. These data indicate that, in fibroblasts, wild-type p53 inhibits angiogenesis through regulation of TSP-1 synthesis.
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PMID:Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. 752 39

The p53 protein is a multifunctional transcription factor which orchestrates cellular responses to DNA damage, so helping to conserve genomic stability. It may also regulate genes involved in intercellular signalling, such as thrombospondin, a negative regulator of angiogenesis and metastatic spread. Activation of p53 target genes requires sequence-specific DNA binding, a function which maps to the central core of the protein. Missense point mutations within this domain inactivate p53 tumour suppressor function and involve either (i) DNA contact residues, or (ii) residues important for conformational structure. Using in vitro techniques we have analysed seven DNA contact mutants and 17 structural mutants known to occur in cancer. We show that DNA contact mutants can be carried into specific DNA interaction when co-expressed with wild type protein. For structural mutants, 9/17 retained DNA binding capacity and, with one exception, DNA binding correlated with conformational flexibility of the mutant protein. The exception was Asp281, which appeared essential for DNA interaction, probably due to its ability to form salt bridges with DNA contact residues Arg273 and Arg280. We suggest that different classes of p53 mutant may prove amenable to different strategies for restoration of wild type tumour suppressor function as means of anti-cancer therapy.
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PMID:Specific DNA binding by different classes of human p53 mutants. 765 40

Fifteen different natural inhibitors of angiogenesis have now been identified that are produced by mammalian cells and are able to block in vivo neovascularization. The majority of these are able to inhibit endothelial cell activities in vitro and all those tested have demonstrated significant antitumor activity. Most normal cells produce inhibitors of neovascularization that must be downregulated before the cells can develop into angiogenic, malignant tumors. In several cases the production of inhibitors ceases when tumor suppressor genes are inactivated. In the BT549 human breast carcinoma cell line, the reintroduction of a wild type p53 tumor suppressor gene resulted in the stimulation of the secretion of an inhibitor of angiogenesis, thrombospondin-1, and as a result the cells lost their angiogenic phenotype and became able to suppress angiogenesis induced by the parental tumor line. These results provide a new example of tumor suppressor gene control of a natural inhibitor of angiogenesis and add support to the concept that thrombospondin loss may play an important role in the development of some human breast cancers.
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PMID:The modulation of thrombospondin and other naturally occurring inhibitors of angiogenesis during tumor progression. 853 61

Loss of normal p53 tumor-suppressor gene function is characteristic of the majority of squamous carcinomas. During the course of gene transfer studies in the human squamous carcinoma cell line, A253, which does not express p53 mRNA or protein, we incidentally observed increased levels of p53 expression in up to 20% of clonal cell lines derived from parental A253 cells. p 53-expressing A253 cells (A253-p53) were also isolated by dilutional cloning. Nuclear p53 protein was identified by immunohistochemistry in A253-p53 cells in a wild-type pattern, and p53 mRNA (2.5 kb) was demonstrated by northern blot. Mutational analysis of the p53 gene in A253-p53 cells revealed no evidence for mutations in exons 5-9. A253-p53 cells could be distinguished from native A253 cells by prolonged doubling times (2-5 fold) and by a marked reduction of [3H]-thymidine uptake. Whereas A253 cells were unresponsive to the growth-inhibitory effects of TGF-beta, EGF-stimulated A253-p53 cells responded to TGF-beta with markedly reduced DNA synthetic rates. A253-p53 cells cocultured with A253 demonstrated enhanced cell growth and DNA synthesis rates compared to control A253-p53 cells. Finally, A253-p53 cells show reduced expression of c-fos, fibronectin, thrombospondin and parathyroid hormone-related protein (PTHrP) mRNAs. PTHrP measured by RIA in conditioned medium was approximately 300 pM for A253 but undetectable for A253-p53. We conclude that the A253 cell line contains a subpopulation of cells which express high levels of "wild-type-like" p53 protein. This results in dramatic changes in gene expression and a slower-growing phenotype in vitro.
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PMID:Clonal variation of p53 expression and proliferative phenotype in A253 squamous carcinoma cells. 897 69

As normal cells progress to malignancy they must acquire an angiogenic phenotype that will enable them to attract the blood vessels necessary to support their progressive growth. Here we define the mechanism by which human fibroblasts cultured from Li Fraumeni patients and progressing to tumorigenicity in vitro become angiogenic. Initially cells were anti-angiogenic due to the secretion of high levels of inhibitory thrombospondin that overrode the modest amounts of the major inducer, vascular endothelial cell growth factor (VEGF), that were also produced. Cells became fully angiogenic in two steps, the first dependent on the loss of both alleles of wild-type p53 which caused a drop of at least 20-fold in secreted thrombospondin and a fourfold increase in secreted VEGF. Angiogenic activity increased again upon transformation by activated ras due to a further twofold increase in VEGF. Changes in relative levels of VEGF mRNA were sufficient to account for changes in secreted protein levels and in overall angiogenic activity. These studies demonstrate that an angiogenic phenotype able to support tumorigenicity can arise in a step-wise fashion in response to both oncogene activation and tumor suppressor gene loss and involve both a decrease in the secretion of inhibitors and the sequential ratcheting up of the secretion of inducers of angiogenesis.
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PMID:Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity. 913 93

The highly metastatic amelanotic C8161 human melanoma line was found to exhibit complete dominance of its undifferentiated and metastatic phenotype in multiple somatic cell hybridization studies designed to bypass the presence of potential tumor suppressor genes. In a three armed approach involving somatic cell fusions of C8161 with recipient lines of greater differentiation, different lineage, and different tumorigenicity status, the metastatic and undifferentiated phenotype of C8161 was promiscuously dominant. In somatic cell hybrids produced between the C8161 and a group of non-metastatic human melanoma lines which exhibited melanocyte differentiation markers including S100, HMB-45, NKI/C3, and melanin, the fusions were uniformly metastatic and undifferentiated. In somatic cell hybrids of C8161 and MCF-7 the fusions exhibited an estrogen independent and unresponsive, estrogen receptor (ER) negative, and highly metastatic phenotype. In fusions between C8161 and HMS-1, an immortalized 'benign' human myoepithelial line which produced an abundant extracellular matrix (ECM) and high levels of protease and angiogenic inhibitors including maspin, tissue inhibitor of metalloproteinase-1 (TIMP-1), alpha1-antitrypsin (alpha1-AT), protease nexin II (PN-II), thrombospondin-1 and soluble basic fibroblast growth factor (bFGF) receptors, the hybrids showed complete absence of matrix, absent maspin expression, markedly decreased protease inhibitor and angiogenic inhibitor production, high levels of proteases and angiogenic factors, and a highly metastatic phenotype. In our somatic cell fusions, the human-human hybrids represented true and complete fusions and not hybrid clones selected for by loss of dominant-acting growth suppressor genes. This finding was supported by detailed comparative genomic hybridization (CGH) studies, Q-banding karyotype analysis, and autofusions of representative clones. The purposeful creation of inherently unstable human-murine fusions between C8161 and B16-F1 where loss of putative suppressor loci would be expected, resulted in fusions exhibiting decreased growth and non-metastatic behavior with progressive chromosomal loss. Neither p53, nm23, DNA methyltransferase, activated ras, fibroblast growth factor-4 (FGF-4), or epidermal growth factor receptor (EGFR) mediated the acquisition of the metastatic or undifferentiated phenotype within the C8161-human fusions. These studies are the first studies ever to successfully transfer the complete metastatic phenotype by somatic cell fusion and support the presence of a new high level regulatory pathway(s) involving dominant trans-acting factors which act pleiotropically to regulate an undifferentiated and highly metastatic phenotype.
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PMID:Evidence of a dominant transcriptional pathway which regulates an undifferentiated and complete metastatic phenotype. 936 25

The genetic alteration of p53 is associated with neovascularization during progression of glioma to its more malignant form, glioblastoma. Hence, one or more of the genes transactivated by p53 is likely to function as an angiogenesis inhibitors. We isolated a novel p53-inducible gene that encodes a 1584-amino-acid product containing five thrombospondin type 1 (TSP-type 1) repeats and is specifically expressed in the brain. A recombinant protein corresponding to the TSP-type 1 repeats of this gene product inhibited in vivo neovascularization induced by bFGF in the rat cornea. The expression of this gene, designated BAI1 (brain-specific angiogenesis inhibitor 1) was absent or significantly reduced in eight of nine glioblastoma cell lines, suggesting BAI1 plays a significant role in angiogenesis inhibition, as a mediator of p53.
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PMID:A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. 939 72

The aim of this work was to evaluate the effects of SR 25989, a member of the thienopyridine family devoid of antiplatelet activity but possessing anti-angiogenic properties, on the regulation of proteins involved in matrix remodeling during wound healing or tumor progression. Human endothelial cells grown in the presence of SR 25989 showed moderate increases in the production of activators (tissue plasminogen activator and urokinase) and one inhibitor (plasminogen activator inhibitor type 1) of fibrinolysis, together with a significant rise in intracellular thrombospondin-1. SR 25989 induced a similar increase in thrombospondin-1 in human foreskin fibroblasts. This over-expression of thrombospondin-1 was correlated to a decrease in cell density. A concomitant increase in the tumor suppressor gene protein p53 was observed in endothelial cells and in fibroblasts, in which the slowing down of proliferation could be related to an accumulation of cells in the S and G2/M phases of the cell cycle. Northern blot analysis revealed a temporary rise in thrombospondin-1 transcripts, followed by a decrease along with a moderate increase in p53 transcripts. Thus the anti-angiogenic properties of SR 25989 appear to result from an upregulation of thrombospondin-1 which is possibly mediated by p53. The thienopyridine SR 25989 could therefore be a good candidate for adjuvant anti-angiogenic therapy in cancer.
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PMID:Angiogenesis inhibitor SR 25989 upregulates thrombospondin-1 expression in human vascular endothelial cells and foreskin fibroblasts. 944 4

We recently reported that a p53 encoding plasmid (BAP-p53) complexed to liposomes administered intravenously markedly attenuates the growth of a malignant human breast tumor. We now have found that systemically delivered liposomes complexed to a plasmid expressing an established antiangiogenic peptide of thrombospondin I (BAP-TSPf) decreased the growth of MDA-MB-435 tumors compared to controls in nude mice. Compared to BAP-p53, the BAP-TSPf group had a similar antitumor efficacy. More importantly, liposomes complexed with BAP-TSPf and BAP-p53 synergistically decreased the growth of MDA-MB-435 tumors when compared to either BAP-p53 or BAP-TSPf alone. Furthermore, we also determined that the combination therapy of p53 and TSPf inhibited endothelial cells in vitro more than either p53 or TSPf alone. There was also a significant decrease of the blood vessel density in the combination p53 and TSPf treatment group compared to the control groups. These results suggest that liposomes complexed to a tumor suppressor and antiangiogenic genes may be effective in treating metastatic tumors.
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PMID:Gene therapy with p53 and a fragment of thrombospondin I inhibits human breast cancer in vivo. 956 63

On the basis of reports linking mutant p53 (mp53) to decreased expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) and increased angiogenesis, we compared primary and metastatic melanoma tumor specimens to determine if these factors were associated with metastatic progression. Western blotting, immunohistochemistry (IHC), and image analysis (IA) techniques were employed to evaluate the relationship between p53 status and TSP-1 expression in Zaz and M14 melanoma cell lines, and among p53, TSP-1, and angiogenesis in primary and metastatic melanomas. Zaz cells expressed wild-type p53 (WT p53) and high levels of TSP-1, while the M14 cells expressed mp53 and low TSP-1 levels. Examination of clinical melanoma specimens (N = 99) revealed an incidence of mp53 of 48%. Specimens with WT p53 (N = 46) expressed significantly higher mean levels of TSP-1 (41 +/- 27 vs. 21 +/- 24; p = 0.0004), and lower microvessel counts per 200x field (25 +/- 17 vs. 40 +/- 20; p = 0.0001) than tumors expressing mp53 (N = 42). A significantly higher incidence of mp53 expression was seen in metastatic tumors (64%, 37/58) than in primary tumors (27%, 11/41)(p < 0.0005). Primary tumors specimens had higher levels of TSP-1 (40 +/- 27 vs. 25 +/- 25; p = 0.0054) and lower microvessel counts (26 +/- 18 vs. 39 +/- 20, p = 0.0013) than metastatic tumors. These data suggest that acquisition of mp53, decreased TSP-1, and increased microvessel infiltration may be interrelated and associated with the metastatic phenotype in malignant melanoma.
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PMID:Mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma. 961 39


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