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)

Nitric oxide (NO) has been shown to inhibit migration of cells in which various matrix metalloproteinases (MMPs) are involved. The underlying molecular mechanisms of this inhibition remain elusive. Endothelial cells (ECs) constitutively produce MMP-2. The effect of NO on MMP-2 expression was examined. A dose-dependent inhibition of MMP-2 mRNA level was demonstrated in ECs treated with NO. ECs infected with adenovirus carrying endothelial NO synthase (Ade-NOS) reduced MMP-2 expression. The inhibitory effect of NO on MMP-2 expression was a transcriptional event because NO reduced MMP-2 promoter activity. NO treatment of ECs consequently suppressed MMP-2 secretion revealed by zymographic assay. Functional analysis of MMP-2 promoter (1716 base pairs) indicated that the p53-binding site (-1659 to -1629) was crucial for MMP-2 promoter activity. Activating transcription factor 3 (ATF3) has been reported to act as a transcriptional repressor for p53. ECs treated with NO induced ATF3 expression. Consistently, Ade-NOS-infected ECs showed an increase of ATF3 level. Moreover, ECs either over-expressed ATF3 or, when treated with an ATF3 activator (MG-132; carbobenzoxy-l-leucyl-l-leucyl-l-leucinal), resulted in a repression of MMP-2 promoter activity. Because of MMP-2 suppression by NO, ECs treated with NO inhibited endothelial migration, a phenomenon similar to that of ECs treated with MMP-2 antibody or MG-132. These results indicate that NO-attenuating endothelial migration is mediated at least in part by its reduction of MMP-2 expression via the up-regulation of ATF3. This study provides a molecular basis that supports the notion that NO acts as a negative regulator in endothelial migration.
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PMID:Nitric oxide inhibits matrix metalloproteinase-2 expression via the induction of activating transcription factor 3 in endothelial cells. 1510 41

Sialic acid-containing glycosphingolipids (gangliosides) have been implicated in the regulation of various biological phenomena such as atherosclerosis. Recent report suggests that exogenously supplied disialoganglioside (GD3) serves a dual role in vascular smooth muscle cells (VSMC) proliferation and apoptosis. However, the role of the GD3 synthase gene in VSMC responses has not yet been elucidated. To determine whether a ganglioside is able to modulate VSMC growth, the effect of overexpression of the GD3 synthase gene on DNA synthesis was examined. The results show that the overexpression of this gene has a potent inhibitory effect on DNA synthesis and ERK phosphorylation in cultured VSMC in the presence of PDGF. The suppression of the GD3 synthase gene was correlated with the down-regulation of cyclinE/CDK2, the up-regulation of the CDK inhibitor p21 and blocking of the p27 inhibition, whereas up-regulation of p53 as the result of GD3 synthase gene expression was not observed. Consistently, blockade of GD3 function with anti-GD3 antibody reversed VSMC proliferation and cell cycle proteins. The expression of the GD3 synthase gene also led to the inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by zymography and immunoblot. Furthermore, GD3 synthase gene expression strongly decreased MMP-9 promoter activity in response to TNF-alpha. This inhibition was characterized by the down-regulation of MMP-9, which was transcriptionally regulated at NF-kappaB and activation protein-1 (AP-1) sites in the MMP-9 promoter. Finally, the overexpression of MMP-9 in GD3 synthase transfectant cells rescued VSMC proliferation. However, MMP-2 overexpression was not affected by cell proliferation. These findings suggest that the GD3 synthase gene represents a physiological modulator of VSMC responses that may contribute to plaque instability in atherosclerosis.
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PMID:Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle progression, and matrix metalloproteinase-9 expression. 1517 38

Three canine osteosarcoma cell lines were established from spontaneous pelvic and radial osteosarcomas. The cell populations cultured exhibited characteristics of malignancy and consisted of adherent, pleomorphic, mostly large spindle-shaped or polyhedral cells, characterised by the presence of numerous cytoplasmic granules and vacuoles. The main ultrastructural features included the presence of abundant rough endoplasmic reticulum and numerous cytoplasmic vesicles, deposit vacuoles and small cytoplasmic protrusions. Zymography showed that the cell lines produce high levels of MMP-2 and MMP-9, enzymes directly involved in crucial aspects of the metastatic process. Consistent with their osteoblastic lineage and malignant phenotype, all cell lines were immunoreactive to vimentin, osteopontin, PCNA, p53, MMP-2 and MMP-9, while they were negative for cytokeratin, desmin, SMA, Factor VIII, NSE, GFAP, Rb and p21 protein. No retroviral particles or RNA were detected ultrastructurally or with RT-PCR, although the possibility of viral involvement in osteosarcoma cannot be excluded. The new cell lines provide excellent in vitro models that may allow further studies on the pathobiology of canine osteosarcoma to be undertaken.
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PMID:Characterisation of three novel canine osteosarcoma cell lines producing high levels of matrix metalloproteinases. 1519 3

Androgen withdrawal is the only effective therapy for patients with advanced prostate cancer, but progression to androgen independence ultimately occurs in almost all patients. Novel therapeutic strategies targeting molecular mechanisms that mediate resistance to hormonal and chemotherapeutic treatment are highly warranted. Here, we aimed to evaluate the expression of potential therapeutic targets in advanced prostate cancer. A tissue microarray (TMA) containing samples from 535 tissue blocks was constructed, including benign prostatic hyperplasia as controls (n = 65), prostatic intraepithelial neoplasia (PIN; n = 78), clinically localized prostate cancers (n = 181), as well as hormone-refractory local recurrences (n = 120) and distant metastases (n = 91). The expression of 13 different proteins was analyzed using immunohistochemistry (Bcl-2, p53, ILK, Syndecan-1, MUC-1, EGFR, HER2/neu, HSP-90, Ep-CAM, MMP-2, CD-10, CD-117 and Ki67). Significant overexpression in hormone-refractory prostate cancer and metastatic tissue compared to localized prostate cancer was found for Ki67 (64% vs. 9%), Bcl-2 (11% vs. 1%), p53 (35% vs. 4%), Syndecan-1 (38% vs. 3%), EGFR (16% vs. 1%) and HER2/neu (16% vs. 0%). Overexpression of CD-117 was restricted to 1 single metastasis. All other markers did not show relevant differences in expression between subgroups. Taken together, p53, Bcl-2, Syndecan-1, EGFR and HER2/neu are preferentially expressed in hormone-refractory and metastatic prostate cancer. Selected inhibition of these targets might offer a strategy to treat advanced tumors and prevent further progression. Treatment decisions should not be based on findings in primary tumors but rather on tissues from recurrent or metastatic lesions.
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PMID:Expression patterns of potential therapeutic targets in prostate cancer. 1547 3

The matrix metalloproteinases (MMPs) have been shown to play important roles in cancer progression. In this study we examined whether common genetic variants in two key MMPs are associated with phenotypic features of breast cancers and patient outcome. A single nucleotide polymorphism in the promoter region of MMP-2 (-1306 C-->T) abolishes Sp1 binding and is associated with lower transcriptional activity, while another in the promoter region of MMP-9 (-1562 C-->T) increases the transcription of this gene. MMP-2 TT homozygous patients had smaller tumors (p=0.006) and contained lower concentrations of estrogen receptor (ER; p=0.002) compared to patients with the MMP-2 CC or CT genotype. Homozygosity for the MMP-2 -1306 T allele was associated with markedly different patient survival depending upon tumor ER status. For patients with ER negative tumors, the MMP-2 TT genotype was associated with poor survival (2/8 patients alive at end of study, 25%) compared to the CC or CT genotypes (59/70, 84%; p < 0.001). For patients with ER positive tumors, the MMP-2 TT genotype was associated with a trend for very good survival (10/10, 100%) compared to the CC or CT genotypes (130/157, 83%; p=0.16). The MMP-9 -1562 T allele was associated with features of good prognosis including non-ductal type histology, positive ER status and the absence of TP53 mutation. Patients with MMP-9 -1562 CT or TT genotypes showed marginally better prognosis compared to CC homozygotes (p=0.06). These findings suggest that breast cancer phenotype and outcome can be influenced by common functional polymorphisms in MMP genes.
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PMID:Genetic polymorphisms in the MMP-2 and MMP-9 genes and breast cancer phenotype. 1560 21

The secretion of matrix metalloproteinases (MMPs) is crucial in the metastasis of cancer cells, since MMPs are responsible for the degradation of extracellular matrix (ECM). Among them, matrix metalloproteinase-7 (MMP-7) or matrilysin 1 is a stromelysin which degrades type-IV collagen, fibronectin and laminin. Immunohistochemistry was performed to detect MMP-7 protein in infiltrative breast carcinomas. MMP-7 was studied along with clinicopathological parameters, disease-free and overall survival, and p53, c-erbB-2, topoIIa, MMP-2, uPAR and beta-catenin. MMP-7 immunoreactivity was detected in the cytoplasm of cancer cells in 54.2% (96/177) and tumor stromal cells in 47.5% (84/177), as well as in normal epithelium adjacent to malignant epithelium. MMP-7 reactivity in cancer cells displayed an inverse association with nuclear grade (p=0.049) and topoIIa (p=0.03). A parallel association was observed between the expression of MMP-7 in both malignant and stromal cells with uPAR in cancer cells (p=0.033 and p=0.027, respectively). MMP-7 of tumor stromal cells depicted a parallel correlation with MMP-2 of the same cell type (p=0.044), while abnormal beta-catenin expression was inversely associated with MMP-7 of cancer cells (p=0.047). Our results show the multifunctional role of MMP-7 in the mammary gland, since it seems to be associated with a less aggressive phenotype, while, at the same time, being involved in invasion, through its collaboration with indicators of invasion.
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PMID:The multifunctional role of the immunohistochemical expression of MMP-7 in invasive breast cancer. 1586 5

Cutaneous malignant melanoma remains the leading cause of skin cancer death in industrialized countries. Melanoma progression is well defined in its clinical and histopathological aspects (Breslow's index, tumour size, ulceration, or vascular invasion), which also give hints to prognosis of the patient. Use of molecular markers should therefore give additional information which cannot be determined by routine histopathology. Markers showing only a correlation to Clark level or tumour size are not useful. Several molecules influencing invasiveness and metastatic dissemination of melanoma have been identified. Expression of these molecules has been studied in primary melanoma and correlated with prognosis. Moreover, several tumour suppressors and oncogenes have been shown to be involved in melanoma pathogenesis, including CDKN2A, PTEN, TP53, RAS and MYC, but have not been related to melanoma subtypes or validated as prognostic markers. In the past, in melanoma, an increase in the number of positive tumour cells for Ki67 (detected by Mib1), cyclin A, cyclin D, MMP-2, integrins beta1 and beta3 or osteonectin were considered as factors of poor prognosis as well as the decrease in p16, p27, and Melan A. However, only a small subset of these proteins has a prognostic value independent of tumour thickness. The recent development of high-throughput technologies analyzing global molecular profiles of cancer is bringing up previously unknown candidate genes involved in melanoma, such as Wnt-5A and B-raf. Here, recently published data related to new genes involved in melanoma pathogenesis, which may represent important biomarkers for the identification of genetic profiles or indication of progression of melanoma, are reviewed.
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PMID:Novel biomarkers in malignant melanoma. 1648 Jun 99

The current chemotherapeutic treatment of glioblastoma patients has minor success. Little is known about the molecular and cellular mechanisms of the resistance of gliomas towards current therapies. This study investigated both suppressive cellular effects and regulation of extracellular matrix remodeling proteins with pro-invasive activity in surviving human glioblastoma cells under clinically relevant treatments. All cellular and molecular biological investigations were performed on the genetically well-defined and clinically relevant p53-wild type U87Mg glioma cells. Malignant glioma cells underwent either radiation or temozolomide treatments alone, or combined chemo/radio treatment. Protein expression patterns were investigated by two-dimensional polyacrylamide gel electrophoresis followed by protein spot identification using tandem mass spectrometry analysis. Specific expression levels were quantified by Western-blotting. Extracellular gelatinase activities for both metalloproteinases MMP-2 and MMP-9 were determined by zymogramms. Survival curves indicated no effective suppression of glioma cells under all treatment conditions tested. Morphological changes demonstrated sub-lethal effect of both temozolomide and combined treatment. Expression of MMP-2, MMP-9, and membrane type 1 matrix metalloproteinases (MT1-MMP) was differentially up-regulated by increasing cellular density and treatment conditions. A significantly enhanced extracellular degrading activity under all treatment conditions tested was demonstrated for MMP-2 only. Being a marker for brain tumour progression and angiogenesis, lysozyme c was highly up-regulated under the combined chemo/radio treatment. The activation of proteins with pro-invasive activity indicates an increasing malignancy grade of surviving glioma cells under treatment conditions tested correlating well with more aggressive tumour phenotypes observed clinically in recurrences of treated glioblastomas.
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PMID:Pro-invasive gene regulating effect of irradiation and combined temozolomide-radiation treatment on surviving human malignant glioma cells. 1680 66

Matrix metalloproteinases (MMPs) are group of enzymes thought to play an important role in trophoblastic and tumor invasion. The aim of our study was to investigate the trophoblastic expression of MMPs and p53 in normal trophoblast and hydatidiform moles (HM). Paraffin sections of 45 specimens, including 14 complete hydatidiform moles (CM), 15 partial hydatidiform moles (PM), 8 atypical partial hydatidiform moles (aPM), and 8 controls were selected. Classification of HM was established on histologic criteria and supported by the DNA ploidy results. Tissue sections from each case were immunostained with monoclonal antibodies, cytokeratin-7, MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, and p53 wild type (p53wt) and mutant types (mutp53). Staining for cytokeratin-7 revealed a positive reaction in 93% of the samples. MMP-2 was mainly expressed in the syncytiotrophoblast of HM and found in 62% of aPM, 60% PM, and 93% CM. The mutp53 was mainly and focally expressed in syncytiotrophoblastic cells and was found in 63% of aPM, 80% PM, and 93% CM. Expression of MMP-2 and mutp53 was both significantly greater in HM vs control group (P < 0.05) and greater in CM vs PM and aPM (P < 0.05). No significant difference was observed for cytokeratin-7, MMP-9, TIMP-1, and p53wt between the HM subgroups and between HM and control group. MMP-2 and mutp53 are overexpressed in HM as compared with normal trophoblast and might participate in the invasive behavior of the HM.
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PMID:Expression of matrix metalloproteinase-2 and mutant p53 is increased in hydatidiform mole as compared with normal placenta. 1688 84

Biocompatibility and cell seeding capability of a new cell scaffold made of textured polylactic acid (PLA) fibers was investigated as a new material for tissue engineering of anterior cruciate ligaments (ACL). Adhesion and proliferation of human mesenchymal progenitor cells (MPC) was investigated after 15 days by scanning electron microscopy and standard histology. Expression of collagen type I and III, fibronectin, tenascin C, decorin, smooth muscle actin, and the matrix metalloproteinases MMP-1 and MMP-2, as well as their tissue inhibitors TIMP-1 and TIMP-2 was analyzed using real-time PCR. Protein expression of collagen I and III, tenascin C, and proliferating nuclear antigen (PCNA) was determined by immunohistology. Apoptosis was analyzed by detection of p53 expression and TUNEL staining. MPC seeded the scaffold homogeneously and showed good cell growth and no increased rate of apoptosis. After 15 days, the matrix forming genes collagen type I, tenascin C, and decorin were upregulated, indicating the formation of a ligament-like matrix. MMP-1 and TIMP-1 were also significantly increased, suggesting initial matrix remodeling. It was concluded that the new porous PLA scaffold allowed homogeneous cell seeding, a fibroblastic phenotype and the production of a ligament-like matrix and, therefore, might be a suitable cell carrier for ACL tissue engineering.
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PMID:Human mesenchymal progenitor cell responses to a novel textured poly(L-lactide) scaffold for ligament tissue engineering. 1692 14


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