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 found that p53-deficient (p53(-/-)) lung carcinoma (H1299) cells express robust levels of cell surface uPAR and uPAR mRNA. Expression of p53 protein in p53(-/-) cells suppressed basal and urokinase (uPA)-induced cell surface uPAR protein and increased uPAR mRNA degradation. Inhibition of p53 by RNA silencing in Beas2B human airway epithelial cells conversely increased basal as well as uPA-mediated uPAR expression and stabilized uPAR mRNA. Purified p53 protein specifically binds to the uPAR mRNA 3' untranslated region (3'UTR), and endogenous uPAR mRNA associates with p53. The p53 binding region involves a 37-nucleotide uPAR 3'UTR sequence, and insertion of the p53 binding sequence into beta-globin mRNA destabilized beta-globin mRNA. Inhibition of p53 expression in these cells reverses decay of chimeric beta-globin-uPAR mRNA. These observations demonstrate a novel regulatory role for p53 as a uPAR mRNA binding protein that down-regulates uPAR expression, destabilizes uPAR mRNA, and thereby contributes to the viability of human airway epithelial or lung carcinoma cells.
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PMID:Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA. 1754 71

Previous study reported that the activation of Ras pathway cooperated with E6/E7-mediated inactivation of p53/pRb to transform immortalized normal human astrocytes (NHA/hTERT) into intracranial tumors strongly resembling human astrocytomas. The mechanism of how H-Ras contributes to astrocytoma formation is unclear. Using genetically modified NHA cells (E6/E7/hTERT and E6/E7/hTERT/Ras cells) as models, we investigated the mechanism of Ras-induced tumorigenesis. The overexpression of constitutively active H-RasV12 in E6/E7/hTERT cells robustly increased the levels of urokinase plasminogen activator (uPA) mRNA, protein, activity and invasive capacity of the E6/E7/hTERT/Ras cells. However, the expressions of MMP-9 and MMP-2 did not significantly change in the E6/E7/hTERT and E6/E7/hTERT/Ras cells. Furthermore, E6/E7/hTERT/Ras cells also displayed higher level of uPA activity and were more invasive than E6/E7/hTERT cells in 3D culture, and formed an intracranial tumor mass in a NOD-SCID mouse model. uPA specific inhibitor (B428) and uPA neutralizing antibody decreased uPA activity and invasion in E6/E7/hTERT/Ras cells. uPA-deficient U-1242 glioblastoma cells were less invasive in vitro and exhibited reduced tumor growth and infiltration into normal brain in xenograft mouse model. Inhibitors of Ras (FTA), Raf (Bay 54-9085) and MEK (UO126), but not of phosphatidylinositol 3-kinase (PI3K) (LY294002) and of protein kinase C (BIM) pathways, inhibited uPA activity and cell invasion. Our results suggest that H-Ras increased uPA expression and activity via the Ras/Raf/MEK signaling pathway leading to enhanced cell invasion and this may contribute to increased invasive growth properties of astrocytomas.
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PMID:H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway. 1838 43

Lung carcinoma (H1299) cells deficient in p53 (p53(-/-)) express large amounts of urokinase-type plasminogen activator (uPA) protein and uPA mRNA, and exhibit slower degradation of uPA mRNA than that of p53-expressing nonmalignant Beas2B human airway epithelial cells. Expression of p53 protein in H1299 cells, upon transfection with p53 cDNA, suppressed basal as well as uPA-induced expression of uPA protein in both conditioned media and cell lysates, and decreased the level of steady-state uPA mRNA primarily due to increased uPA mRNA turnover. Inhibition of p53 expression by RNA silencing (SiRNA) in Beas2B cells enhanced basal and uPA-mediated uPA protein and mRNA expression with stabilization of uPA mRNA. Purified p53 binds to the uPA mRNA 3' untranslated region (UTR) in a sequence-specific manner and endogenous uPA mRNA associates with p53 protein isolated from Beas2B cytosolic extracts. p53 binds to a 35-nucleotide uPA 3'UTR sequence and insertion of this sequence into beta-globin mRNA accelerates degradation of otherwise stable beta-globin mRNA. These observations confirm a new role for p53 as a uPA mRNA binding protein that down-regulates uPA mRNA stability and decreases cellular uPA expression.
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PMID:Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover. 1839 Apr 74

H1299 lung carcinoma cells lacking p53 (p53-/-) express minimal amounts of plasminogen activator inhibitor-1 (PAI-1) protein as well as mRNA. p53(-/-) cells express highly unstable PAI-1 mRNA. Transfection of p53 in p53(-/-) cells enhanced PAI-1 expression and stabilized PAI-1 mRNA. On the contrary, inhibition of p53 expression by RNA silencing in non-malignant human lung epithelial (Beas2B) cells decreased basal as well as urokinase-type plasminogen activator-induced PAI-1 expression because of accelerated degradation of PAI-1 mRNA. Purified p53 protein specifically binds to the PAI-1 mRNA 3'-un-translated region (UTR), and endogenous PAI-1 mRNA forms an immune complex with p53. Treatment of purified p53 protein with anti-p53 antibody abolished p53 binding to the 3'-UTR of PAI-1 mRNA. The p53 binding region maps to a 70-nucleotide PAI-1 mRNA 3'-UTR sequence, and insertion of the p53-binding sequence into beta-globin mRNA destabilized the chimeric transcript. Deletion experiments indicate that the carboxyl-terminal region (amino acid residues 296-393) of p53 protein interacts with PAI-1 mRNA. These observations demonstrate a novel role for p53 as an mRNA-binding protein that regulates increased PAI-1 expression and stabilization of PAI-1 mRNA in human lung epithelial and carcinoma cells.
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PMID:Regulation of plasminogen activator inhibitor-1 expression by tumor suppressor protein p53. 1846 3

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic alterations and molecular expression in experimental models as well as in pre-cancerous and cancerous tissues by mean of molecular amplification and large scale transcriptome analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating mutation of the K-ras oncogene on codon 12 seems to occur early in pancreatic carcinogenesis and detecting its mutation in tumor samples could have a clinical relevance in term of positive (improvement of current histological diagnosis) and differential diagnosis (versus chronic pancreatitis) of pancreatic cancer. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, nerve growth factor, gastrin, bombesin), of proangiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, beta integrin, urokinase and tissue plasminogen activator) occur. All these molecular events contribute to the progression and to the metastatic potential of this carcinoma. New markers and targets are currently studied among microRNA and epigenetics events such as methylation and acetylation. Among all these molecular markers, some are now tested for their potential clinical interest in term of diagnosis or therapeutic target.
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PMID:[New molecular targets in pancreatic cancer]. 1854 14

Dysregulation of the plasminogen activation cascade is a prototypic feature in many malignant epithelial cancers. Principally, this is thought to occur through activation of overexpressed urokinase plasminogen activator (uPA) concomitant with binding to its high specificity cell surface receptor urokinase plasminogen activator receptor (uPAR). Up-regulation of uPA and uPAR in cancer appears to potentiate the malignant phenotype, either (i) directly by triggering plasmin-mediated degradation or activation of uPA's or plasmin's proteolytic targets (e.g., extracellular matrix zymogen proteases or nascent growth factors) or indirectly by simultaneously altering a range of downstream functions including signal transduction pathways ( Romer, J. ; Nielsen, B. S. ; Ploug, M. The urokinase receptor as a potential target in cancer therapy Curr. Pharm. Des. 2004, 10 ( 19), 235976 ). Because many malignant epithelial cancers express high levels of uPAR, uPA or other components of the plasminogen activation cascade and because these are often associated with poor prognosis, characterizing how uPAR changes the downstream cellular "proteome" is fundamental to understanding any role in cancer. This study describes a carefully designed proteomic study of the effects of antisense uPAR suppression in a previously studied colon cancer cell line (HCT116). The study utilized replicate 2DE gels and two independent gel image analysis software packages to confidently identify 64 proteins whose expression levels changed (by > or =2 fold) coincident with a moderate ( approximately 40%) suppression of cell-surface uPAR. Not surprisingly, many of the altered proteins have previously been implicated in the regulation of tumor progression (e.g., p53 tumor suppressor protein and c-myc oncogene protein among many others). In addition, through a combination of proteomics and immunological methods, this study demonstrates that stathmin 1alpha, a cytoskeletal protein implicated in tumor progression, undergoes a basic isoelectric point shift (p I) following uPAR suppression, suggesting that post-translational modification of stathmin occur secondary to uPAR suppression. Overall, these results shed new light on the molecular mechanisms involved in uPAR signaling and how it may promulgate the malignant phenotype.
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PMID:Differential proteome expression associated with urokinase plasminogen activator receptor (uPAR) suppression in malignant epithelial cancer. 1880 75

The urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) are key components of the fibrinolytic system and are expressed by lung epithelial cells. uPA, uPAR, and PAI-1 have been strongly implicated in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. Recently, it has become clear that regulation of uPA, uPAR, and PAI-1 occurs at the posttranscriptional level of mRNA stability in lung epithelial cells. uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability. In addition, uPA-mediated signaling controls the expression of the tumor suppressor protein p53 in lung epithelial cells at the posttranslational level. p53 has recently been shown to be a trans-acting uPA, uPAR, and PAI-1 mRNA-binding protein that regulates the stability of these mRNAs. It is now clear that signaling initiated by uPA mediates dose-dependent regulation of lung epithelial cell apoptosis and likewise involves changes in p53, uPA, uPAR, and PAI-1 expression. These findings demonstrate that the uPA-uPAR-PAI-1 system of lung epithelial cells mediates a broad repertoire of responses that encompass but extend well beyond traditional fibrinolysis, involve newly recognized interactions with p53 that influence the viability of the lung epithelium, and are thereby implicated in the pathogenesis of ALI and its repair.
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PMID:The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability. 1883 29

In this study, we investigated the expression level of Ras-homologous (Rho) GTPases and the Rho guanine exchange factor (GEF) T-cell lymphoma invasion and metastasis 1 (Tiam1) in breast tumor specimens (n=106) by immunohistochemistry. Rho and Rho-GEF expression scores were compared to clinically established diagnostic and prognostic parameters. We found that RhoA and RhoB scores slightly increased with tumor grade, whereas the Rac1 score remained unaffected. The most significant effects were observed for the Rac1-specific GEF Tiam1. Tiam1 expression scores significantly decreased with the increase in tumor grade, tumor spreading and proliferation. Furthermore, Tiam1 expression was inversely related to the plasminogen activator inhibitor (PAI-1) and estrogen receptor (ER) expression but not the progesterone receptor (PR) and urokinase plasminogen activator (uPA). A low Tiam1 expression was associated with p53 positivity without being related to HER2/neu status. The data show that Tiam1 expression decreases with the progression of breast carcinomas and is inversely associated with several established breast tumor markers. Therefore, we suggest that Tiam1 counteracts the progression of breast carcinomas and is suitable as a novel breast tumor marker.
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PMID:Progression of breast tumors is accompanied by a decrease in expression of the Rho guanine exchange factor Tiam1. 1908 65

The hamster buccal pouch (HBP) carcinogenesis model is one of the most well characterized animal systems for analyzing the development of oral squamous cell carcinoma (OSCC), a common malignancy worldwide. HBP carcinomas that closely mimic human OSCC are useful in understanding the molecular mechanisms of neoplastic transformation. The present study is a comparative evaluation of markers of carcinogen activation, oxidative stress, cell proliferation, apoptosis, invasion, and angiogenesis in human and hamster OSCCs. Enhanced expression of CYP1A1 and CYP1B1 isoforms in both human and hamster oral tumours was associated with significantly increased expression of 8-hydroxy 2-deoxyguanosine (8-OHdG) indicating oxidative DNA damage. Analysis of markers of cell survival and proliferation revealed increased expression of PCNA, GST-P, and NF-kappaB with downregulation of p21, p53 and IkappaB in both human and hamster OSCCs. In addition, both human and hamster oral carcinomas displayed invasive, and angiogenic properties as revealed by dysregulated cytokeratin expression, downregulation of RECK, and increased expression of uPA, MMP-2 and-9, HIF-1alpha, and VEGF. The results reveal aberrant expression of multiple molecules in key signaling pathways in both human OSCCs and HBP carcinomas rendering the HBP model as an important tool for monitoring oral oncogenesis.
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PMID:Of humans and hamsters: a comparative evaluation of carcinogen activation, DNA damage, cell proliferation, apoptosis, invasion, and angiogenesis in oral cancer patients and hamster buccal pouch carcinomas. 1925 Aug 57

PIK3CA, which codes for the p110alpha catalytic subunit of phosphatidylinositol-3-kinase (PI3K), is implicated as an oncogene. Despite importance of PIK3CA in cancer, little is known about what drives up its expression in tumor cells. We recently characterized the PIK3CA promoter and reported that it is transcriptionally silenced by the tumor suppressor protein p53. In the present study, we demonstrate that PIK3CA can be induced by the oncogenic transcription factor Y-box binding protein-1 (YB-1). Three YB-1-responsive elements were identified on the PIK3CA promoter using chromatin immunoprecipitation and electrophoretic mobility shift assays. Interestingly, silencing YB-1 with siRNA in models of basal-like breast cancer decreased p110alpha protein levels regardless of whether PIK3CA was wild type, amplified or mutated. This decrease in p110alpha led to a reduction in PI3K activity and the downstream signaling primarily through p90 ribosomal S6 kinase and S6 ribosomal protein. Disruption in PIK3CA-dependent signaling suppressed cellular invasion correlative with loss of urokinase plasminogen activator (uPA). Similarly, silencing YB-1 suppressed invasion and uPA production however this was reversible through the introduction of constitutively active PIK3CA. In conclusion, YB-1 is the first reported oncogene to induce the expression of PIK3CA through transcriptional control of its promoter.
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PMID:The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1. 1943 Apr 91


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