Regulation of Urokinase Receptor Expression by p53: Novel Role in Stabilization of uPAR mRNA

University of Texas at Tyler, Tyler, Texas, United States
Molecular and Cellular Biology (Impact Factor: 4.78). 09/2007; 27(16):5607-18. DOI: 10.1128/MCB.00080-07
Source: PubMed


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 β-globin mRNA destabilized β-globin mRNA. Inhibition of p53 expression in these cells reverses decay
of chimeric β-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.

Download full-text


Available from: Yashodhar Bhandary, Mar 17, 2014
  • Source
    • "Role of p53–uPA system cross in silica-induced apoptosis in AECs in vivo Since silica induces p53 and PAI-1 and suppresses uPA in AECs, and since p53 augments PAI-1 and inhibits uPA expression during lung injury (Shetty et al., 2007; P. Shetty et al., 2008; S. Shetty et al., 2008; Bhandary et al., 2012, 2013), we next exposed WT, p53-, PAI-1-and uPA-deficient mice to silica for seven days and analyzed the lung sections for apoptosis by TUNEL staining. We found that both WT and uPA-deficient mice exposed to silica showed increased TUNEL positive staining ((Fig. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Silica is the major component of airborne dust generated by wind, manufacturing and/or demolition. Chronic occupational inhalation of silica dust containing crystalline quartz is by far the predominant form of silicosis in humans. Silicosis is a progressive lung disease that typically arises after a very long latency and is a major occupational concern with no known effective treatment. The mechanism of silicosis is not clearly understood. However, silicosis is associated with increased cell death, expression of redox enzymes and pro-fibrotic cytokines and chemokines. Since alveolar epithelial cell (AEC) death and disruption of alveolar fibrinolysis is often associated with both acute and chronic lung injuries, we explored whether p53-mediated changes in the urokinase-type plasminogen activator (uPA) system contributes to silica-induced lung injury. We further sought to determine whether caveolin-1 scaffolding domain peptide (CSP), which inhibits p53 expression, mitigates lung injury associated with exposure to silica. Lung tissues and AECs isolated from wild-type (WT) mice exposed to silica exhibit increased apoptosis, p53 and PAI-1, and suppression of uPA expression. Treatment of WT mice with CSP inhibits PAI-1, restores uPA expression and prevents AEC apoptosis by suppressing p53, which is otherwise induced in mice exposed to silica. The process involves CSP-mediated inhibition of serine-15 phosphorylation of p53 by inhibition of protein phosphatase 2A-C (PP2A-C) interaction with silica-induced caveolin-1 in AECs. These observations suggest that changes in the p53-uPA fibrinolytic system cross-talk contribute to lung injury caused by inhalation of silica dust containing crystalline quartz and is protected by CSP by targeting this pathway. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Toxicology and Applied Pharmacology
  • Source
    • "Dual regulation of uPAR signaling in A549 cells 809 Am J Cancer Res 2014;4(6):801-810 [17], and can also regulate uPAR expression [6]. Although previous studies have reported only inhibitory effects of GT1b on uPAR-α5β1 integrin signaling, in the current study, uPAR was increased, whereas caveolin-1, FN, FAK, ERK, and α5β1 integrin were decreased in GT1b-treated A549 lung cancer cells (Figure 5). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Urokinase receptor interacts with α5β1-integrin and enhances cancer cell proliferation and metastasis. Activation of α5β1-integrin requires caveolin-1 and is regulated by uPAR, which upregulates persistently the activated ERK necessary for tumor growth. In this study, we show that the ganglioside GT1b induces proapoptotic signaling through two uPAR-ERK signaling pathways in A549 lung cancer cells. GT1b downregulated the expression of α5β1 integrin, caveolin-1, fibronectin, FAK, and ERK, whereas GT1b upregulated the expression of p53 and uPAR, suggesting GT1b mediated depletion of caveolin-1 in uPAR-expressing A549 cells also disrupts uPAR/integrin complexes, resulting in downregulation of fibronectin-α5β1-integrin-ERK signaling. Following p53 siRNA treatment, FAK and ERK expression was recovered, meaning the presence of reentry uPAR-FAK-ERK signaling pathway. These findings reveal that GT1b is involved in both caveolin-1-dependent uPAR-α5β1-integrin-ERK signaling and caveolin-1-independent uPAR-FAK-ERK signaling. These results suggest a novel function of GT1b as a dual regulator of ERK by modulating caveolin-1 and p53.
    Full-text · Article · Dec 2014 · American Journal of Cancer Research
  • Source
    • "For example, RNA binding protein Hu antigen R and heterogeneous nuclear ribonucleoprotein C stabilize uPAR mRNA by directly binding to the AU-rich element (ARE) in the 3'-untranslated region (3'-UTR) of the uPAR mRNA 48, 49. In the contrary, tumor suppressor protein p53 accelerates uPAR mRNA degradation through binding to a 37-nucleotide element in the 3'-UTR of uPAR mRNA 50. Recent studies also indicate the role of microRNA in uPAR expression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Elevated level of urokinase receptor (uPAR) is detected in various aggressive cancer types and is closely associated with poor prognosis of cancers. Binding of uPA to uPAR triggers the conversion of plasminogen to plasmin and the subsequent activation of metalloproteinases. These events confer tumor cells with the capability to degrade the components of the surrounding extracellular matrix, thus contributing to tumor cell invasion and metastasis. uPA-uPAR interaction also elicits signals that stimulate cell proliferation/survival and the expression of tumor-promoting genes, thus assisting tumor development. In addition to its interaction with uPA, uPAR also interacts with vitronectin and this interaction promotes cancer metastasis by activating Rac and stimulating cell migration. Although underlying mechanisms are yet to be fully elucidated, uPAR has been shown to facilitate epithelial-mesenchymal transition (EMT) and induce cancer stem cell-like properties in breast cancer cells. The fact that uPAR lacks intracellular domain suggests that its signaling must be mediated through its co-receptors. Indeed, uPAR interacts with diverse transmembrane proteins including integrins, ENDO180, G protein-coupled receptors and growth factor receptors in cancer cells and these interactions are proven to be critical for the role of uPAR in tumorigenesis. Inhibitory peptide that prevents uPA-uPAR interaction has shown the promise to prolong patients' survival in the early stage of clinical trial. The importance of uPAR's co-receptor in uPAR's tumor-promoting effects implicate that anti-cancer therapeutic agents may also be developed by disrupting the interactions between uPAR and its functional partners.
    Preview · Article · Jun 2013 · Theranostics
Show more