Posttranscriptional Regulation of Urokinase Receptor Expression by Heterogeneous Nuclear Ribonuclear Protein C †
Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U.S. Highway 271, Tyler, Texas 75708, USA. Biochemistry
(Impact Factor: 3.02).
07/2008; 47(24):6508-17. DOI: 10.1021/bi702338y
Interaction of urokinase-type plasminogen activator (uPA) with its receptor, uPAR, is a key regulatory step in uPA-mediated cell proliferation and migration. Our previous studies demonstrated that posttranscriptional stabilization of uPAR mRNA by uPA contributes to the induction of cell surface uPAR expression, and heterogeneous nuclear ribonuclear protein C1 (hnRNPC) binds to a 110 nt sequence of uPAR mRNA 3'-UTR, thereby preventing its degradation. These observations indicate that hnRNPC could be involved in the induction of uPAR expression by uPA. In the present study, we investigated this possibility and confirmed that uPA increased the binding of hnRNPC to the 3'-UTR of uPAR mRNA. Furthermore, uPA induced tyrosine phosphorylation of hnRNPC and uPAR expression through mRNA stabilization. Inhibition of hnRNPC tyrosine phosphorylation abolished its interaction with uPAR mRNA and suppressed mRNA stabilization and cell surface uPAR expression. Deletion experiments revealed that hnRNPC binds to uPAR mRNA through its RNA binding domain (RBD). Site-directed mutagenesis studies further indicated that phosphorylation of tyrosine residue 57 (Y57) present in RBD of hnRNPC by uPA is essential for uPAR 3'-UTR mRNA binding and uPAR expression. Increased hnRNPC interaction with the uPAR mRNA 3'-UTR through phosphorylation of Y57 represents a novel mechanism by which uPA regulates posttranscriptional uPAR mRNA turnover and cell surface uPAR expression.
Available from: Ding-Gan Liu
- "The difference between the two isoforms is that C2 has an additional 13 amino acid insert after Ser107(4). hnRNPC plays multiple roles in post-transcriptional regulation, including alternative splicing (5), nuclear retention and export (6), stability (7,8) and translation (3,9,10). Several studies have shown that hnRNPC is overexpressed in tumors, including hepatocellular carcinoma and breast cancer (2,11). "
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ABSTRACT: Heterogeneous ribonuclear protein C2 (hnRNPC2), an RNA binding protein, is a component of hnRNPC which is upregulated in many tumors. Multinucleation exists in many tumors and is positively correlated with tumor grade. To uncover the correlation between hnRNPC2 and multi-nucleation in hepatocellular carcinoma SMMC-7721 cells, we constructed a pEGFP-hnRNPC2 vector and transfected it into cancer cells. Our results revealed that overexpression of hnRNPC2 induced multinucleation in SMMC-7721 cells. Tracking tests indicated that the induced multinucleated cells were unable to recover to mononuclear cells and finally died as a result of defects in cell division. Furthermore, Aurora B, which was localized at the midbody and plays a role in cytokinesis, was repressed in hnRNPC2-overexpressing cells, whose knockdown by RNA interference also induced multinucleation in SMMC-7721 cells. Quantitative polymerase chain reaction (qPCR) and mRNA-protein co-immunoprecipitation results revealed that Aurora B mRNA did not decrease in hnRNPC2-overexpressing cells, instead it bound more hnRNPC2 and less eIF4E, an mRNA cap binding protein and translational initiation factor. Moreover, hnRNPC2 bound more eIF4E in hnRNPC2-overexpressing cells. These results indicate that hnRNPC2 repressed Aurora B binding with eIF4F, which must bind with Aurora B mRNA in order to initiate its translation. This induced multinucleation in hepatocellular carcinoma cells. In addition, hnRNPC2 accelerated hepatocellular carcinoma cell proliferation. Collectively, these data suggest that hnRNPC2 may be a potential target for hepatocellular carcinoma cell diagnosis and treatment.
Available from: Tae-Don Kim
- "Heterogeneous nuclear ribonuclear protein C1 (hnRNP C1) and HuR bind to the uPA 3'-UTR, which leads to uPA mRNA stabilization (4). Similarly, hnRNP C1 binds to a 110-nucleotide sequence of the uPAR mRNA 3'-UTR, thereby preventing its degradation (5). Conversely, p53 decreased both uPA and uPAR mRNA stability by binding to a 35-nucleotide sequence in the uPA 3'-UTR and a 37-nucleotide sequence in the uPAR 3'-UTR, resulting in decreased cellular expression. "
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ABSTRACT: Natural killer (NK) cells play key roles in innate and adaptive immune defenses. NK cell responses are mediated by two major mechanisms: the direct cytolysis of target cells, and immune regulation by production of various cytokines. Many previous reports show that the complex NK cell activation process requires de novo gene expression regulated at both transcriptional and post-transcriptional levels. Specialized un-translated regions (UTR) of mRNAs are the main mechanisms of post-transcriptional regulation. Analysis of post-transcriptional regulation is needed to clearly understand NK cell biology and, furthermore, harness the power of NK cells for therapeutic aims. This review summarizes the current understanding of mRNA metabolism during NK cell activation, focusing primarily on post-transcriptional regulation.
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ABSTRACT: The association between chronic inflammation and lung cancer has been extensively reported. Despite the differences in the clinical manifestations of chronic obstructive pulmonary disease (COPD) compared with lung cancer, the underlying inflammatory pathogenesis of these two diseases may involve shared biological features. Identifying the mechanisms that regulate specific inflammatory mediators shared by both diseases will represent a major breakthrough. Chemokines play an important role in the inflammatory response. Recent evidence suggests that post-transcriptional regulation, through control of mRNA stability, could be an important mechanism of regulation of chemokine expression. Therefore, it would be important to study the role of RNA-binding proteins, such as hnRNPs, in chemokine expression after initial inflammatory response. HnRNPs have shown the ability to modulate inflammatory mediators expression by affecting mRNA stability of COX-2, TNFalpha and IL-1beta and iNOS. Moreover, overexpression of hnRNPs has been reported in cancer, for example, hnRNP A2/B1 in lung cancer. Thus, investigating the role of hnRNPs in chemokine expression may allow us to understand the molecular mechanisms involved in the regulation of the inflammatory response before its progression to chronic inflammation and/or tumor development.
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