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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 411606.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Comparative 3’UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines
Authors:Winter, Jennifer; Roepcke, Stefan; Krause, Sven; Müller, Eva-Christina; Otto, Albrecht; Vingron, Martin; Schweiger, Susann
Research Context:The work was funded by the Deutsche Volkswagenstiftung and the Deutsche Forschungsgemeinschaft (SFB 577, project A6 to SS).
Date of Publication (YYYY-MM-DD):2008-07-23
Title of Journal:PLoS One
Journal Abbrev.:PloS ONE
Issue / Number:7
Start Page:e2780
End Page:e2780
Full name of Issue-Editor(s):Thomas Preiss, Victor Chang Cardiac Research Institute, Australia
Copyright:All site content, except where otherwise noted, is licensed under a Creative Commons Attribution License.

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Review Status:not specified
Audience:Experts Only
Abstract / Description:Eph receptors are the largest family of receptor tyrosine kinases. Together with their ligands, the ephrins, they fulfill multiple biological functions. Aberrant expression of Ephs/ephrins leading to increased Eph receptor to ephrin ligand ratios is a critical factor in tumorigenesis, indicating that tight regulation of Eph and ephrin expression is essential for normal cell behavior. The 3'-untranslated regions (3'UTRs) of transcripts play an important yet widely underappreciated role in the control of protein expression. Based on the assumption that paralogues of large gene families might exhibit a conserved organization of regulatory elements in their 3'UTRs we applied a novel bioinformatics/molecular biology approach to the 3'UTR sequences of Eph/ephrin transcripts. We identified clusters of motifs consisting of cytoplasmic polyadenylation elements (CPEs), AU-rich elements (AREs) and HuR binding sites. These clusters bind multiple RNA-stabilizing and destabilizing factors, including HuR. Surprisingly, despite its widely accepted role as an mRNA-stabilizing protein, we further show that binding of HuR to these clusters actually destabilizes Eph/ephrin transcripts in tumor cell lines. Consequently, knockdown of HuR greatly modulates expression of multiple Ephs/ephrins at both the mRNA and protein levels. Together our studies suggest that overexpression of HuR as found in many progressive tumors could be causative for disarranged Eph receptor to ephrin ligand ratios leading to a higher degree of tissue invasiveness.
Comment of the Author/Creator:Competing interests: The authors have declared that no competing interests exist.

External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Max-Delbrueck Center of Molecular Medicine, Berlin, Germany; 2.Department of Dermatology, Charité-Hospital, Berlin, Germany;
3.Department of Neuroscience and Pathology, College of Medicine, University of Dundee, Dundee, United Kingdom.
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