Comparative 3'UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines.
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.
Winter
Jennifer
J
Max-Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany. winter@immunbio.mpg.de
Roepcke
Stefan
S
Krause
Sven
S
Müller
Eva-Christina
EC
Otto
Albrecht
A
Vingron
Martin
M
Schweiger
Susann
S
D020413:3' Untranslated Regions; D020816:Amino Acid Motifs; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D036382:Ephrin-A1 / Q000378:metabolism*; D036388:Ephrin-B2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016601:RNA-Binding Proteins / Q000378:metabolism*; D036081:Receptors, Eph Family / Q000096:biosynthesis*; D012689:Sequence Homology, Nucleic Acid
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D036382:Ephrin-A1; D036388:Ephrin-B2; D016601:RNA-Binding Proteins; D036081:Receptors, Eph Family