Modulation of eucaryotic initiation factor-4E binding to 5'-capped oligoribonucleotides by modified anti-sense oligonucleotides.
The 5' cap structure of eucaryotic mRNA plays a pivotal role in mRNA metabolism. This report demonstrates that anti-sense oligonucleotides equipped with 3'-overhanging nucleotides modulate the amount of recombinant human eucaryotic initiation factor-4E that binds to a 5'-capped oligoribonucleotide. The degree of inhibition or enhancement of protein binding is dependent upon the number and sequence of overhanging nucleotides. A 45% inhibition of complexation was observed by the addition of one 3'-overhanging guanosine residue. Addition of a second residue (+2/GN) resulted in a higher degree of inhibition, 77-88%. In contrast, addition of one adenosine residue enhanced the formation of the eucaryotic initiation factor-4E-m7GpppRNA complex by 213%. Modulation of protein interactions with the 5'-cap structure is likely to effect several biological events, including pre-mRNA processing, transport of the mRNA from the nucleus to the cytoplasm and translation of the target mRNA. This targeting strategy in anti-sense chemistry may have practical applications in experimental biology and medicine.
Baker
B F
BF
Department of Molecular and Cellular Biology, ISIS Pharmaceuticals, Carlsbad, California 92008.
Miraglia
L
L
Hagedorn
C H
CH
D001483:Base Sequence; D004591:Electrophoresis, Polyacrylamide Gel; D039561:Eukaryotic Initiation Factor-4E; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D009843:Oligoribonucleotides / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
D039561:Eukaryotic Initiation Factor-4E; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D011994:Recombinant Proteins