Chimeric peptide nucleic acid compounds modulate splicing of the bcl-x gene in vitro and in vivo.
Alternative splicing of the bcl-x gene generates two transcripts: the anti-apoptotic bcl-xL isoform and the pro-apoptotic bcl-xS isoform. The ratio between the two isoforms is a key factor in development and in cancer progression. Here, we show that a short antisense chimeric peptide nucleic acid (PNA) oligonucleotide conjugated to a polypeptide containing eight Ser-Arg repeats (SR)(8) can modulate splicing of bcl-x both in vitro and in vivo and induces apoptosis in HeLa cells. The PNA-SR oligo was targeted to a region of bcl-x that does not contain splicing regulatory sequences and was able to override the complex network of splicing enhancers and silencers that regulates the ratio between the two bcl-x isoforms. Thus, PNA-SR oligos are powerful tools that can potentially modulate splice site choice in endogenous genes independent of the presence of other splicing regulatory mechanisms on the target gene.
Wilusz
Jeremy E
JE
Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA.
Devanney
Sean C
SC
Caputi
Massimo
M
D017398:Alternative Splicing; D017209:Apoptosis; D006367:HeLa Cells; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology*; D020135:Peptide Nucleic Acids / Q000737:chemistry / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D020135:Peptide Nucleic Acids; D016601:RNA-Binding Proteins; D051020:bcl-X Protein