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Nucleic Acids Research 2005 33(20):6547-6554; doi:10.1093/nar/gki960
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Published online 18 November 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Chimeric peptide nucleic acid compounds modulate splicing of the bcl-x gene in vitro and in vivo

Jeremy E. Wilusz, Sean C. Devanney1 and Massimo Caputi1,*

Department of Biology, The Johns Hopkins University Baltimore, MD 21218, USA 1Biomedical Science Department, Florida Atlantic University Boca Raton, FL 33431, USA

*To whom correspondence should be addressed. Tel: +1 561 297 0627; Fax: +1 561 297 2221; Email: mcaputi{at}fau.edu

Received August 16, 2005. Revised October 5, 2005. Accepted October 28, 2005.

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.

Present address: Jeremy E. Wilusz, Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA


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