Chimeric peptide nucleic acid compounds modulate splicing of the bcl-x gene in vitro and in vivo
Chimeric peptide nucleic acid compounds modulate splicing of the bcl-x gene in vitro and in vivo
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DOI：
10.1093/nar/gki960
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发表时间：
2005-01-01
影响因子：
14.9
通讯作者：
Caputi, M
中科院分区：
文献类型：
--
作者：
Wilusz, JE;Devanney, SC;Caputi, M
bcl-x基因的选择性剪接产生两种转录本：抗凋亡bcl-xL同种型和促凋亡bcl-xS同种型。两种亚型之间的比例是癌症发展和进展的关键因素。在这里，我们发现，与含有8个Ser-Arg重复序列（SR）的多肽偶联的短反义嵌合肽核酸（PNA）寡核苷酸（8）可以在体外和体内调节bcl-x的剪接，并诱导HeLa细胞凋亡。PNA-SR oligo靶向bcl-x的一个区域，该区域不含剪接调节序列，并且能够覆盖剪接增强子和沉默子的复杂网络，该网络调节两种bcl-x同种型之间的比例。因此，PNA-SR寡核苷酸是一种强有力的工具，它可以潜在地调节内源基因中剪接位点的选择，而不依赖于靶基因上其他剪接调节机制的存在。
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.