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A Dominant Negative Antisense Approach Targeting ?-Catenin.


ABSTRACT: There have been many attempts to unveil the therapeutic potential of antisense molecules during the last decade. Due to its specific role in canonical Wnt signalling, ?-catenin is a potential target for an antisense-based antitumour therapy. In order to establish such a strategy with peptide nucleic acids, we developed a reporter assay for quantification of antisense effects. The luciferase-based assay detects splice blocking with high sensitivity. Using this assay, we show that the splice donor of exon 13 of ?-catenin is particularly suitable for an antisense strategy, as it results in a truncated protein which lacks transactivating functions. Since the truncated proteins retain the interactions with Tcf/Lef proteins, they act in a dominant negative fashion competing with wild-type proteins and thus blocking the transcriptional activity of ?-catenin. Furthermore, we show that the truncation does not interfere with binding of cadherin and ?-catenin, both essential for its function in cell adhesion. Therefore, the antisense strategy blocks Wnt signalling with high efficiency but retains other important functions of ?-catenin.

SUBMITTER: Vonbrull M 

PROVIDER: S-EPMC5918491 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A Dominant Negative Antisense Approach Targeting β-Catenin.

Vonbrüll Matthias M   Riegel Elisabeth E   Halter Christian C   Aigner Michaela M   Bock Holger H   Werner Birgit B   Lindhorst Thomas T   Czerny Thomas T  

Molecular biotechnology 20180501 5


There have been many attempts to unveil the therapeutic potential of antisense molecules during the last decade. Due to its specific role in canonical Wnt signalling, β-catenin is a potential target for an antisense-based antitumour therapy. In order to establish such a strategy with peptide nucleic acids, we developed a reporter assay for quantification of antisense effects. The luciferase-based assay detects splice blocking with high sensitivity. Using this assay, we show that the splice donor  ...[more]

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