Readthrough of Premature Termination Codons in the Adenomatous Polyposis Coli Gene Restores Its Biological Activity in Human Cancer Cells
Open Access
- 31 August 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (8), e24125
- https://doi.org/10.1371/journal.pone.0024125
Abstract
The APC tumor suppressor gene is frequently mutated in human colorectal cancer, with nonsense mutations accounting for 30% of all mutations in this gene. Reintroduction of the WT APC gene into cancer cells generally reduces tumorigenicity or induces apoptosis. In this study, we explored the possibility of using drugs to induce premature termination codon (PTC) readthrough (aminoglycosides, negamycin), as a means of reactivating endogenous APC. By quantifying the readthrough of 11 nonsense mutations in APC, we were able to identify those giving the highest levels of readthrough after treatment. For these mutations, we demonstrated that aminoglycoside or negamycin treatment led to a recovery of the biological activity of APC in cancer cell lines, and showed that the level of APC activity was proportional to the level of induced readthrough. These findings show that treatment with readthrough inducers should be considered as a potential strategy for treating cancers caused by nonsense mutations APC gene. They also provide a rational basis for identifying mutations responsive to readthrough inducers.Keywords
This publication has 35 references indexed in Scilit:
- Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosidesNucleic Acids Research, 2010
- A comprehensive analysis of translational missense errors in the yeastSaccharomyces cerevisiaeRNA, 2010
- Drug‐induced readthrough of premature stop codons leads to the stabilization of laminin α2 chain mRNA in CMD myotubesThe Journal of Gene Medicine, 2007
- Negamycin Binds to the Wall of the Nascent Chain Exit Tunnel of the 50S Ribosomal SubunitAntimicrobial Agents and Chemotherapy, 2007
- A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticinProceedings of the National Academy of Sciences of the United States of America, 2007
- In vitroprediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot studyBMC Medicine, 2007
- Discrimination Between Defects in Elongation Fidelity and Termination Efficiency Provides Mechanistic Insights into Translational ReadthroughJournal of Molecular Biology, 2005
- Readthrough of dystrophin stop codon mutations induced by aminoglycosidesAnnals of Neurology, 2004
- Negamycin Restores Dystrophin Expression in Skeletal and Cardiac Muscles of mdx MiceThe Journal of Biochemistry, 2003
- Structural origins of aminoglycoside specificity for prokaryotic ribosomesJournal of Molecular Biology, 2001