Tuning of Alternative Splicing - Switch From Proto-Oncogene to Tumor Suppressor
| Autor: | Alexander V. Kazansky, Michael W. Lehker, Meghan Boyle, Karen S. Martirosyan, Ivan Mendez, Boris Ermolinsky, Aleksandra Shchelkunova |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
RNA splicing splice-switching oligonucleotides tumor suppressor Oligonucleotides Applied Microbiology and Biotechnology Proto-Oncogene Mas stat law.invention 03 medical and health sciences Exon 0302 clinical medicine law Cell Line Tumor Proto-Oncogenes STAT5 Transcription Factor Humans cell-cycle progression Genes Tumor Suppressor Molecular Biology Ecology Evolution Behavior and Systematics STAT5 030304 developmental biology 0303 health sciences biology Alternative splicing Cell Cycle Intron Cell Biology STAT proteins Alternative Splicing Tumor progression 030220 oncology & carcinogenesis Cancer research STAT protein biology.protein Suppressor Developmental Biology Research Paper |
| Zdroj: | International Journal of Biological Sciences |
| ISSN: | 1449-2288 |
| Popis: | STAT5B, a specific member of the STAT family, is intimately associated with prostate tumor progression. While the full form of STAT5B is thought to promote tumor progression, a naturally occurring truncated isoform acts as a tumor suppressor. We previously demonstrated that truncated STAT5 is generated by insertion of an alternatively spliced exon and results in the introduction of an early termination codon. Present approaches targeting STAT proteins based on inhibition of functional domains of STAT's, such as DNA-binding, cooperative binding (protein-protein interaction), dimerization and phosphorylation will halt the action of the entire gene, both the proto-oncogenic and tumor suppressor functions of Stat5B. In this report we develop a new approach aimed at inhibiting the expression of full-length STAT5B (a proto-oncogene) while simultaneously enhancing the expression of STAT5∆B (a tumor suppressor). We have demonstrated the feasibility of using steric-blocking splice-switching oligonucleotides (SSOs) with a complimentary sequence to the targeted exon-intron boundary to enhance alternative intron/exon retention (up to 10%). The functional effect of the intron/exon proportional tuning was validated by cell proliferation and clonogenic assays. The new scheme applies specific steric-blocking splice-switching oligonucleotides and opens an opportunity for anti-tumor treatment as well as for the alteration of functional abilities of other STAT proteins. |
| Databáze: | OpenAIRE |
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