Int J Biol Sci 2013; 9(1):45-54. doi:10.7150/ijbs.5194
Tuning of Alternative Splicing - Switch From Proto-Oncogene to Tumor Suppressor
1. Department of Biomedicine, The University of Texas at Brownsville, Brownsville, TX 78520, USA;
2. Department of Physics and Astronomy, The University of Texas at Brownsville, Brownsville, TX 78520, USA;
3. Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Shchelkunova A, Ermolinsky B, Boyle M, Mendez I, Lehker M, Martirosyan KS, Kazansky AV. Tuning of Alternative Splicing - Switch From Proto-Oncogene to Tumor Suppressor. Int J Biol Sci 2013; 9(1):45-54. doi:10.7150/ijbs.5194. Available from http://www.ijbs.com/v09p0045.htm
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.
Keywords: STAT proteins, RNA splicing, tumor suppressor, splice-switching oligonucleotides, cell-cycle progression.