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RNA aptamers targeting the cell death inhibitor CED-9 induce cell killing in Caenorhabditis elegans
Chonglin Yang1, Nieng Yan, Jay Parish
1Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
Abstract:
Bcl-2 family proteins include anti- and proapoptotic factors that play important roles in regulating apoptosis in diverse species. Identification of compounds that can modulate the activities of Bcl-2 family proteins will facilitate development of drugs for treatment of apoptosis-related human diseases. We used an in vitro selection method named systematic evolution of ligands by exponential enrichment (SELEX) to isolate RNA aptamers that bind the Caenorhabditis elegans Bcl-2 homolog CED-9 with high affinity and specificity and tested whether these aptamers modulate programmed cell death in C. elegans. Five CED-9 aptamers were isolated and classified into three groups based on their predicted secondary structures. Biochemical analyses indicated that two of these aptamers, R9-2 and R9-7, and EGL-1, an endogenous CED-9-binding proapoptotic protein, bound to distinct regions of CED-9. However, these two aptamers shared overlapping CED-9 binding sites with CED-4, another CED-9-binding proapoptotic factor. Importantly ectopic expression of these two aptamers in touch receptor neurons induced efficient killing of these neurons largely in a CED-3 caspase-dependent manner. These findings suggest that RNA aptamers can be used to modulate programmed cell death in vivo and can potentially be used to develop drugs to treat human diseases caused by abnormal apoptosis.
Insights
Researchers developed RNA aptamers to target CED-9, a protein regulating cell death. These aptamers effectively modulated programmed cell death in vivo, showing potential for treating apoptosis-related diseases.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Bcl-2 family proteins regulate apoptosis, a crucial biological process.
- Modulating Bcl-2 family protein activity is key for developing treatments for apoptosis-related diseases.
- The Caenorhabditis elegans Bcl-2 homolog, CED-9, is a critical regulator of programmed cell death.
Purpose of the Study:
- To isolate RNA aptamers that bind to CED-9 with high affinity and specificity.
- To investigate whether these RNA aptamers can modulate programmed cell death in C. elegans.
- To explore the potential therapeutic applications of RNA aptamers in apoptosis-related human diseases.
Main Methods:
- Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was used to isolate RNA aptamers.
- Biochemical analyses were performed to determine binding sites of aptamers on CED-9.
- Ectopic expression of aptamers in C. elegans touch receptor neurons was used to assess in vivo function.
Main Results:
- Five CED-9-binding RNA aptamers were isolated and classified.
- Two aptamers, R9-2 and R9-7, bound to distinct regions of CED-9, with overlapping sites with CED-4.
- Ectopic expression of R9-2 and R9-7 aptamers induced efficient neuronal cell death in a CED-3 caspase-dependent manner.
Conclusions:
- RNA aptamers can effectively modulate programmed cell death in vivo.
- Isolated aptamers demonstrate potential as therapeutic agents for diseases involving abnormal apoptosis.
- This study highlights the utility of RNA aptamers in biological research and drug development.
