Abstract
Short double-stranded RNAs (dsRNA) are potent biological entities triggering a number of cellular effects. Most prominent among these is the post-transcriptional gene silencing of target genes by small interfering RNAs (siRNAs). In addition dsRNAs activate signal transduction processes through molecules like PKR or the Toll-like receptor important in viral defense and in explaining off target effects of siRNAs. Only a few of these dsRNA triggered pathways have been characterized yet. Here we show that the splicing variant D of the TAK1 gene is activated by short double-stranded RNAs in a sequence-specific manner. Activation of TAK1-D leads to the downstream activation of the p38 MAPK and of SAPK/JNK but not the NFκB pathway. In the human lung cancer cell line NCI-H460 the activation of these pathways leads to cell cycle arrest and apoptosis. Our results demonstrate that TAK1-D is activated by siRNAs of specific sequences, offering a new explanation for off target effects triggered by these molecules. In addition the dsRNA triggered activation of a cell death pathway in the human lung cancer cell line studied suggests that TAK1-D might be a new and promising therapeutic target for the treatment of nonsmall cell lung cancer. Published by Cold Spring Harbor Laboratory Press.
Original language | English (US) |
---|---|
Pages (from-to) | 535-542 |
Number of pages | 8 |
Journal | RNA |
Volume | 14 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2008 |
Keywords
- Apoptosis
- Cell cycle
- TAK1
- siRNA
ASJC Scopus subject areas
- Molecular Biology