Sequence-specific activation of TAK1-D by short double-stranded RNAs induces apoptosis in NCI-H460 cells.
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 NFkappaB 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.
Kodym
Reinhard
R
Division of Molecular Radiation Biology, Department of Radiation Oncology, The University of Texas Southwestern Medical Center, 2201 Inwood Road, Dallas, TX 75390-9187, USA. reinhard.kodym@utsouthwestern.edu
Kodym
Elisabeth
E
Story
Micheal D
MD
D017398:Alternative Splicing; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D012313:RNA; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000099151:MAP Kinase Kinase Kinase 7