title: Short RNA duplexes elicit RIG-I-mediated apoptosis in a cell type- and length-dependent manner.
abstract: Short double-stranded RNAs (dsRNAs) induce type I interferon (IFN)-mediated innate immune responses. In functional studies with short interfering RNAs or synthetic mimics of microRNA precursors in vitro, we found that short dsRNAs readily induced apoptosis in cells derived from human granulosa cell tumors, but not in other cell types. Apoptosis was independent of the sequence of the dsRNA, but depended on its length, and was induced by 23- and 24-nucleotide (nt) dsRNAs, but not by shorter dsRNAs (< 22 nt) or by the long dsRNA polyinosinic-polycytidylic acid. Microarray analysis revealed that apoptosis was accompanied by the increased expression of IFN-stimulated genes; however, several lines of evidence showed that IFNs did not directly induce apoptosis. Subsequent analyses revealed that the short dsRNAs increased the expression of retinoic acid-inducible gene I (RIG-I) through dsRNA-activated protein kinase (PKR). Although these dsRNAs bore 3' overhangs and nontriphosphate 5' termini, which are not thought to be RIG-I-activating structures, the dsRNAs bound to RIG-I and triggered proapoptotic signaling mostly by activating RIG-I, which was followed by activation of the mitogen-activated protein kinase p38. Thus, we suggest that ligand recognition and subsequent signaling by RNA sensors are more complicated than previously believed. In addition, short dsRNAs may serve as pharmacological agents to target specific tumors, such as granulosa cell tumors.
authors: Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan.
authors: Osamu
authors: O
authors: Ishibashi
authors: Md Moksed
authors: MM
authors: Ali
authors: Shan-Shun
authors: SS
authors: Luo
authors: Takashi
authors: T
authors: Ohba
authors: Hidetaka
authors: H
authors: Katabuchi
authors: Toshiyuki
authors: T
authors: Takeshita
authors: Toshihiro
authors: T
authors: Takizawa
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009928:Organ Specificity; D012330:RNA, Double-Stranded / Q000378:metabolism* / Q000494:pharmacology; D011971:Receptors, Immunologic; D019892:eIF-2 Kinase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases