title: Long-lived microRNA-Argonaute complexes in quiescent cells can be activated to regulate mitogenic responses.
abstract: Cellular proliferation depends on the integration of mitogenic stimuli with environmental conditions. Increasing evidence suggests that microRNAs play a regulatory role in this integration. Here we show that during periods of cellular quiescence, mature microRNAs are stabilized and stored in Argonaute protein complexes that can be activated by mitogenic stimulation to repress mitogen-stimulated targets, thus influencing subsequent cellular responses. In quiescent cells, the majority of microRNAs exist in low molecular weight, Argonaute protein-containing complexes devoid of essential components of the RNA-induced silencing complex (RISC). For at least 3 wk, this pool of Argonaute-associated microRNAs is stable and can be recruited into RISC complexes subsequent to mitogenic stimulation. Using several model systems, we demonstrate that stable Argonaute protein-associated small RNAs are capable of repressing mitogen-induced transcripts. Therefore, mature microRNAs may represent a previously unappreciated form of cellular memory that allows cells to retain posttranscriptional regulatory information over extended periods of cellular quiescence.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Olejniczak
authors.forename: Gaspare
authors.initials: G
authors.lastname: La Rocca
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Gruber
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism*; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation; D002850:Chromatography, Gel; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D008156:Luciferases; D046911:Macromolecular Substances / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D046911:Macromolecular Substances; D035683:MicroRNAs; D034741:RNA, Small Interfering; D008156:Luciferases