Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):157-62. doi: 10.1073/pnas.1219958110. Epub 2012 Dec 17.
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.
细胞增殖取决于有丝分裂刺激与环境条件的整合。越来越多的证据表明，microRNAs 在这种整合中发挥调节作用。在这里，我们表明在细胞静止期，成熟的 microRNAs 被稳定并储存在 Argonaute 蛋白复合物中，这些复合物可以被有丝分裂刺激激活，从而抑制有丝分裂刺激的靶标，从而影响随后的细胞反应。在静止细胞中，大多数 microRNAs 存在于低分子量的 Argonaute 蛋白中，缺乏 RNA 诱导沉默复合物（RISC）的必需成分。至少在 3 周内，这种 Argonaute 相关 microRNAs 的池是稳定的，可以在有丝分裂刺激后被招募到 RISC 复合物中。使用几种模型系统，我们证明稳定的 Argonaute 蛋白相关的小 RNA 能够抑制有丝分裂诱导的转录物。因此，成熟的 microRNAs 可能代表一种以前未被认识的细胞记忆形式，使细胞能够在细胞静止期的长时间内保留转录后调节信息。
