Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Mol Cell. 2010 Aug 13;39(3):373-84. doi: 10.1016/j.molcel.2010.07.011.
The signal transducers of the transforming growth factor beta (TGFbeta)/bone morphogenetic protein (BMP), the Smads, promote the expression of a subset of miRNAs by facilitating the cleavage reaction by Drosha. The mechanism that limits Smad-mediated processing to a selective group of miRNAs remained hitherto unexplored. In this study, we expand the number of TGFbeta/BMP-regulated miRNAs (T/B-miRs) to 20. Of interest, a majority of T/B-miRs contain a consensus sequence (R-SBE) within the stem region of the primary transcripts of T/B-miRs (pri-T/B-miRs). Here, we demonstrate that Smads directly bind the R-SBE. Mutation of the R-SBE abrogates TGFbeta/BMP-induced recruitment of Smads, Drosha, and DGCR8 to pri-T/B-miRs and impairs their processing, whereas introduction of R-SBE to unregulated pri-miRNAs is sufficient to recruit Smads and to allow regulation by TGFbeta/BMP. Thus, Smads are multifunctional proteins that modulate gene expression transcriptionally through DNA binding and posttranscriptionally through pri-miRNA binding and regulation of miRNA processing.
转化生长因子β（TGFβ）/骨形态发生蛋白（BMP）的信号转导物 Smads 通过促进 Drosha 的切割反应来促进一组 miRNA 的表达。迄今为止，限制 Smad 介导的加工为一组选择性 miRNA 的机制仍未得到探索。在这项研究中，我们将 TGFβ/BMP 调节的 miRNA（T/B-miRs）的数量扩展到 20 个。有趣的是，大多数 T/B-miRs 在 T/B-miRs（pri-T/B-miRs）的初级转录本的茎区含有一个保守序列（R-SBE）。在这里，我们证明 Smads 直接结合 R-SBE。R-SBE 的突变消除了 TGFβ/BMP 诱导的 Smads、Drosha 和 DGCR8 到 pri-T/B-miRs 的募集，并损害了它们的加工，而将 R-SBE 引入不受调节的 pri-miRNAs 足以募集 Smads 并允许 TGFβ/BMP 调节。因此，Smads 是多功能蛋白，可通过 DNA 结合进行转录调控，通过 pri-miRNA 结合和 miRNA 加工调控进行转录后调控。
