SMAD proteins control DROSHA-mediated microRNA maturation
SMAD proteins control DROSHA-mediated microRNA maturation
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DOI：
10.1038/nature07086
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发表时间：
2008-07-03
期刊：
影响因子：
64.8
通讯作者：
Hata, Akiko
中科院分区：
文献类型：
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作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
微小RNA（miRNAs）是一类参与信使RNA和蛋白质合成的时空调控的非编码小RNA。异常的miRNA表达导致发育异常和疾病，如心血管疾病和癌症;然而，调节miRNA生物发生的刺激和过程在很大程度上是未知的。生长因子的转化生长因子β（TGF-β）和骨形态发生蛋白（BMP）家族协调发育和成人组织（包括脉管系统）的稳态中的基本生物学过程。在这里，我们表明，在人血管平滑肌细胞中，TGF-β和BMP诱导的收缩表型是由miR- 21介导的。miR- 21下调PDCD 4（程序性细胞死亡4），PDCD 4反过来又作为平滑肌收缩基因的负调节因子。令人惊讶的是，TGF-β和BMP信号传导通过转录后步骤促进成熟miR- 21表达的快速增加，促进miR- 21的初级转录物（pri-miR- 21）通过DROSHA（也称为RNASEN）复合物加工成前体miR- 21（pre-miR- 21）。TGF-β和BMP-特异性SMAD信号转导子被募集到与RNA解旋酶p68（也称为DDX 5）复合的pri-miR- 21中，所述RNA解旋酶p68是DROSHA微处理器复合体的组分。该过程不需要共享的辅因子SMAD 4。因此，通过配体特异性SMAD蛋白调节miRNA生物发生对于控制血管平滑肌细胞表型和潜在地对于由TGF-β和BMP信号传导途径介导的SMAD 4非依赖性应答是关键的。
MicroRNAs ( miRNAs) are small non- coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor beta ( TGF-beta) and bone morphogenetic protein ( BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR- 21. miR- 21 downregulates PDCD4 ( programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signalling promotes a rapid increase in expression of mature miR- 21 through a post- transcriptional step, promoting the processing of primary transcripts of miR- 21 ( pri- miR- 21) into precursor miR- 21 ( pre- miR- 21) by the DROSHA ( also known as RNASEN) complex. TGF-beta- and BMP- specific SMAD signal transducers are recruited to pri- miR- 21 in a complex with the RNA helicase p68 ( also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand- specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4- independent responses mediated by the TGF-beta and BMP signalling pathways.