SMAD proteins control DROSHA-mediated microRNA maturation

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.