SMAD proteins control DROSHA-mediated microRNA maturation

• Published in: Nature 2008-07, Vol.454 (7200), p.56-61
• Main Authors: Hata, Akiko, Lagna, Giorgio, Davis, Brandi N, Hilyard, Aaron C
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Bone Morphogenetic Protein 4; Bone morphogenetic proteins; Bone Morphogenetic Proteins - metabolism; Bone Morphogenetic Proteins - pharmacology; Breast Neoplasms - genetics; Cell death; Cell Line; Cells; Cercopithecus aethiops; DEAD-box RNA Helicases - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation - drug effects; Genotype & phenotype; Growth factors; Humanities and Social Sciences; Humans; Ligands; Mice; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - metabolism; Molecular and cellular biology; Molecular genetics; multidisciplinary; Muscle, Smooth - metabolism; Muscular system; Phenotype; Protein Binding; Protein biosynthesis; Protein synthesis; Proteins; Ribonuclease III - metabolism; Ribonucleic acid; RNA; RNA Processing, Post-Transcriptional; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction - drug effects; Smad Proteins - metabolism; Transcription. Transcription factor. Splicing. Rna processing; Transducers; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; Transforming growth factors
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature07086

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 β (TGF-β) 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-β 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-β 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-β- 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-β and BMP signalling pathways. SMAD proteins and microRNA processing Abnormal microRNA (miRNA) processing is a contributing factor in development of cardiovascular disorders and cancer. In this work, SMAD proteins, which act as signalling molecules for the TGFβ/BMP family of growth factors, are found to have an additional role as regulators of miRNA processing. In human vascular smooth muscle cells, the induction of contractility by TGF-β/BMP is mediated by miR-21. The SMAD proteins promote enhanced processing of miR-21 from a primary copy of RNA (pri-miRNA) to precursor miRNA (pre-miRNA) form. This occurs through a direct interaction of the SMAD proteins with the DROSHA miRNA processing complex. This work opens new avenues in the study of TGF-β family signalling pathways and miRNA biogenesis regulation. Some of the TGF-β family of growth factors are responsible for contractility in vascular smooth muscle ce