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. Author manuscript; available in PMC: 2018 Feb 13.
Published in final edited form as: Cold Spring Harb Perspect Biol. 2016 Sep 1;8(9):a022061. doi: 10.1101/cshperspect.a022061

Figure 3.

Figure 3

MicroRNA (miRNA) biogenesis pathway and its regulation by Smad proteins. (A) The miRNA biogenesis pathway. The biogenesis of a miRNA is a stepwise process that includes (1) transcription of a primary transcript (pri-miRNA), (2) nuclear cropping to produce the precursor-miRNA (pre-miRNA), (3) export to the cytoplasm, and (4) cytoplasmic cropping to a double-stranded (ds) miRNA precursor. miRNA genes are generally transcribed by RNA polymerase II (Pol II) as long, 5′-capped and 3′-polyadenylated transcripts (pri-miRNAs) that are processed by the RNase III enzyme, Drosha, in the microprocessor complex to generate hairpin-loop RNAs, known as pre-miRNAs. Pre-miRNAs are recognized by the exportin 5 (Xpo5)/Ran-GTP transporter and exported to the cytoplasm, where another enzyme of the RNase III family, Dicer, catalyzes secondary processing (“dicing”) to produce miRNA/miRNA* duplexes. Dicer, TRBP, and Argonaute (Ago) proteins mediate the processing of pre-miRNAs and the assembly of the RNA-induced silencing complex (RISC) in mammalian cells. Ago proteins associate with Dicer in both the cropping and RISC assembly steps (Hata and Lieberman 2015). (From Hata and Lieberman 2015; adapted, with permission, from the authors.) (B) Transcription of miRNA genes can be regulated by TGF-β and BMP signaling pathways either by a direct binding of Smad complex (R-Smad/co-Smad) to Smad-binding element (SBE) in the promoter regions of miRNA genes or by transcriptional regulation of other transcription factors, which, in turn, modulate the transcription of miRNA genes. (C) Pri-miRNA to pre-miRNA processing of a subset of miRNAs catalyzed by Drosha and its cofactors p68 and p72 is positively regulated by transcription factors, such as R-Smad and p53, and negatively regulated by YAP, a signal transducer of the Hippo pathway. Specific binding of R-Smads to a dsRNA sequence motif located in the pre-miRNA provides specificity of this regulation. TF, Transcription factor. (From Hata and Lieberman 2015; adapted, with permission, from the authors.)