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A mirror of two faces: Lin28 as a master regulator of both miRNA and mRNA

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Abstract Lin28 is an evolutionarily conserved RNA‐binding protein that plays important roles in development, pluripotency, tumorigenesis, and metabolism. Emerging evidence suggests that the pleiotropic roles of Lin28 in the diverse physiological and pathological processes are mechanistically linked to its ability to modulate not only the biogenesis of miRNAs, particularly the let‐7 family miRNAs, but also the translation of mRNAs important for cell growth and metabolism. Let‐7 negatively regulates the translation of oncogenes, cell cycle regulators, and metabolic pathway components. Lin28 relieves this repression by blocking the production of mature let‐7. Lin28 binds to the terminal loops of let‐7 precursors, leading to inhibition of processing and the induction of uridylation and precursor degradation. Lin28 also is a direct translational regulator: it selectively binds to a cohort of mRNAs and stimulates their translation. Recent advances in our understanding of Lin28‐mediated mechanisms of posttranscriptional regulation of gene expression reveal important roles of this protein in the fields of development, stem cells, metabolic diseases, and cancer. WIREs RNA 2012, 3:483–494. doi: 10.1002/wrna.1112 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Regulation Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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Domain organization of human Lin28 and Lin28B proteins. The CSD and CCHC domains are marked. Numbers denote amino acids.

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Model for Lin28‐mediated regulation of miRNA and mRNA. (a) The folded CSD and CCHC domains (in blue) and the linker region (in purple) of Lin28 are shown. The CSD inserts itself into the loop of a preferred sequence at one end of the terminal loop (in orange) of let‐7, while the CCHC contacts a conserved GGAG motif at the other end. These interactions prevent pri/pre‐let‐7 from being processed by Drosha and/or Dicer, but trigger the recruitment of TUT4 to uridylate pre‐let‐7, thereby leading to decreased production of mature let‐7. (b) The folded CSD and CCHC are hypothesized to bind to distinct regions of the LRE (in orange) of Lin28 target mRNA, leading to recruitment of RNA helicase A (RHA) to facilitate translation.

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Translation > Translation Regulation
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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