Involvement of MicroRNA in AU-Rich Element-Mediated mRNA Instability

Abstract

AU-rich elements (AREs) in the 3' untranslated region (UTR) of unstable mRNAs dictate their degradation. An RNAi-based screen performed in Drosophila S2 cells has revealed that Dicer1, Argonaute1 (Ago1) and Ago2, components involved in microRNA (miRNA) processing and function, are required for the rapid decay of mRNA containing AREs of tumor necrosis factor-alpha. The requirement for Dicer in the instability of ARE-containing mRNA (ARE-RNA) was confirmed in HeLa cells. We further observed that miR16, a human miRNA containing an UAAAUAUU sequence that is complementary to the ARE sequence, is required for ARE-RNA turnover. The role of miR16 in ARE-RNA decay is sequence-specific and requires the ARE binding protein tristetraprolin (TTP). TTP does not directly bind to miR16 but interacts through association with Ago/eiF2C family members to complex with miR16 and assists in the targeting of ARE. miRNA targeting of ARE, therefore, appears to be an essential step in ARE-mediated mRNA degradation.

Coordinate Suppression of ERBB2 and ERBB3 by Enforced Expression of Micro-RNA miR-125a or miR-125b

“…Aside from identifying a conserved miR-125 targeting element in both ERBB2 and ERBB3, BLAST analysis also identified homologous U-rich regions in the 3Ј-UTRs of ERBB2 and ERBB3. Such U-rich 3Ј-UTR regions have been reported in other genes to be essential for the mediation of miRNA-induced transcript destabilization (28). Luciferase constructs containing the 3Ј-UTRs of ERBB2 and ERBB3 demonstrated significantly less activity in miR-125a-and miR-125b-overexpressing SKBR3 cells relative to controls.…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…MiRNAs can also cooperate with these RBPs to regulate mRNA stability or translation. 104 For example, miR-16 cooperates with tristetraprolin to mediate Tnf mRNA destabilization, 105 miR-221 associates with tristetraprolin and can accelerate Tnf mRNA decay, and miR-579 and miR125b inhibit Tnf mRNA translation through translational inhibitor recruitment. 106 In addition to cooperating with RBPs to destabilize mRNA, miRNAs can also interact with RBPs to protect mRNAs from degradation.…”

Principles and effects of microRNA-mediated post-transcriptional gene regulation

“…In spite of the fact that miRNAs bind their targets by following an almost universal mechanism, the only exception so far is miR-16 that was suggested to basepair with its target by initiating a non-canonical conformation (Jing et al, 2005), it seems that at the level of gene regulation the outcome of these interactions can be diverse. The worm lin-4, the founding member of miRNAs, together with its target RNAs associate with polyribosomes but no protein is made suggesting that the lin-4 miRNA inhibits translation after the initiation step, most likely slowing down the rate of polypeptide elongation or stability (Olsen and Ambros, 1999;Seggerson et al, 2002).…”

“…For instance, miR-16 may recruit TTP to canonical AREs through the members of the Argonaute family. Interestingly, TTP forms a complex with hDcp1a, hDcp2 and hXrn1, and overexpressed TTP colocalizes with PBs (Jing et al, 2005;Kedersha et al, 2005;Lykke-Andersen and Wagner, 2005). Moreover, the ARE binding protein HuR involved in reversing the miR-122-mediated repression of the CAT-1 mRNA (Bhattacharyya et al, 2006).…”