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Bone morphogenetic protein/SMAD signaling orients cell fate decision by impairing KSRP-dependent microRNA maturation.

Authors
  • Pasero, Michela1
  • Giovarelli, Matteo
  • Bucci, Gabriele
  • Gherzi, Roberto
  • Briata, Paola
  • 1 University of Genova, IRCCS Azienda Universitaria Ospedaliera San Martino-IST, 16132 Genova, Italy. , (Italy)
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Nov 29, 2012
Volume
2
Issue
5
Pages
1159–1168
Identifiers
DOI: 10.1016/j.celrep.2012.10.020
PMID: 23177623
Source
Medline
Language
English
License
Unknown

Abstract

MicroRNAs (miRNAs) are essential regulators of development, physiology, and evolution, and their biogenesis is strictly controlled at multiple levels. Regulatory proteins, such as KSRP, modulate rates and timing of enzymatic reactions responsible for maturation of select miRNAs from their primary transcripts in response to specific stimuli. Here, we show that KSRP silencing in mesenchymal C2C12 cells produces a change in the transcriptome largely overlapping that induced by bone morphogenetic protein 2 (BMP2) signaling activation. This induces osteoblastic differentiation while preventing myogenic differentiation. KSRP silencing- and BMP2-dependent myogenic miRNA (myomiR) maturation blockade is required for osteoblastic differentiation of C2C12 cells. Our results demonstrate that phosphorylated R-SMAD proteins, the transducers of BMP2 signal, associate with phosphorylated KSRP and block its interaction with primary myomiRs. This abrogates KSRP-dependent myomiR maturation, with SMAD4, SMAD5, and SMAD9 silencing being able to rescue KSRP function. Thus, SMAD-induced blockade of KSRP-dependent myomiR maturation is critical for orienting C2C12 cell differentiation toward osteoblastic lineage. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

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