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Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis

Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide variety of cellular responses, but the exact mechanisms that control Smurf2 abundance are largely unknown. Here we identify microRNA-32...

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Autores principales: Cao, Shan, Xiao, Lan, Rao, Jaladanki N., Zou, Tongtong, Liu, Lan, Zhang, Dee, Turner, Douglas J., Gorospe, Myriam, Wang, Jian-Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982989/
https://www.ncbi.nlm.nih.gov/pubmed/24554769
http://dx.doi.org/10.1091/mbc.E13-09-0560
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author Cao, Shan
Xiao, Lan
Rao, Jaladanki N.
Zou, Tongtong
Liu, Lan
Zhang, Dee
Turner, Douglas J.
Gorospe, Myriam
Wang, Jian-Ying
author_facet Cao, Shan
Xiao, Lan
Rao, Jaladanki N.
Zou, Tongtong
Liu, Lan
Zhang, Dee
Turner, Douglas J.
Gorospe, Myriam
Wang, Jian-Ying
author_sort Cao, Shan
collection PubMed
description Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide variety of cellular responses, but the exact mechanisms that control Smurf2 abundance are largely unknown. Here we identify microRNA-322 (miR-322) and miR-503 as novel factors that regulate Smurf2 expression posttranscriptionally. Both miR-322 and miR-503 interact with Smurf2 mRNA via its 3′-untranslated region (UTR) and repress Smurf2 translation but do not affect total Smurf2 mRNA levels. Studies using heterologous reporter constructs reveal a greater repressive effect of miR-322/503 through a single binding site in the Smurf2 3′-UTR, whereas point mutation of this site prevents miR-322/503–induced repression of Smurf2 translation. Increased levels of endogenous Smurf2 via antagonism of miR-322/503 inhibits TGF-β–induced Smad2 activation by increasing degradation of phosphorylated Smad2. Furthermore, the increase in Smurf2 in intestinal epithelial cells (IECs) expressing lower levels of miR-322/503 is associated with increased resistance to apoptosis, which is abolished by Smurf2 silencing. These findings indicate that miR-322/503 represses Smurf2 translation, in turn affecting intestinal epithelial homeostasis by altering TGF-β/Smad2 signaling and IEC apoptosis.
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spelling pubmed-39829892014-06-30 Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis Cao, Shan Xiao, Lan Rao, Jaladanki N. Zou, Tongtong Liu, Lan Zhang, Dee Turner, Douglas J. Gorospe, Myriam Wang, Jian-Ying Mol Biol Cell Articles Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide variety of cellular responses, but the exact mechanisms that control Smurf2 abundance are largely unknown. Here we identify microRNA-322 (miR-322) and miR-503 as novel factors that regulate Smurf2 expression posttranscriptionally. Both miR-322 and miR-503 interact with Smurf2 mRNA via its 3′-untranslated region (UTR) and repress Smurf2 translation but do not affect total Smurf2 mRNA levels. Studies using heterologous reporter constructs reveal a greater repressive effect of miR-322/503 through a single binding site in the Smurf2 3′-UTR, whereas point mutation of this site prevents miR-322/503–induced repression of Smurf2 translation. Increased levels of endogenous Smurf2 via antagonism of miR-322/503 inhibits TGF-β–induced Smad2 activation by increasing degradation of phosphorylated Smad2. Furthermore, the increase in Smurf2 in intestinal epithelial cells (IECs) expressing lower levels of miR-322/503 is associated with increased resistance to apoptosis, which is abolished by Smurf2 silencing. These findings indicate that miR-322/503 represses Smurf2 translation, in turn affecting intestinal epithelial homeostasis by altering TGF-β/Smad2 signaling and IEC apoptosis. The American Society for Cell Biology 2014-04-15 /pmc/articles/PMC3982989/ /pubmed/24554769 http://dx.doi.org/10.1091/mbc.E13-09-0560 Text en © 2014 Cao et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Cao, Shan
Xiao, Lan
Rao, Jaladanki N.
Zou, Tongtong
Liu, Lan
Zhang, Dee
Turner, Douglas J.
Gorospe, Myriam
Wang, Jian-Ying
Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis
title Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis
title_full Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis
title_fullStr Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis
title_full_unstemmed Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis
title_short Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis
title_sort inhibition of smurf2 translation by mir-322/503 modulates tgf-β/smad2 signaling and intestinal epithelial homeostasis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982989/
https://www.ncbi.nlm.nih.gov/pubmed/24554769
http://dx.doi.org/10.1091/mbc.E13-09-0560
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