MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors

The pro-apoptotic p53 target Noxa is a BH3-only protein that antagonizes the function of selected anti-apoptotic Bcl-2 family members. While much is known regarding the transcriptional regulation of Noxa, its posttranscriptional regulation remains relatively unstudied. In this study, we therefore in...

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Main Authors:	Lerner, Mikael, Haneklaus, Moritz, Harada, Masako, Grandér, Dan
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352905/

id	pubmed-3352905
recordtype	oai_dc
spelling	pubmed-33529052012-05-21 MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors Lerner, Mikael Haneklaus, Moritz Harada, Masako Grandér, Dan Research Article The pro-apoptotic p53 target Noxa is a BH3-only protein that antagonizes the function of selected anti-apoptotic Bcl-2 family members. While much is known regarding the transcriptional regulation of Noxa, its posttranscriptional regulation remains relatively unstudied. In this study, we therefore investigated whether Noxa is regulated by microRNAs. Using a screen combining luciferase reporters, bioinformatic target prediction analysis and microRNA expression profiling, we identified miR-200c as a negative regulator of Noxa expression. MiR-200c was shown to repress basal expression of Noxa, as well as Noxa expression induced by various stimuli, including proteasomal inhibition. Luciferase reporter experiments furthermore defined one miR-200c target site in the Noxa 3′UTR that is essential for this direct regulation. In spite of the miR-200c:Noxa interaction, miR-200c overexpression led to increased sensitivity to the clinically used proteasomal inhibitor bortezomib in several cell lines. This apparently contradictory finding was reconciled by the fact that in cells devoid of Noxa expression, miR-200c overexpression had an even more pronounced positive effect on apoptosis induced by proteasomal inhibition. Together, our data define miR-200c as a potentiator of bortezomib-induced cell death. At the same time, we show that miR-200c is a novel negative regulator of the pro-apoptotic Bcl-2 family member Noxa. Public Library of Science 2012-05-15 /pmc/articles/PMC3352905/ /pubmed/22615771 http://dx.doi.org/10.1371/journal.pone.0036490 Text en Lerner et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Lerner, Mikael Haneklaus, Moritz Harada, Masako Grandér, Dan
spellingShingle	Lerner, Mikael Haneklaus, Moritz Harada, Masako Grandér, Dan MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors
author_facet	Lerner, Mikael Haneklaus, Moritz Harada, Masako Grandér, Dan
author_sort	Lerner, Mikael
title	MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors
title_short	MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors
title_full	MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors
title_fullStr	MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors
title_full_unstemmed	MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors
title_sort	mir-200c regulates noxa expression and sensitivity to proteasomal inhibitors
description	The pro-apoptotic p53 target Noxa is a BH3-only protein that antagonizes the function of selected anti-apoptotic Bcl-2 family members. While much is known regarding the transcriptional regulation of Noxa, its posttranscriptional regulation remains relatively unstudied. In this study, we therefore investigated whether Noxa is regulated by microRNAs. Using a screen combining luciferase reporters, bioinformatic target prediction analysis and microRNA expression profiling, we identified miR-200c as a negative regulator of Noxa expression. MiR-200c was shown to repress basal expression of Noxa, as well as Noxa expression induced by various stimuli, including proteasomal inhibition. Luciferase reporter experiments furthermore defined one miR-200c target site in the Noxa 3′UTR that is essential for this direct regulation. In spite of the miR-200c:Noxa interaction, miR-200c overexpression led to increased sensitivity to the clinically used proteasomal inhibitor bortezomib in several cell lines. This apparently contradictory finding was reconciled by the fact that in cells devoid of Noxa expression, miR-200c overexpression had an even more pronounced positive effect on apoptosis induced by proteasomal inhibition. Together, our data define miR-200c as a potentiator of bortezomib-induced cell death. At the same time, we show that miR-200c is a novel negative regulator of the pro-apoptotic Bcl-2 family member Noxa.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352905/
_version_	1611529890142617600

MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors

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