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MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade

It is increasingly clear that the biological functions of a transcription factor cannot be fully understood solely on the basis of protein-coding genes that fall under its control. Many transcription factors regulate expression of miRNAs, which affect the cell by modulating translation and stability...

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Autores principales: Mechtler, Peter, Singhal, Ruchi, Kichina, Julia V., Bard, Jonathan E., Buck, Michael J., Kandel, Eugene S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627294/
https://www.ncbi.nlm.nih.gov/pubmed/26020802
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author Mechtler, Peter
Singhal, Ruchi
Kichina, Julia V.
Bard, Jonathan E.
Buck, Michael J.
Kandel, Eugene S.
author_facet Mechtler, Peter
Singhal, Ruchi
Kichina, Julia V.
Bard, Jonathan E.
Buck, Michael J.
Kandel, Eugene S.
author_sort Mechtler, Peter
collection PubMed
description It is increasingly clear that the biological functions of a transcription factor cannot be fully understood solely on the basis of protein-coding genes that fall under its control. Many transcription factors regulate expression of miRNAs, which affect the cell by modulating translation and stability of mRNAs. The identities and the roles of NF-κB-regulated miRNAs have been attracting research interest for a long time. We revisited this issue in a system with controlled expression of one of the key regulators of NF-κB, RIPK1. Several regulated miRNAs were identified, including miR-146a, miR-215 and miR-497. The miRNAs were also inducible by IL-1β, but not when NF-κB activity was repressed by mutant IκBα. The presence of a miR-497 site was predicted in the 3′-UTR of IKBKB gene, which encodes IKKβ. Using appropriately engineered reporters, we confirmed that this site can be a target of suppressive action of miR-497. Our findings suggest that NF-κB controls expression of a miRNA, which may reduce production of IKKβ. Considering the role of IKKβ in the canonical pathway of NF-κB activation, our observations may indicate a new mechanism that modulates the magnitude of such activation, as well as the propensity of a cell to engage canonical vs. non-canonical pathways.
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spelling pubmed-46272942015-12-02 MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade Mechtler, Peter Singhal, Ruchi Kichina, Julia V. Bard, Jonathan E. Buck, Michael J. Kandel, Eugene S. Oncotarget Research Paper It is increasingly clear that the biological functions of a transcription factor cannot be fully understood solely on the basis of protein-coding genes that fall under its control. Many transcription factors regulate expression of miRNAs, which affect the cell by modulating translation and stability of mRNAs. The identities and the roles of NF-κB-regulated miRNAs have been attracting research interest for a long time. We revisited this issue in a system with controlled expression of one of the key regulators of NF-κB, RIPK1. Several regulated miRNAs were identified, including miR-146a, miR-215 and miR-497. The miRNAs were also inducible by IL-1β, but not when NF-κB activity was repressed by mutant IκBα. The presence of a miR-497 site was predicted in the 3′-UTR of IKBKB gene, which encodes IKKβ. Using appropriately engineered reporters, we confirmed that this site can be a target of suppressive action of miR-497. Our findings suggest that NF-κB controls expression of a miRNA, which may reduce production of IKKβ. Considering the role of IKKβ in the canonical pathway of NF-κB activation, our observations may indicate a new mechanism that modulates the magnitude of such activation, as well as the propensity of a cell to engage canonical vs. non-canonical pathways. Impact Journals LLC 2015-05-16 /pmc/articles/PMC4627294/ /pubmed/26020802 Text en Copyright: © 2015 Mechtler et al. http://creativecommons.org/licenses/by/2.5/ 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 credited.
spellingShingle Research Paper
Mechtler, Peter
Singhal, Ruchi
Kichina, Julia V.
Bard, Jonathan E.
Buck, Michael J.
Kandel, Eugene S.
MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade
title MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade
title_full MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade
title_fullStr MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade
title_full_unstemmed MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade
title_short MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade
title_sort microrna analysis suggests an additional level of feedback regulation in the nf-κb signaling cascade
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627294/
https://www.ncbi.nlm.nih.gov/pubmed/26020802
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