title: MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade.
abstract: 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.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Mechtler
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.|Cellecta, Inc., Mountain View, CA, USA.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Singhal
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Kichina
authors.affiliation: Department of Biochemistry, State University of New York, Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Bard
authors.affiliation: Department of Biochemistry, State University of New York, Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buck
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kandel
mesh_terms: D002460:Cell Line; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis; D015151:Immunoblotting; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C559640:MIRN497 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D051550:I-kappa B Kinase
keywords: IKKβ; RIPK1; miR-146a; miR-215; miR-497