The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB–Inducing Kinase
Hanbit Jang1,2, Seulki Park2,3, Jaehoon Kim1, Jong Hwan Kim6, Seon-Young Kim6, Sayeon Cho7, Sung Goo Park2,3, Byoung Chul Park2,4,*, Sunhong Kim2,5,*, and Jeong-Hoon Kim2,3,*
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea, 2Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea, 3Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea, 4Department of Proteome Structural Biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea, 5Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea, 6Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141, Korea, 7College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
Received October 22, 2019; Revised November 26, 2019; Accepted November 27, 2019.; Published online December 24, 2019.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB–inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.
Keywords: cancer, microRNA, NF-κB, NF-κB–inducing kinase, p53, tumor suppressor gene
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31 December 2019 Volume 42,
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