The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNAInduced Silencing of NF-κB-Inducing Kinase.

Abstract

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.

• Authors: Hanbit Jang, Seulki Park, Jaehoon Kim, Jong Hwan Kim, Seon-Young Kim, Sayeon Cho, Sung Goo Park, Byoung Chul Park, Sunhong Kim, Jeong-Hoon Kim
• Journal: Molecules and cells (Mol Cells) Vol. 43 Issue 1 Pg. 23-33 (Jan 31 2020) ISSN: 0219-1032 [Electronic] United States
• PMID: 31870133 (Publication Type: Journal Article)

Chemical References

• Imidazoles
• MIRN34 microRNA, human
• MicroRNAs
• NF-kappa B
• Piperazines
• TP53 protein, human
• Tumor Suppressor Protein p53
• nutlin 3
• I-kappa B Kinase
• Endonucleases
• SND1 protein, human

Topics

• Endonucleases (genetics, metabolism)
• Gene Expression Regulation
• Gene Silencing
• HeLa Cells
• Humans
• I-kappa B Kinase (metabolism)
• Imidazoles (metabolism)
• MicroRNAs (genetics)
• NF-kappa B (metabolism)
• Phosphorylation
• Piperazines (metabolism)
• Signal Transduction
• Tumor Suppressor Protein p53 (genetics, metabolism)