[논문]The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB-Inducing Kinase

Jang, Hanbit; Park, Seulki; Kim, Jaehoon; Kim, Jong Hwan; Kim, Seon-Young; Cho, Sayeon; Park, Sung Goo; Park, Byoung Chul; Kim, Sunhong; Kim, Jeong-Hoon

doi:10.14348/molcells.2019.0239

[국내논문] The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB-Inducing Kinase 원문보기

Molecules and cells, v.43 no.1, 2020년, pp.23 - 33

Jang, Hanbit (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) , Park, Seulki (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Kim, Jaehoon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) , Kim, Jong Hwan (Personalized Genomic Medicine Research Center, KRIBB) , Kim, Seon-Young (Personalized Genomic Medicine Research Center, KRIBB) , Cho, Sayeon (College of Pharmacy, Chung-Ang University) , Park, Sung Goo (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Park, Byoung Chul (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Kim, Sunhong (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Kim, Jeong-Hoon (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))

Abstract ▼ AI-Helper

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.

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표/그림 (5)

그림 Fig. 1. Identification of p53 as a negative regulator of NIK protein and the non-canonical NF-κB pathway via RNAi screening.
그림 Fig. 2. p53 suppresses protein levels of NIK and non-canonical NF-κB activity.
그림 Fig. 3. p53 suppresses the expression of NIK through miRNA-mediated gene silencing, but not UPS or lysosomal degradation.
그림 Fig. 4. p53-induced miR-34b negatively regulates the non-canonical NF-κB pathway by targeting the CDS of NIK.
그림 Fig. 4. Continued.

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