Role of tumor suppressor p53 as a negative regulator of the non-canonical NF- $\kappa$ B signaling through miRNA-mediated silencing of NIK

Abstract

NF- $\kappa$ B signaling through both canonical and non-canonical pathways plays a central role in cell proliferation, inflammation and immune responses. NF- $\kappa$ B -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 more than half of all human cancers. While the non-canonical NF- $\kappa$ B 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, I 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- $\kappa$ B pathway. Conversely, its knockdown led to increased levels of NIK, IKK $\alpha$ 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- $\kappa$ B signaling. My collective findings support a novel cross-talk mechanism between non-canonical NF- $\kappa$ B and p53.