Title: Tumor-suppressor NFκB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494.
Authors: Wang, Y; Xu, J; Gao, G; Li, J; Huang, H; Jin, H; Zhu, J; Che, X; Huang, C
Published In Oncogene, (2016 Aug 04)
Abstract: Emerging evidence from The Cancer Genome Atlas has revealed that nuclear factor κB2 (nfκb2) gene encoding p100 is genetically deleted or mutated in human cancers, implicating NFκB2 as a potential tumor suppressor. However, the molecular mechanism underlying the antitumorigenic action of p100 remains poorly understood. Here we report that p100 inhibits cancer cell anchorage-independent growth, a hallmark of cellular malignancy, by stabilizing the tumor-suppressor phosphatase and tensin homolog (PTEN) mRNA via a mechanism that is independent of p100's inhibitory role in NFκB activation. We further demonstrate that the regulatory effect of p100 on PTEN expression is mediated by its downregulation of miR-494 as a result of the inactivation of extracellular signal-regulated kinase 2 (ERK2), in turn leading to inhibition of c-Jun/activator protein-1-dependent transcriptional activity. Furthermore, we identify that p100 specifically interacts with non-phosphorylated ERK2 and prevents ERK2 phosphorylation and nuclear translocation. Moreover, the death domain at C-terminal of p100 is identified as being crucial and sufficient for its interaction with ERK2. Taken together, our findings provide novel mechanistic insights into the understanding of the tumor-suppressive role for NFκB2 p100.
PubMed ID: 26686085
MeSH Terms: Active Transport, Cell Nucleus; HCT116 Cells; Humans; MicroRNAs/antagonists & inhibitors*; MicroRNAs/physiology; Mitogen-Activated Protein Kinase 1/physiology*; NF-kappa B p52 Subunit/physiology*; PTEN Phosphohydrolase/antagonists & inhibitors; PTEN Phosphohydrolase/genetics*; Phosphorylation; Proto-Oncogene Proteins c-jun/physiology; RNA Stability*; Signal Transduction; Tumor Suppressor Proteins/physiology*