A novel role of MNT as a negative regulator of REL and the NF-κB pathway

Abstract

MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix-loop-helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and c-REL (REL), the oncogenic member of the REL/NF-κB family. REL is involved in important biological processes and it is found altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona-fide REL target. Indeed, both MNT and REL bind to the IκBα gene at a region mapping in the first exon, suggesting its regulation as a MNT-REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two different mechanisms: 1) retention of REL in the cytoplasm by MNT protein interaction and 2) MNT-driven repression of REL-target genes through a MNT-REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and the NF-κB pathways, two of the most prominent pathways involved in cancer.