A novel role of MNT as a negative regulator of REL and the NF-κB pathwayA novel role of MNT as a negative regulator of REL and the NF-κB pathwayLiaño-Pons J, Lafita-Navarro MC, García-Gaipo L, Colomer C, Rodríguez J, von Kriegsheim A, Hurlin PJ, Ourique F, Delgado MD, Bigas A, Espinosa ML, León J.2021-01-07T23:00:00Z<h3>​Abstract<br></h3><div><br></div><div>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 REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is 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. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT-REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT-REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.<br></div><p><br></p><p>​Oncogenesis. 2021 Jan 8;10(1):5. doi: 10.1038/s41389-020-00298-4.</p><div><br><br></div><p><br></p><p><br></p>354