Journal
ONCOGENESIS
Volume 10, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41389-020-00298-4
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Funding
- Agencia Estatal de Investigacion, Spanish Government [SAF2017-88026-R]
- F.P.U. fellowships
- F.P.I. fellowship from the Spanish Government
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The study finds that MNT acts as a transcription factor to repress the activation of the NF-kappa B pathway by interacting with REL, and forms a complex with REL to inhibit the expression of REL target genes through two mechanisms.
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-kappa B 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 I kappa B and translocates to the nucleus when the NF-kappa B 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-kappa B pathway. Meanwhile, MNT overexpression results in the repression of I kappa B alpha, a bona fide REL target. Both MNT and REL bind to the I kappa B alpha 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-kappa B 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-kappa B pathways, two of the most prominent pathways in cancer.
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