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A novel role of MNT as a negative regulator of REL and the NF-?B 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 REL, the oncogenic member of the NF-?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?B and translocates to the nucleus when the NF-?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-?B pathway. Meanwhile, MNT overexpression results in the repression of I?B?, a bona fide REL target. Both MNT and REL bind to the I?B? 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-?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-?B pathways, two of the most prominent pathways in cancer.

 Fuente: Oncogenesis. 2021 Jan 8;10(1):5

Editorial: Springer Nature

 Año de publicación: 2021

Nº de páginas: 14

Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s41389-020-00298-4

ISSN: 2157-9024

Proyecto español: SAF2017-88026-R

Url de la publicación: https://doi.org/10.1038/s41389-020-00298-4

Autores/as

JUDIT LIAÑO PONS

MARIA DEL CARMEN LAFITA NAVARRO

LORENA GARCIA GAIPO

COLOMER, CARLOTA

RODRÍGUEZ, JAVIER

KRIESGHEIM, ALEX VON

HURLIN, PETER J

FABIANA OURIQUE DA SILVA

ESPINOSA, ML