The MNT transcription factor autoregulates its expression and supports proliferation in MYC-associated factor X (MAX)-deficient cells

The MAX network transcriptional repressor (MNT) is an MXD family transcription factor of the basic helix-loop-helix (bHLH) family. MNT dimerizes with another transcriptional regulator, MYC-associated factor X (MAX), and down-regulates genes by binding to E-boxes. MAX also dimerizes with MYC, an oncogenic bHLH transcription factor. Upon E-box binding, the MYC-MAX dimer activates gene expression. MNT also binds to the MAX dimerization protein MLX (MLX), and MNT-MLX and MNT-MAX dimers co-exist. However, all MNT functions have been attributed to MNT-MAX dimers, and no functions of the MNT-MLX dimer have been described. MNT's biological role has been linked to its function as a MYC oncogene modulator, but little is known about its regulation. We show here that MNT localizes to the nucleus of MAX-expressing cells and that MNT-MAX dimers bind and repress the MNT promoter, an effect that depends on one of the two E-boxes on this promoter. In MAX-deficient cells, MNT was overexpressed and redistributed to the cytoplasm. Interestingly, MNT was required for cell proliferation even in the absence of MAX. We show that in MAX-deficient cells, MNT binds to MLX, but also forms homodimers. RNA-sequencing experiments revealed that MNT regulates the expression of several genes even in the absence of MAX, with many of these genes being involved in cell cycle regulation and DNA repair. Of note, MNT-MNT homodimers regulated the transcription of some genes involved in cell proliferation. The tight regulation of MNT and its functionality even without MAX suggest a major role for MNT in cell proliferation.This work was supported by Grant SAF2017-88026-R from Agencia Estatal de Investigación, Spanish Government (to J. L. and M. D. D.), funded in part by FEDER Program from the European Union, National Institutes of Health Grant CA57138/CA from NCI (to R. N. E.), and grants from Shriners Hospitals for Children (to P. J. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Papel de la oncoproteína Myc en la regulación de la transcripción, diferenciación y senescencia

MYC es un oncogén y factor de transcripción que pertenece a la familia de proteínas con dominio bHLH-LZ. Además es uno de los oncogenes más frecuentemente desregulado en tumores humanos. Los mecanismos por los que Myc estimula la proliferación han sido estudiados en detalle, mientras que los mecanismos por los que Myc bloquea la diferenciación son mucho menos conocidos. Previos trabajos indican que, al menos en algunos sistemas, Myc bloquea la diferenciación reprimiendo genes que conducen a la diferenciación. Sin embargo, a pesar de que casi la mitad de los genes regulados por Myc están reprimidos, se conoce sobre los mecanismos responsables de la represión dependiente de Myc. Se ha demostrado la interacción entre Myc y un conocido represor transcripcional, Sin3. Además hemos estudiado un nuevo mecanismo de regulación de Myc a través de la activación de la proteína kinasa ERK y la función de Myc como inhibidor de la senescencia celular