Mnt transcriptional repressor is functionally regulated during cell cycle progression.

The Myc/Max/Mad network of transcription factors regulates cell proliferation, differentiation, and transformation. Similar to other proteins of the network, Mnt forms heterodimers with Max and binds CACGTG E-Box elements. Transcriptional repression by Mnt is mediated through association with mSin3, and deletion of the mSin3-interacting domain (SID) converts Mnt to a transcriptional activator. Mnt is coexpressed with Myc in proliferating cells and has been suggested to be a modulator of Myc function. We report that Mnt is expressed both in growth-arrested and proliferating mouse fibroblasts and is phosphorylated when resting cells are induced to re-enter the cell cycle. Importantly, the interaction between Mnt and mSin3 is disrupted upon serum stimulation resulting in decreased Mnt-associated HDAC activity. Furthermore, we demonstrate that Mnt binds and recruits mSin3 to the Myc target gene cyclin D2 in quiescent mouse fibroblasts. Interference with Mnt expression by RNAi resulted in upregulation of cyclin D2 expression in growth-arrested fibroblasts, supporting the view that Mnt represses cyclin D2 transcription in quiescent cells. Our data suggest a model in which phosphorylation of Mnt at cell cycle entry results in disruption of Mnt-mSin3-HDAC1 interaction, which allows induction of Myc target genes by release of Mnt-mediated transcriptional repression.

Popov N ，Wahlström T ，Hurlin PJ ，Henriksson M ... -  《ONCOGENE》

Mnt takes control as key regulator of the myc/max/mxd network.

Wahlström T ，Henriksson M 《-》

Regulation of cyclin D2 gene expression by the Myc/Max/Mad network: Myc-dependent TRRAP recruitment and histone acetylation at the cyclin D2 promoter.

Bouchard C ，Dittrich O ，Kiermaier A ，Dohmann K ，Menkel A ，Eilers M ，Lüscher B ... -  《GENES & DEVELOPMENT》

Analysis of Myc/Max/Mad network members in adipogenesis: inhibition of the proliferative burst and differentiation by ectopically expressed Mad1.

Transcription factors of the Myc/Max/Mad network affect multiple aspects of cellular behavior, including proliferation, differentiation, and apoptosis. Recent studies have shown that Mad proteins can inhibit cellular growth and transformation and thus antagonize the function of Myc proteins. To define further the contribution of these proteins to cellular growth control, we have studied the expression of the respective genes and proteins in 3T3-L1 cells, both upon serum stimulation of quiescent cells and during adipocytic differentiation in response to insulin, dexamethasone, and isobutylmethylxanthine. We found distinct expression patterns for the mad genes. Mad4 was induced when cells exit the cell cycle and, together with mad1, during the late phase of differentiation. In contrast, mad3 expression was associated with progression through S phase and the proliferative burst of differentiating preadipocytes, overlapping in part c-myc expression. DNA binding analyses revealed that the most prominent network complex both in cycling and in differentiating cells was Mnt/Max, whereas c-Myc/Max complexes were detectable only during peak c-Myc expression periods. Ectopic expression of Mad1 in preadipocytes resulted in the inhibition of S phase and the proliferation associated with the proliferative burst; as a consequence, adipocytic differentiation was significantly inhibited. Our findings suggest that the precise temporal regulation of Myc/Max/Mad network proteins is critical for determining cellular behavior.

Pulverer B ，Sommer A ，McArthur GA ，Eisenman RN ，Lüscher B ... -  《JOURNAL OF CELLULAR PHYSIOLOGY》

Mnt-deficient mammary glands exhibit impaired involution and tumors with characteristics of myc overexpression.

Toyo-oka K ，Bowen TJ ，Hirotsune S ，Li Z ，Jain S ，Ota S ，Escoubet-Lozach L ，Garcia-Bassets I ，Lozach J ，Rosenfeld MG ，Glass CK ，Eisenman R ，Ren B ，Hurlin P ，Wynshaw-Boris A ... -  《CANCER RESEARCH》