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
Nikita
N
Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, SE-171 77 Stockholm, Sweden.
Wahlström
Therese
T
Hurlin
Peter J
PJ
Henriksson
Marie
M
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D015854:Up-Regulation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D056572:Histone Deacetylase Inhibitors; C484561:Mnt protein, mouse; C489428:Myc protein, mouse; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex