Mnt, a novel Max-interacting protein is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites.
The small constitutively expressed bHLHZip protein Max is known to form sequence-specific DNA binding heterodimers with members of both the Myc and Mad families of bHLHZip proteins. Myc:Max complexes activate transcription, promote proliferation, and block terminal differentiation. In contrast, Mad:Max heterodimers act as transcriptional repressors, have an antiproliferative effect, and are induced upon differentiation in a wide variety of cell types. We have identified a novel bHLHZip Max-binding protein, Mnt, which belongs to neither the Myc nor the Mad families and which is coexpressed with Myc in a number of proliferating cell types. Mnt:Max heterodimers act as transcriptional repressors and efficiently suppress Myc-dependent activation from a promoter containing proximal CACGTG sites. Transcription repression by Mnt maps to a 13-amino-acid amino-terminal region related to the Sin3 interaction domain (SID) of Mad proteins. We show that this region of Mnt mediates interaction with mSin3 corepressor proteins and that its deletion converts Mnt from a repressor to an activator. Furthermore, wild-type Mnt suppresses Myc+Ras cotransformation of primary cells, whereas Mnt containing a SID deletion cooperates with Ras in the absence of Myc to transform cells. This suggests that Mnt and Myc regulate an overlapping set of target genes in vivo. When mnt is expressed as a transgene under control of the beta-actin promoter in mice the transgenic embryos exhibit a delay in development and die during mid-gestation, when c- and N-Myc functions are critical. We propose that Mnt:Max:Sin3 complexes normally function to restrict Myc:Max activities associated with cell proliferation.
Hurlin
P J
PJ
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
Quéva
C
C
Eisenman
R N
RN
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D002455:Cell Division / Q000235:genetics; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014170:Transformation, Genetic / Q000235:genetics
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C499479:Mad protein, mouse; C499329:Max protein, rat; C067850:Myc associated factor X; C068422:Max protein, mouse