Abstract
The Myc/Max/Mad family of transcription factors plays a fundamental role in the regulation of cell proliferation, oncogenic transformation, and cell differentiation. However, it remains unclear whether different heterodimers, such as Myc/Max and Mad/Max, recognize the same or different target genes in vivo. We show by chromatin immunoprecipitation that Myc target genes are also recognized by Mad1 in differentiated HL60 cells. We also substituted the complete basic region of Myc for the corresponding region of Mad. Wild-type c-Myc was then compared with c-Myc(Mad-BR) in oncogenic transformation, regulation of cell proliferation, induction of apoptosis, activation of chromosomal gene expression, and direct binding to chromosomal sites by chromatin immunoprecipitation. We find that the wild-type c-Myc and c-Myc/MadBR proteins have indistinguishable biological activity and target gene recognition in vivo. These data are consistent with a model in which Myc and Mad regulate a common set of target genes.
Highlights
The c-myc gene encodes a transcription factor, c-Myc, that dimerizes with Max to serve as a master regulator of cell growth, cell division, and cell differentiation in all metazoans
We show by chromatin immunoprecipitation that Myc target genes are recognized by Mad1 in differentiated HL60 cells
We conclude that there is no measurable difference in DNA site recognition in vivo between the Myc and Mad1 basic regions, and that these two domains can recognize equivalent sets of target genes
Summary
The c-myc gene encodes a transcription factor, c-Myc, that dimerizes with Max to serve as a master regulator of cell growth, cell division, and cell differentiation in all metazoans (reviewed in Ref. 1). Mad/ Max heterodimers recognize consensus binding sites in vitro that are indistinguishable from those recognized by Myc/Max, suggesting that these alternate Max complexes may activate and repress common target genes. This is an appealing model, there remains only limited evidence to support it. To assess the basic region of Mad/Mxi proteins, we constructed a hybrid Myc protein in which the entire basic region of Myc was exchanged for the corresponding region of Mad while retaining the Myc HLH/LZ domain We find that this Myc(Mad-BR) hybrid protein has the ability to oncogenically transform cells, induce apoptosis, and regulate cellular promoters that is indistinguishable from that of Myc family proteins. We conclude that there is no inherent structural difference between the Myc and Mad/Mxi basic regions that would promote the regulation of distinct sets of cellular target genes
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