The Eisenman laboratory is interested in how cell proliferation, growth, and differentiation are regulated through the actions of transcriptional networks, and how this regulation is subverted during tumor progression. The laboratory employs the tools of molecular biology as well as mammalian and Drosophila genetics to study basic mechanisms underlying normal and neoplastic cellular functions.
We have focused on a transcription factor network - the Max network- whose interacting components together comprise a transcriptional switching system that has been highly conserved throughout evolution. One of the components of the network is the Myc oncoprotein, the product of an oncogene profoundly involved in the genesis of many different tumors, but also normally involved in cell proliferation, differentiation, and death. Myc interacts in a specific manner with its dimerization partner, Max, permitting the Myc-Max heterodimer to bind DNA and regulate gene expression.
Importantly, Max not only interacts with Myc family proteins but also dimerizes with other bHLHZ proteins including the Mxd (formerly known as Mad) family, Mnt, and Mga. These proteins act as transcriptional repressors. Mad and Mnt proteins repress by interacting with the mSin3-histone deacetylase corepressor complex.
This co-repressor complex, which is brought to specific sites in chromatin through its binding with Mxd:Max heterodimers, causes deacetylation of the N-terminal tails of nucleosomal histones. This in turn is believed to lead to formation of a repressive chromatin structure. Because Mxd proteins are expressed during terminal differentiation of many cell types the Mad proteins provide a link between transcriptional repression, chromatin structure, and terminal differentiation. Recent evidence suggests that Myc-Max and Mxd-Max as well as Mnt-Max dimers bind a common set of target genes suggesting that the balance between the activating factors and the repressing factors is likely to control major aspects of cell behavior through modification of chromatin structure. We have called this interacting group of transcription factors the Max network.
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