MERIT Award Recipient: Robert N. Eisenman, Ph.D.
Myc Oncoprotein Function
The Eisenman laboratory is focused on understanding how cell proliferation, growth, and differentiation are regulated through the actions of specific transcription factors. Over the last decade they have focused on a network of interacting transcription factors--the Max network--whose 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 a cancer gene profoundly involved in the genesis of many different tumors, but also normally involved in cell proliferation, differentiation, and death. Myc does not function alone, but interacts in a highly specific manner with its dimerization partner, Max, permitting the Myc-Max heterodimer to bind DNA (at the E-box sequence CACGTG) and regulate gene expression.
Importantly, Max also interacts with other proteins, including a group called the Mad family. Whereas Myc-Max dimers activate transcription at E-box sites, Mad:Max heterodimers repress transcription at the same sites and thus appear to oppose the gene activation function of Myc:Max. Normally, Mad is expressed during the terminal differentiation of many cell types, at a time when Myc is usually turned off. The Eisenman laboratory has been able to demonstrate switching of Myc-Max to Mad-Max complexes during differentiation of several cell types. They have also shown that Max interacts with other interesting bHLHZ proteins including Mga and Mnt. The balance between these proteins is likely to be critical for determining the behavior of cells.
Protein interactions also govern the transcriptional activities of these proteins. They have shown that Mad represses transcription by binding to the co-repressor mSin3 which in turn interacts with Class I histone deacetylases. A major project in the lab is directed towards understanding the structural basis and specificity of the Mad-Sin3 interaction as well as elucidating the broader functions of mSin3 in development.
They have also identified conserved versions of Myc, Max and Mad proteins in the fruit fly Drosophila melanogaster and are using this powerful genetic model in order to elucidate the normal functions and global gene targets of the network proteins more fully. Information gleaned from the Drosophila system can be immediately applied to mammalian cells. Finally, the Eisenman lab is using Myc's ability to rapidly cause lymphomas in mice as a means of discovering genes that cooperate with Myc in the development of tumors.