The Myc family of oncoproteins are involved in key aspects of cellular function including proliferation, apoptosis, differentiation, and oncogenesis. Myc functions as a DNA binding transcriptional activator by forming heterodimeric complexes with Max. Max also specifically interacts with other proteins including the members of the Mad protein family. In contrast to Myc-Max, the Mad-Max complexes function as transcriptional repressors. This raises the possibility that Mad proteins act as antagonists of Myc. Indeed ectopic expression of Mad blocks Myc functions in proliferation and transformation. Mad is normally expressed during terminal differentiation of a wide range of cell types during development and may therefore act to attenuate expression of myc-induced proliferation genes. This proposal is concerned with understanding the molecular and biological functions of the Mad family proteins and with defining a functional """"""""pathway"""""""" for the components of the Max network. Mad-Max complexes repress transcription by recruiting to DNA a """"""""repression complex"""""""" consisting of the mSin3 co-repressor and histone deacetylases. We will determine whether repression by Mad-Max results in changes in chromatin structure and acetylation of nucleosomal histones at target sites. The function of the """"""""repression complex"""""""" itself will be explored in detail by characterization of additional protein components, and it will be determined whether the complex is involved in other basic repression systems. The biological roles of Mad family proteins will be studied by extending our analyses of mice with targeted deletions in one or multiple mad loci. Mice deleted for the mad1 gene display a decreased ability to exit the cell cycle during differentiation of specific precursor cells. Additional gene deletions will determine whether other Mad family members play distinct roles in cell cycle exit during differentiation. We will also determine whether loss of mad function leads to increased predisposition to cancer either alone or in combination with other gene mutations. Homologs of Myc, Max, and Mad have now been identified in Drosophila, permitting use of the power of fly genetics and developmental biology to analyze function and define interacting genes. We will determine the effects of both dMyc overexpression and null mutations on development in flies. Mutations will be employed in a genetic screen to identify genes that modify the dmyc mutant phenotypes. We will also identify downstream target genes for dMyc-dMax and dMad-dMax. Information gained from these studies will lead to an understanding of a transcription factor network that regulates cell behavior.
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