Reconstructing MYC

Who is MYC?

The c-myc protooncogene is a senior administrator of the cell helping to allocate resources and direct proliferation, growth, differentiation, and apoptosis. As an oncogene, MYC is a high-ranking member of the gang of molecular thugs that hijacks cells and perpetrates cellular terror. We know a lot about MYC and its associates (Dang et al. 1999; Grandori et al. 2000; Boxer and Dang 2001; Eisenman 2001; Luscher 2001; Levens 2002; Lutz et al. 2002). The structural and biochemical features of the MYC family (MYC, N-MYC, and L-MYC) mark them as direct regulators of gene expression. As basic helix–loop–helix leucine zipper proteins (bHLH-ZIP), the MYCs acquire the capacity to bind the DNA sequence CACGTG (E-box) when dimerized with MAX (another bHLH-ZIP; McMahon et al. 2000; Bouchard et al. 2001). A head-to-tail pair of MYC–MAX dimers may, in turn, form a heterotetramer capable of bridging distant E-boxes (Nair and Burley 2003). MAX is titrated away from MYC by heterodimerizing with the competing MAD family members or with Mnt. All of these heterodimers also bind E-boxes, as do MAX homodimers. Each species of heterodimer associates with particular effector protein complexes to exert its influence on genomic targets. Among the broadly distributed positive enforcers of MYC action that are often recruited to target genes are chromatin remodeling (SWI/SNF relatives) and modifying complexes (TRAPP/GCN5 and relatives); these complexes mobilize nucleosomes and acetylate histones and/or other targets to activate gene expression (Cheng et al. 1999; McMahon et al. 2000; Luscher 2001). MYC binds TBP along an auxiliary pathway to control gene expression (Fig.1). MAD and MNT generally oppose MYC action by enlisting histone deacetylase complexes (Fig. 1). Belying the terrifying organismal consequences of MYC misregulation, its influence on the expression of most target genes is only modest; …