Evaluation of Molecular Inhibitors of the c-Myc Oncoprotein

Abstract

Abstract : c-Myc is a bHLH-ZIP transcription factor that regulates the expression of a large number of target genes, which collectively promote transformation (1,2). The active form of c-Myc exists as a heterodimer with another bHLH-ZIP protein, Max (3,4). This interaction, along with c-Myc- Max sequence-specific DNA binding ability (3,4) is necessary for all of c-Myc's biological properties, including transformation. c-Myc and Max are members of a group of interacting bHLH-ZIP proteins collectively referred to as the Myc network (3,4). Opposing the effects of c-Myc-Max heterodimers are four additional, closely related members termed the Mad family (Mad1, Mxi1, Mad3, and Mad4) and several less related proteins Mnt, Mga, and Mlx. Positive regulation of target genes is a result of DNA binding by c-Myc-Max. Consensus sites, termed E-boxes (CAC/TGTG), are found in virtually all positively regulated c-Myc target genes (3,4). However, c-Myc-Max binding to these sites and activation of the adjacent gene(s) is also dependent upon other factors, including the affinity of the sites for the heterodimers, the levels of c-Myc, competition with other E-box binding factors, and the cell type (1,2). In addition to Mad-dependent regulation, c-Myc also negatively regulates a separate subset of genes in an E-box- and Mad-independent manner. The means by which this occurs is somewhat obscure, although the most well-characterized example involves the interaction of c-Myc-Max with Miz1, a ubiquitously expressed POZ domain-zinc finger protein. This results in the transcriptional silencing of Miz1-dependent promoters (5). Similar forms of control may exist for other transcription factors such as YY1 and Sp1 (6,7). As in the case for c-Myc-dependent activation, repression also appears to be Max-dependent (6,7).