New Myc-interacting proteins: a second Myc network emerges

Despite its intensive investigation for almost two decades, c-Myc remains a fascinating and enigmatic subject. A large and compelling body of evidence indicates that c-Myc is a transcription factor with central roles in the regulation of cell proliferation, differentiation, and apoptosis, but its exact function has remained elusive. In this review we survey recent advances in the identification and analysis of c-Myc-binding proteins, which suggest insights into the transcriptional roles of c-Myc but which also extend the existing functional paradigms. The C-terminal domain (CTD) of c-Myc mediates interaction with Max and physiological recognition of DNA target sequences, events needed for all biological actions. Recently described interactions between the CTD and other cellular proteins, including YY-1, AP-2, BRCA-1, TFII-I, and Miz-1, suggest levels of regulatory complexity beyond Max in controlling DNA recognition by c-Myc. The N-terminal domain (NTD), which includes the evolutionarily conserved and functionally crucial Myc Box sequences (MB1 and MB2), contains the transcription activation domain (TAD) of c-Myc as well as regions required for transcriptional repression, cell cycle regulation, transformation, and apoptosis. In addition to interaction with the retinoblastoma family protein p107, the NTD has been shown to interact with alpha-tubulin and the novel adaptor proteins Binl, MM-1, Pam, TRRAP, and AMY-1. The structure of these proteins and their effects on c-Myc actions suggest links to the transcriptional regulatory machinery as well as to cell cycle regulation, chromatin modeling, and apoptosis. Investigations of this emerging NTD-based network may reveal how c-Myc is regulated and how it affects cell fate, as well as providing tools to distinguish the physiological roles of various Myc target genes.