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 r egulation of cell proliferation, differentiation, and apoptosis, but its ex act function has remained elusive. In this review we survey recent advances in the identification and analysis of c-Myc-binding proteins, which sugges t insights into the transcriptional roles of c-Myc but which also extend th e existing functional paradigms. The C-terminal domain (CTD) of c-Myc media tes interaction with Max and physiological recognition of DNA target sequen ces, events needed for all biological actions. Recently described interacti ons 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 i n controlling DNA recognition by c-Myc, The N-terminal domain (NTD), which includes the evolutionarily conserved and functionally crucial Myc Box sequ ences (MB1 and MB2), contains the transcription activation domain (TAD) of c-Myc as well as regions required for transcriptional repression, cell cycl e regulation, transformation, and apoptosis, In addition to interaction wit h the retinoblastoma family protein p107, the NTD has been shown to interac t with alpha-tubulin and the novel adaptor proteins Bin1, MM-1, Pam, TRRAP, and AMY-I, The structure of these proteins and their effects on c-Myc acti ons suggest links to the transcriptional regulatory machinery as well as to cell cycle regulation, chromatin modeling, and apoptosis, Investigations o f 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 physio logical roles of various Myc target genes.