Myc degradation: dancing with ubiquitin ligases.

Abstract

Two articles, one by Welcker et al. (1) in this issue of PNAS and one in the EMBO Journal (2), report that the F-box protein Fbw7, a component of an SCF-class ubiquitin ligase (E3) complex, mediates recognition and ubiquitination of the c-Myc transcription factor when the latter is phosphorylated on Thr 58. This regulatory connection is conserved throughout evolution, because the Fbw7 homologue Archipelago fulfills the same function for the Drosophila Myc protein, dMyc (3). Here, these findings are discussed alongside recent progress in our understanding of the posttranslational modifications regulating Myc turnover in vivo (4) and previous work connecting another F-box protein, Skp2, to Myc regulation (5, 6). c-Myc (Myc, Fig. 1 A ) is a transcription factor of the basic helix–loop–helix leucine zipper (bHLH-LZ) family. Through dimerization with Max, Myc binds the DNA element CACGTG and contributes to transcriptional activation. Myc also represses transcription at alternative DNA sites through association with other transcriptional activators such as Miz-1. The first 143 residues contain sequences required for both transcriptional activation and repression (7–10) and include two highly conserved “Myc boxes” (MB). MB1 includes threonine-58 (T58) and serine-62 (S62), that are phosphorylated in an interdependent manner: phosphorylation of S62, believed to be catalyzed by ERK kinases (11), is a prerequisite for phosphorylation of T58 by GSK3 (10, 12). Fig. 1. Emergence of a “Myc modification cycle” regulating protein turnover and activity. ( A ) Structure of Myc and Max. ( B ) A series of posttranslational modifications in MB1 regulates Myc's interactions with ubiquitin ligases and may impact its transcriptional activities. Question marks indicate unresolved or hypothetical connections. The importance of T58 in the regulation of Myc function was suggested by observations in human lymphomas. Oncogenic activation of c- myc (e.g., by gene translocation or amplification) commonly results in deregulated expression of c- …