Destruction of Myc by ubiquitin-mediated proteolysis: cancer-associated and transforming mutations stabilize Myc

The human proto-oncogene c-myc encodes a highly unstable transcription fact or that promotes cell proliferation. Although the extreme instability of My c plays an important role in preventing its accumulation in normal cells, l ittle is known about how Myc is targeted for rapid destruction. Here, we ha ve investigated mechanisms regulating the stability of Myc. We show that My c is destroyed by ubiquitin-mediated proteolysis, and define two elements i n Myc that oppositely regulate its stability: a transcriptional activation domain that promotes Myc destruction, and a region required for association with the POZ domain protein Miz-1 that stabilizes Myc. We also show that M yc is stabilized by cancer-associated and transforming mutations within its transcriptional activation domain. Our data reveal a complex network of in teractions regulating Myc destruction, and imply that enhanced protein stab ility contributes to oncogenic transformation by mutant Myc proteins.