Se. Salghetti et al., Destruction of Myc by ubiquitin-mediated proteolysis: cancer-associated and transforming mutations stabilize Myc, EMBO J, 18(3), 1999, pp. 717-726
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.