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Destruction of Myc by ubiquitin‐mediated proteolysis: cancer‐associated and transforming mutations stabilize Myc
Author(s) -
Salghetti Simone E.,
Young Kim So,
Tansey William P.
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.3.717
Subject(s) - biology , proteolysis , ubiquitin , transcription factor , proto oncogene proteins c myc , microbiology and biotechnology , transcription (linguistics) , mutant , mutation , proteasome , gene , cancer research , genetics , biochemistry , enzyme , linguistics , philosophy
The human proto‐oncogene c‐ myc encodes a highly unstable transcription factor that promotes cell proliferation. Although the extreme instability of Myc plays an important role in preventing its accumulation in normal cells, little is known about how Myc is targeted for rapid destruction. Here, we have investigated mechanisms regulating the stability of Myc. We show that Myc is destroyed by ubiquitin‐mediated proteolysis, and define two elements in 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 Myc is stabilized by cancer‐associated and transforming mutations within its transcriptional activation domain. Our data reveal a complex network of interactions regulating Myc destruction, and imply that enhanced protein stability contributes to oncogenic transformation by mutant Myc proteins.