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

EMBO J. 1999 Feb 1;18(3):717-26. doi: 10.1093/emboj/18.3.717.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic
  • DNA-Binding Proteins / metabolism
  • Drug Stability
  • Endopeptidases / metabolism
  • Genes, myc*
  • Humans
  • Kruppel-Like Transcription Factors
  • Mice
  • Mutation*
  • Neoplasms / genetics*
  • Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Transcription Factors
  • Ubiquitins / metabolism*

Substances

  • DNA-Binding Proteins
  • Kruppel-Like Transcription Factors
  • Proto-Oncogene Proteins c-myc
  • Recombinant Proteins
  • Transcription Factors
  • Ubiquitins
  • ZBTB17 protein, human
  • Endopeptidases