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PMID: 9927431 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The EMBO journal ·Vol. 18 ·No. 3 ·1999-02-01 ·Pages 717-26

Salghetti SE, Kim SY, Tansey WP

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.

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,metabolism Proto-Oncogene Mas Proto-Oncogene Proteins c-myc/genetics,metabolism Recombinant Proteins/genetics,metabolism Saccharomyces cerevisiae/genetics,metabolism Transcription Factors Ubiquitins/metabolism
Chemicals
DNA-Binding Proteins Kruppel-Like Transcription Factors MAS1 protein, human Proto-Oncogene Mas Proto-Oncogene Proteins c-myc Recombinant Proteins Transcription Factors Ubiquitins ZBTB17 protein, human Endopeptidases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Salghetti S E
Cold Spring Harbor Laboratory, 1 Bungtown Road, PO Box 100, Cold Spring Harbor, NY 11724, USA.
Kim S Y
Tansey W P
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/18.3.717
Published
1999-02-01
Pages
717-26
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1171164
Subset
IM
Grants
NCI NIH HHS · CA-13106 · United States
NCI NIH HHS · CA45508 · United States
External Links
PubMed source DOI: 10.1093/emboj/18.3.717 PMC Full Text View journal details
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